Introduction - Thorax



Randomised Vitamin E Supplementation and Risk of Chronic Lung Disease in the Women’s Health StudyAnne H. Agler1, Tobias Kurth2,4,5, J. Michael Gaziano2,3,6, Julie E. Buring2, and Patricia A. Cassano11Division of Nutritional Sciences, Cornell University, Ithaca, New York, USA; 2Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; 3 Division of Aging, Brigham and Women's Hospital, Boston, Massachusetts, USA; 4INSERM Unit 708–Neuroepidemiology, Paris, France; 5University Pierre et Marie Curie, Paris, France; 6Massachusetts Veteran's Epidemiology, Research and Information Center (MAVERIC), Geriatric Research Education and Clinical Center (GRECC), VA Boston Healthcare System, Boston, Massachusetts, USA.Correspondence and reprint requests should be addressed to Dr. P.A. Cassano, 209 Savage Hall, Cornell University, Ithaca, NY, USA 14853; ph. 607-255-7551, fax 607-255-2691 pac6@cornell.eduKey words (MeSH): pulmonary disease, chronic obstructive; antioxidants; tocopherols; intervention studies; randomised controlled trial Word count: 2,954 ABSTRACTBackground The oxidant/antioxidant balance in lung tissue is hypothesised to contribute to chronic obstructive pulmonary disease (COPD) risk. Observational studies consistently report higher antioxidant status associated with lower COPD risk, but few randomised studies have been reported. Methods A post-hoc analysis of 38,597 women without chronic lung disease at baseline was conducted in the Women’s Health Study (WHS) to test the effect of vitamin E on risk of incident chronic lung disease. The WHS was a randomised, double-blind, placebo-controlled, factorial trial of vitamin E (600 IU every other day) and aspirin (100 mg every other day) in female health professionals aged ≥45. Using Cox proportional hazards models, the effect of randomised vitamin E assignment on self-reported, physician-diagnosed chronic lung disease was evaluated. Results During 10 years of follow-up (376,710 person-years), 760 first occurrences of chronic lung disease were reported in the vitamin E arm compared to 846 in the placebo arm (Hazard Ratio [HR] 0.90; 95% confidence interval [CI] 0.81-0.99; p=0.029). This 10% reduction in the risk of incident chronic lung disease was not modified by cigarette smoking, age, randomised aspirin assignment, multivitamin use, or dietary vitamin E intake (minimum P for interaction = 0.19). Current cigarette smoking was a strong predictor of chronic lung disease risk (HR 4.17; 95% CI 3.70-4.70; versus never smokers). Conclusions In this large, randomised trial, assignment to 600 IU of vitamin E led to a 10% reduction in the risk of chronic lung disease in women.Word count: 242INTRODUCTIONChronic obstructive pulmonary disease (COPD) is characterised by progressive, irreversible airflow limitation and comprises a significant public health burden, with increasing trends in incidence and prevalence. ADDIN REFMGR.CITE <Refman><Cite><Author>Lopez</Author><Year>2006</Year><RecNum>9</RecNum><IDText>Chronic obstructive pulmonary disease: current burden and future projections</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>9</Ref_ID><Title_Primary>Chronic obstructive pulmonary disease: current burden and future projections</Title_Primary><Authors_Primary>Lopez,A.D.</Authors_Primary><Authors_Primary>Shibuya,K.</Authors_Primary><Authors_Primary>Rao,C.</Authors_Primary><Authors_Primary>Mathers,C.D.</Authors_Primary><Authors_Primary>Hansell,A.L.</Authors_Primary><Authors_Primary>Held,L.S.</Authors_Primary><Authors_Primary>Schmid,V.</Authors_Primary><Authors_Primary>Buist,S.