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De Gonzalez A.B.,U.S. National Institutes of Health | Hartge P.,U.S. National Institutes of Health | Cerhan J.R.,Rochester College | Flint A.J.,Harvard University | And 28 more authors.
New England Journal of Medicine | Year: 2010

BACKGROUND: A high body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) is associated with increased mortality from cardiovascular disease and certain cancers, but the precise relationship between BMI and all-cause mortality remains uncertain. METHODS: We used Cox regression to estimate hazard ratios and 95% confidence intervals for an association between BMI and all-cause mortality, adjusting for age, study, physical activity, alcohol consumption, education, and marital status in pooled data from 19 prospective studies encompassing 1.46 million white adults, 19 to 84 years of age (median, 58). RESULTS: The median baseline BMI was 26.2. During a median follow-up period of 10 years (range, 5 to 28), 160,087 deaths were identified. Among healthy participants who never smoked, there was a J-shaped relationship between BMI and all-cause mortality. With a BMI of 22.5 to 24.9 as the reference category, hazard ratios among women were 1.47 (95 percent confidence interval [CI], 1.33 to 1.62) for a BMI of 15.0 to 18.4; 1.14 (95% CI, 1.07 to 1.22) for a BMI of 18.5 to 19.9; 1.00 (95% CI, 0.96 to 1.04) for a BMI of 20.0 to 22.4; 1.13 (95% CI, 1.09 to 1.17) for a BMI of 25.0 to 29.9; 1.44 (95% CI, 1.38 to 1.50) for a BMI of 30.0 to 34.9; 1.88 (95% CI, 1.77 to 2.00) for a BMI of 35.0 to 39.9; and 2.51 (95% CI, 2.30 to 2.73) for a BMI of 40.0 to 49.9. In general, the hazard ratios for the men were similar. Hazard ratios for a BMI below 20.0 were attenuated with longer-term follow-up. CONCLUSIONS: In white adults, overweight and obesity (and possibly underweight) are associated with increased all-cause mortality. All-cause mortality is generally lowest with a BMI of 20.0 to 24.9. Copyright © 2010 Massachusetts Medical Society.


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.


Bao Y.,Brigham and Women's 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.


Larsson J.,National Institute of Environmental Medicine | Larsson J.,Karolinska Institutet | Larsson J.,Karolinska University Hospital | Perry C.P.,Royal Prince Alfred Hospital | And 6 more authors.
Journal of Applied Physiology | Year: 2011

The occurrence of refractoriness and mast cell mediator release following mannitol-induced bronchoconstriction. J Appl Physiol 110: 1029-1035, 2011. First published January 20, 2011; doi:10.1152/japplphysiol.00978.2010.-For several hours after exercise- induced bronchoconstriction, there is diminished responsiveness to repeated challenge. The mechanism causing this refractoriness is unclear. Inhalation of dry powder mannitol is a new bronchial provocation test that has been suggested as a surrogate for an exercise challenge. Refractoriness to repeated mannitol challenge has however not been established. Our objective was to investigate if repeated challenge with mannitol is associated with refractoriness and diminished release of mast cell mediators of bronchoconstriction. Sixteen subjects with asthma underwent repeated inhalation of mannitol 90 min apart. Lung function was assessed by forced expiratory volume in 1 s (FEV1). The urinary excretion (ng/mmol creatinine) of the mediators 9α,11β-prostaglandin (PG) F2 and leukotriene (LT) E4 were measured. The group mean fall in FEV1 after the second challenge was 48.5 ± 5.8% of the first (P < 0.001). The protection afforded by the initial challenge, however, varied considerably between subjects (range 88-0%). Furthermore, the urinary excretion of the two mediators was increased after both challenges. The average excretion of mediators after the challenges was significantly higher for the six most refractory subjects. This was observed both for LTE4 (95.6 ± 5.2 vs. 58.0 ± 2.4 for the 6 least refractory) (P < 0.001) and for 9=,11β- PGF2 (137.6 ± 6.7 vs. 50.1 ± 1.1 for the 6 least refractory) (P < 0.002). As occurs with exercise-induced bronchoconstriction, repeated inhalation of mannitol induced refractoriness. We propose that refractoriness is due to tachyphylaxis at the level of the airway smooth muscle responsiveness to mediators of bronchoconstriction rather than due to fatigue of their release from mast cells. Copyright © 2011 the American Physiological Society.