</Authors_Primary><Date_Primary>2006/2</Date_Primary><Keywords>Cost of Illness</Keywords><Keywords>Epidemiologic Methods</Keywords><Keywords>epidemiology</Keywords><Keywords>Forecasting</Keywords><Keywords>Humans</Keywords><Keywords>Models,Statistical</Keywords><Keywords>Prevalence</Keywords><Keywords>Pulmonary Disease,Chronic Obstructive</Keywords><Keywords>World Health</Keywords><Reprint>Not in File</Reprint><Start_Page>397</Start_Page><End_Page>412</End_Page><Periodical>Eur.Respir.J.</Periodical><Volume>27</Volume><Issue>2</Issue><Address>University of Queensland, Brisbane, Australia</Address><Web_URL>PM:16452599</Web_URL><ZZ_JournalStdAbbrev><f name="System">Eur.Respir.J.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>[1] COPD prevalence in the U.S. adult population is 3-4% and, worldwide COPD prevalence is about 10%. ADDIN REFMGR.CITE <Refman><Cite><Author>Lopez</Author><Year>2006</Year><RecNum>9</RecNum><IDText>Chronic obstructive pulmonary disease: current burden and future projections</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>9</Ref_ID><Title_Primary>Chronic obstructive pulmonary disease: current burden and future projections</Title_Primary><Authors_Primary>Lopez,A.D.</Authors_Primary><Authors_Primary>Shibuya,K.</Authors_Primary><Authors_Primary>Rao,C.</Authors_Primary><Authors_Primary>Mathers,C.D.</Authors_Primary><Authors_Primary>Hansell,A.L.</Authors_Primary><Authors_Primary>Held,L.S.</Authors_Primary><Authors_Primary>Schmid,V.</Authors_Primary><Authors_Primary>Buist,S.</Authors_Primary><Date_Primary>2006/2</Date_Primary><Keywords>Cost of Illness</Keywords><Keywords>Epidemiologic Methods</Keywords><Keywords>epidemiology</Keywords><Keywords>Forecasting</Keywords><Keywords>Humans</Keywords><Keywords>Models,Statistical</Keywords><Keywords>Prevalence</Keywords><Keywords>Pulmonary Disease,Chronic Obstructive</Keywords><Keywords>World Health</Keywords><Reprint>Not in File</Reprint><Start_Page>397</Start_Page><End_Page>412</End_Page><Periodical>Eur.Respir.J.</Periodical><Volume>27</Volume><Issue>2</Issue><Address>University of Queensland, Brisbane, Australia</Address><Web_URL>PM:16452599</Web_URL><ZZ_JournalStdAbbrev><f name="System">Eur.Respir.J.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Buist</Author><Year>2008</Year><RecNum>11</RecNum><IDText>Worldwide burden of COPD in high- and low-income countries. Part I. The burden of obstructive lung disease (BOLD) initiative</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>11</Ref_ID><Title_Primary>Worldwide burden of COPD in high- and low-income countries. Part I. The burden of obstructive lung disease (BOLD) initiative</Title_Primary><Authors_Primary>Buist,A.S.</Authors_Primary><Authors_Primary>Vollmer,W.M.</Authors_Primary><Authors_Primary>McBurnie,M.A.</Authors_Primary><Date_Primary>2008/7</Date_Primary><Keywords>Adult</Keywords><Keywords>Cost of Illness</Keywords><Keywords>Developed Countries</Keywords><Keywords>Developing Countries</Keywords><Keywords>diagnosis</Keywords><Keywords>epidemiology</Keywords><Keywords>Female</Keywords><Keywords>Humans</Keywords><Keywords>Male</Keywords><Keywords>Middle Aged</Keywords><Keywords>Occupational Exposure</Keywords><Keywords>Prevalence</Keywords><Keywords>Pulmonary Disease,Chronic Obstructive</Keywords><Keywords>Questionnaires</Keywords><Keywords>Risk Factors</Keywords><Keywords>Spirometry</Keywords><Keywords>statistics &amp; numerical data</Keywords><Reprint>Not in File</Reprint><Start_Page>703</Start_Page><End_Page>708</End_Page><Periodical>Int.J.Tuberc.Lung Dis.</Periodical><Volume>12</Volume><Issue>7</Issue><Address>Oregon Health &amp; Science University, Portland, Oregon 97239, USA. buists@ohsu.edu</Address><Web_URL>PM:18544191</Web_URL><ZZ_JournalStdAbbrev><f name="System">Int.J.Tuberc.Lung Dis.