Larsson S.C.,National Institute of Environmental Medicine | Orsini N.,National Institute of Environmental Medicine
Stroke | Year: 2011

Background and Purpose: Fish consumption has been postulated to reduce the risk of stroke. We conducted a dose-response meta-analysis to summarize the evidence from prospective studies regarding the association between fish consumption and stroke risk. Methods: Pertinent studies were identified by searching Embase and PubMed through May 2011 and by reviewing the references of retrieved articles. We included prospective studies that reported relative risks with 95% CIs of stroke for ≥3 categories of fish consumption. Results were combined using a random-effects model. Results: Fifteen prospective studies, with 9360 stroke events among 383 838 participants, were included. An increment of 3 servings/week in fish consumption was associated with a 6% reduction in risk of total stroke (relative risk, 0.94; 95% CI, 0.89-0.99) without heterogeneity among studies (P=0.15, I 2=25.7%). Among 9 studies with results for stroke subtypes, the relative risks were 0.90 (95% CI, 0.84-0.97) for ischemic stroke and 0.90 (95% CI, 0.76-1.06) for hemorrhagic stroke. Conclusions: These findings indicate that fish consumption is weakly inversely associated with the risk of stroke. © 2011 American Heart Association, Inc.


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.


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.


Hjern F.,University of Stockholm | Mahmood M.W.,University of Stockholm | Abraham-Nordling M.,Institution of Molecular Medicine | Wolk A.,National Institute of Environmental Medicine | Hakansson N.,National Institute of Environmental Medicine
British Journal of Surgery | Year: 2015

Background Medication has been suggested as a potential risk factor for diverticular disease. The objective of this study was to investigate the association between the intake of corticosteroids, indometacin or aspirin and diverticular disease. Method This was a prospective population-based cohort study of middle-aged women in the Swedish Mammography Cohort. Use of corticosteroids (oral or inhaled), indometacin or aspirin in 1997 was determined from questionnaires. Cases of diverticular disease were identified from the Swedish national registers until the end of 2010. The relative risk (RR) of diverticular disease requiring hospital admission according to the use of medication was estimated using Cox proportional hazards models, adjusted for age, body mass index, physical activity, fibre intake, diabetes, hypertension, alcohol, smoking and education.Results A total of 36 586 middle-aged women in the Swedish Mammography Cohort were included, of whom 674 (1·8 per cent) were hospitalized with diverticular disease at least once. Some 7·2 per cent of women reported intake of oral corticosteroids and 8·5 per cent use of inhaled corticosteroids. In multivariable analysis, women who reported oral corticosteroid intake had a 37 per cent (RR 1·37, 95 per cent c.i. 1·06 to 1·78; P = 0·012) increased risk of diverticular disease compared with those who reported no intake at all. Use of inhaled corticosteroids was associated with an even more pronounced increase in risk of 71 per cent (RR 1·71, 1·36 to 2·14; P < 0·001). There was a significant dose-response relationship, with the risk increasing with longer duration of inhaled corticosteroids (P for trend < 0·001). Use of indometacin (2·5 per cent of women) or aspirin (44·2 per cent) did not influence the risk.Conclusion There was a significant relationship between corticosteroids (especially inhaled) and diverticular disease requiring hospital admission. Risk highest with inhaled steroids © 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd.


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.


PubMed | National Institute of Environmental Medicine
Type: Journal Article | Journal: The American journal of clinical nutrition | Year: 2012

Prospective studies of dietary magnesium intake in relation to risk of stroke have yielded inconsistent results.We conducted a dose-response meta-analysis to summarize the evidence regarding the association between magnesium intake and stroke risk.Relevant studies were identified by searching PubMed and EMBASE from January 1966 through September 2011 and reviewing reference lists of retrieved articles. We included prospective studies that reported RRs with 95% CIs of stroke for 3 categories of magnesium intake. Results from individual studies were combined by using a random-effects model.Seven prospective studies, with 6477 cases of stroke and 241,378 participants, were eligible for inclusion in the meta-analysis. We observed a modest but statistically significant inverse association between magnesium intake and risk of stroke. An intake increment of 100 mg Mg/d was associated with an 8% reduction in risk of total stroke (combined RR: 0.92; 95% CI: 0.88, 0.97), without heterogeneity among studies (P = 0.66, I(2) = 0%). Magnesium intake was inversely associated with risk of ischemic stroke (RR: 0.91; 95% CI: 0.87, 0.96) but not intracerebral hemorrhage (RR: 0.96; 95% CI: 0.84, 1.10) or subarachnoid hemorrhage (RR: 1.01; 95% CI: 0.90, 1.14).Dietary magnesium intake is inversely associated with risk of stroke, specifically ischemic stroke.

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