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>[1,2] COPD was the 5th leading cause of death in the U.S. in 2001 and is expected to become the 3rd leading cause of death by 2020, largely due to population ageing and increasing cumulative cigarette smoke exposure, the primary risk factor for COPD. ADDIN REFMGR.CITE <Refman><Cite><Author>Lopez</Author><Year>2006</Year><RecNum>9</RecNum><IDText>Chronic obstructive pulmonary disease: current burden and future projections</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>9</Ref_ID><Title_Primary>Chronic obstructive pulmonary disease: current burden and future projections</Title_Primary><Authors_Primary>Lopez,A.D.</Authors_Primary><Authors_Primary>Shibuya,K.</Authors_Primary><Authors_Primary>Rao,C.</Authors_Primary><Authors_Primary>Mathers,C.D.</Authors_Primary><Authors_Primary>Hansell,A.L.</Authors_Primary><Authors_Primary>Held,L.S.</Authors_Primary><Authors_Primary>Schmid,V.</Authors_Primary><Authors_Primary>Buist,S.</Authors_Primary><Date_Primary>2006/2</Date_Primary><Keywords>Cost of Illness</Keywords><Keywords>Epidemiologic Methods</Keywords><Keywords>epidemiology</Keywords><Keywords>Forecasting</Keywords><Keywords>Humans</Keywords><Keywords>Models,Statistical</Keywords><Keywords>Prevalence</Keywords><Keywords>Pulmonary Disease,Chronic Obstructive</Keywords><Keywords>World Health</Keywords><Reprint>Not in File</Reprint><Start_Page>397</Start_Page><End_Page>412</End_Page><Periodical>Eur.Respir.J.</Periodical><Volume>27</Volume><Issue>2</Issue><Address>University of Queensland, Brisbane, Australia</Address><Web_URL>PM:16452599</Web_URL><ZZ_JournalStdAbbrev><f name="System">Eur.Respir.J.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Lopez</Author><Year>1998</Year><RecNum>58</RecNum><IDText>The global burden of disease, 1990-2020</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>58</Ref_ID><Title_Primary>The global burden of disease, 1990-2020</Title_Primary><Authors_Primary>Lopez,A.D.</Authors_Primary><Authors_Primary>Murray,C.C.</Authors_Primary><Date_Primary>1998/11</Date_Primary><Keywords>Disabled Persons</Keywords><Keywords>Disease</Keywords><Keywords>Epidemiologic Measurements</Keywords><Keywords>epidemiology</Keywords><Keywords>Forecasting</Keywords><Keywords>Humans</Keywords><Keywords>statistics &amp; numerical data</Keywords><Keywords>United Nations</Keywords><Keywords>World Health</Keywords><Keywords>World Health Organization</Keywords><Reprint>Not in File</Reprint><Start_Page>1241</Start_Page><End_Page>1243</End_Page><Periodical>Nat.Med.</Periodical><Volume>4</Volume><Issue>11</Issue><Web_URL>PM:9809543</Web_URL><ZZ_JournalStdAbbrev><f name="System">Nat.Med.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>[1,3]Factors that may contribute to rising COPD incidence include: obesity, dietary patterns, environmental and occupational exposures, and improved diagnostic and screening programmes. ADDIN REFMGR.CITE <Refman><Cite><Author>Lopez</Author><Year>2006</Year><RecNum>9</RecNum><IDText>Chronic obstructive pulmonary disease: current burden and future projections</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>9</Ref_ID><Title_Primary>Chronic obstructive pulmonary disease: current burden and future projections</Title_Primary><Authors_Primary>Lopez,A.D.</Authors_Primary><Authors_Primary>Shibuya,K.</Authors_Primary><Authors_Primary>Rao,C.</Authors_Primary><Authors_Primary>Mathers,C.D.</Authors_Primary><Authors_Primary>Hansell,A.L.</Authors_Primary><Authors_Primary>Held,L.S.</Authors_Primary><Authors_Primary>Schmid,V.</Authors_Primary><Authors_Primary>Buist,S.</Authors_Primary><Date_Primary>2006/2</Date_Primary><Keywords>Cost of Illness</Keywords><Keywords>Epidemiologic Methods</Keywords><Keywords>epidemiology</Keywords><Keywords>Forecasting</Keywords><Keywords>Humans</Keywords><Keywords>Models,Statistical</Keywords><Keywords>Prevalence</Keywords><Keywords>Pulmonary Disease,Chronic Obstructive</Keywords><Keywords>World Health</Keywords><Reprint>Not in File</Reprint><Start_Page>397</Start_Page><End_Page>412</End_Page><Periodical>Eur.Respir.J.</Periodical><Volume>27</Volume><Issue>2</Issue><Address>University of Queensland, Brisbane, Australia</Address><Web_URL>PM:16452599</Web_URL><ZZ_JournalStdAbbrev><f name="System">Eur.Respir.J.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Varraso</Author><Year>2007</Year><RecNum>48</RecNum><IDText>Prospective study of dietary patterns and chronic obstructive pulmonary disease among US women</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>48</Ref_ID><Title_Primary>Prospective study of dietary patterns and chronic obstructive pulmonary disease among US women</Title_Primary><Authors_Primary>Varraso,R.</Authors_Primary><Authors_Primary>Fung,T.T.</Authors_Primary><Authors_Primary>Barr,R.G.</Authors_Primary><Authors_Primary>Hu,F.B.</Authors_Primary><Authors_Primary>Willett,W.</Authors_Primary><Authors_Primary>Camargo,C.A.,Jr.</Authors_Primary><Date_Primary>2007/8</Date_Primary><Keywords>Adult</Keywords><Keywords>adverse effects</Keywords><Keywords>analysis</Keywords><Keywords>Asthma</Keywords><Keywords>Body Mass Index</Keywords><Keywords>Cohort Studies</Keywords><Keywords>Diet</Keywords><Keywords>epidemiology</Keywords><Keywords>Female</Keywords><Keywords>Food</Keywords><Keywords>Food Habits</Keywords><Keywords>Forced Expiratory Volume</Keywords><Keywords>Fruit</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Lung</Keywords><Keywords>Middle Aged</Keywords><Keywords>Nurses</Keywords><Keywords>Prospective Studies</Keywords><Keywords>Public Health</Keywords><Keywords>Pulmonary Disease,Chronic Obstructive</Keywords><Keywords>Questionnaires</Keywords><Keywords>Risk</Keywords><Keywords>Smoke</Keywords><Keywords>Smoking</Keywords><Keywords>United States</Keywords><Keywords>Vegetables</Keywords><Reprint>Not in File</Reprint><Start_Page>488</Start_Page><End_Page>495</End_Page><Periodical>Am.J.Clin.Nutr.</Periodical><Volume>86</Volume><Issue>2</Issue><Address>Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA. rvarraso@hsph.harvard.edu</Address><Web_URL>PM:17684223</Web_URL><ZZ_JournalStdAbbrev><f name="System">Am.J.Clin.Nutr.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Sood</Author><Year>2009</Year><RecNum>55</RecNum><IDText>Obesity-Asthma Association: Is It Explained by Systemic Oxidant Stress?</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>55</Ref_ID><Title_Primary>Obesity-Asthma Association: Is It Explained by Systemic Oxidant Stress?</Title_Primary><Authors_Primary>Sood,A.</Authors_Primary><Authors_Primary>Qualls,C.</Authors_Primary><Authors_Primary>Arynchyn,A.</Authors_Primary><Authors_Primary>Beckett,W.S.</Authors_Primary><Authors_Primary>Gross,M.D.</Authors_Primary><Authors_Primary>Steffes,M.W.</Authors_Primary><Authors_Primary>Smith,L.J.</Authors_Primary><Authors_Primary>Holvoet,P.</Authors_Primary><Authors_Primary>Thyagarajan,B.</Authors_Primary><Authors_Primary>Jacobs,D.R.</Authors_Primary><Date_Primary>2009/7/10</Date_Primary><Keywords>Adult</Keywords><Keywords>Asthma</Keywords><Keywords>Body Mass Index</Keywords><Keywords>Cross-Sectional Studies</Keywords><Keywords>epidemiology</Keywords><Keywords>Health</Keywords><Keywords>methods</Keywords><Keywords>Obesity</Keywords><Keywords>pathology</Keywords><Keywords>Risk</Keywords><Reprint>Not in File</Reprint><Periodical>Chest</Periodical><Address>Department of Medicine (Dr. Sood), and the Clinical Translational Sciences Center, University of New Mexico Health Sciences Center, Albuquerque, NM; the Department of Preventive Medicine (Dr. Arynchyn), University of Alabama at Birmingham, Birmingham, AL; the Department of Medicine (Dr. Beckett), Mount Auburn Hospital, Cambridge, MA; the Department of Laboratory Medicine and Pathology (Drs. Gross, Steffes, and Thyagarajan), and the Division of Epidemiology (Dr. Jacobs), University of Minnesota, Minneapolis, MN; the Department of Medicine (Dr. Smith), Feinberg School of Medicine, Northwestern University, Chicago, IL; the Department of Experimental Surgery and Anesthesiology (Dr. Holvoet), Katholieke Universiteit Leuven, Leuven, Belgium; and the Institute for Nutrition Research (Dr. Jacobs), University of Oslo, Oslo, Norway</Address><Web_URL>PM:19592473</Web_URL><ZZ_JournalStdAbbrev><f name="System">Chest</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Smit</Author><Year>1999</Year><RecNum>27</RecNum><IDText>Dietary influences on chronic obstructive lung disease and asthma: a review of the epidemiological evidence</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>27</Ref_ID><Title_Primary>Dietary influences on chronic obstructive lung disease and asthma: a review of the epidemiological evidence</Title_Primary><Authors_Primary>Smit,H.A.</Authors_Primary><Authors_Primary>Grievink,L.</Authors_Primary><Authors_Primary>Tabak,C.</Authors_Primary><Date_Primary>1999/5</Date_Primary><Keywords>administration &amp; dosage</Keywords><Keywords>Adult</Keywords><Keywords>adverse effects</Keywords><Keywords>Antioxidants</Keywords><Keywords>Asthma</Keywords><Keywords>beta Carotene</Keywords><Keywords>Diet</Keywords><Keywords>Eating</Keywords><Keywords>epidemiology</Keywords><Keywords>Fatty Acids,Unsaturated</Keywords><Keywords>Fruit</Keywords><Keywords>Humans</Keywords><Keywords>Lung</Keywords><Keywords>Lung Diseases,Obstructive</Keywords><Keywords>Public Health</Keywords><Keywords>Sodium,Dietary</Keywords><Keywords>Vegetables</Keywords><Keywords>Vitamin E</Keywords><Keywords>Vitamins</Keywords><Reprint>Not in File</Reprint><Start_Page>309</Start_Page><End_Page>319</End_Page><Periodical>Proc.Nutr.Soc.</Periodical><Volume>58</Volume><Issue>2</Issue><Address>Department of Chronic Disease and Environmental Epidemiology, National Institute of Public Health and the Environment (RIVM), Bilthoven, The Netherlands. Jet.smit@rivm.nl</Address><Web_URL>PM:10466172</Web_URL><ZZ_JournalStdAbbrev><f name="System">Proc.Nutr.Soc.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>[1,4-6] Several lines of evidence support the hypothesis that diet plays a role in COPD aetiology.[ ADDIN REFMGR.CITE <Refman><Cite><Author>Varraso</Author><Year>2007</Year><RecNum>48</RecNum><IDText>Prospective study of dietary patterns and chronic obstructive pulmonary disease among US women</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>48</Ref_ID><Title_Primary>Prospective study of dietary patterns and chronic obstructive pulmonary disease among US women</Title_Primary><Authors_Primary>Varraso,R.</Authors_Primary><Authors_Primary>Fung,T.T.</Authors_Primary><Authors_Primary>Barr,R.G.</Authors_Primary><Authors_Primary>Hu,F.B.</Authors_Primary><Authors_Primary>Willett,W.</Authors_Primary><Authors_Primary>Camargo,C.A.,Jr.</Authors_Primary><Date_Primary>2007/8</Date_Primary><Keywords>Adult</Keywords><Keywords>adverse effects</Keywords><Keywords>analysis</Keywords><Keywords>Asthma</Keywords><Keywords>Body Mass Index</Keywords><Keywords>Cohort Studies</Keywords><Keywords>Diet</Keywords><Keywords>epidemiology</Keywords><Keywords>Female</Keywords><Keywords>Food</Keywords><Keywords>Food Habits</Keywords><Keywords>Forced Expiratory Volume</Keywords><Keywords>Fruit</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Lung</Keywords><Keywords>Middle Aged</Keywords><Keywords>Nurses</Keywords><Keywords>Prospective Studies</Keywords><Keywords>Public Health</Keywords><Keywords>Pulmonary Disease,Chronic Obstructive</Keywords><Keywords>Questionnaires</Keywords><Keywords>Risk</Keywords><Keywords>Smoke</Keywords><Keywords>Smoking</Keywords><Keywords>United States</Keywords><Keywords>Vegetables</Keywords><Reprint>Not in File</Reprint><Start_Page>488</Start_Page><End_Page>495</End_Page><Periodical>Am.J.Clin.Nutr.</Periodical><Volume>86</Volume><Issue>2</Issue><Address>Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA. rvarraso@hsph.harvard.edu</Address><Web_URL>PM:17684223</Web_URL><ZZ_JournalStdAbbrev><f name="System">Am.J.Clin.Nutr.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Smit</Author><Year>1999</Year><RecNum>27</RecNum><IDText>Dietary influences on chronic obstructive lung disease and asthma: a review of the epidemiological evidence</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>27</Ref_ID><Title_Primary>Dietary influences on chronic obstructive lung disease and asthma: a review of the epidemiological evidence</Title_Primary><Authors_Primary>Smit,H.A.</Authors_Primary><Authors_Primary>Grievink,L.</Authors_Primary><Authors_Primary>Tabak,C.</Authors_Primary><Date_Primary>1999/5</Date_Primary><Keywords>administration &amp; dosage</Keywords><Keywords>Adult</Keywords><Keywords>adverse effects</Keywords><Keywords>Antioxidants</Keywords><Keywords>Asthma</Keywords><Keywords>beta Carotene</Keywords><Keywords>Diet</Keywords><Keywords>Eating</Keywords><Keywords>epidemiology</Keywords><Keywords>Fatty Acids,Unsaturated</Keywords><Keywords>Fruit</Keywords><Keywords>Humans</Keywords><Keywords>Lung</Keywords><Keywords>Lung Diseases,Obstructive</Keywords><Keywords>Public Health</Keywords><Keywords>Sodium,Dietary</Keywords><Keywords>Vegetables</Keywords><Keywords>Vitamin E</Keywords><Keywords>Vitamins</Keywords><Reprint>Not in File</Reprint><Start_Page>309</Start_Page><End_Page>319</End_Page><Periodical>Proc.Nutr.Soc.</Periodical><Volume>58</Volume><Issue>2</Issue><Address>Department of Chronic Disease and Environmental Epidemiology, National Institute of Public Health and the Environment (RIVM), Bilthoven, The Netherlands. Jet.smit@rivm.nl</Address><Web_URL>PM:10466172</Web_URL><ZZ_JournalStdAbbrev><f name="System">Proc.Nutr.Soc.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Romieu</Author><Year>2001</Year><RecNum>65</RecNum><IDText>Diet and obstructive lung diseases</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>65</Ref_ID><Title_Primary>Diet and obstructive lung diseases</Title_Primary><Authors_Primary>Romieu,I.</Authors_Primary><Authors_Primary>Trenga,C.</Authors_Primary><Date_Primary>2001</Date_Primary><Keywords>administration &amp; dosage</Keywords><Keywords>Adult</Keywords><Keywords>Air Pollutants</Keywords><Keywords>Antioxidants</Keywords><Keywords>Asthma</Keywords><Keywords>beta Carotene</Keywords><Keywords>Causality</Keywords><Keywords>Diet</Keywords><Keywords>Disease</Keywords><Keywords>Epidemiologic Studies</Keywords><Keywords>epidemiology</Keywords><Keywords>Fatty Acids</Keywords><Keywords>Fatty Acids,Unsaturated</Keywords><Keywords>Flavonoids</Keywords><Keywords>Fruit</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Incidence</Keywords><Keywords>Infant</Keywords><Keywords>Lung</Keywords><Keywords>Magnesium</Keywords><Keywords>metabolism</Keywords><Keywords>methods</Keywords><Keywords>Nutrition Policy</Keywords><Keywords>Occupational Exposure</Keywords><Keywords>Oxidants</Keywords><Keywords>Oxidative Stress</Keywords><Keywords>Ozone</Keywords><Keywords>Prevalence</Keywords><Keywords>Public Health</Keywords><Keywords>Pulmonary Disease,Chronic Obstructive</Keywords><Keywords>Risk</Keywords><Keywords>Risk Factors</Keywords><Keywords>Selenium</Keywords><Keywords>Smoking</Keywords><Keywords>Sodium</Keywords><Keywords>Sodium,Dietary</Keywords><Keywords>Vegetables</Keywords><Keywords>Vitamin E</Keywords><Keywords>Vitamins</Keywords><Reprint>Not in File</Reprint><Start_Page>268</Start_Page><End_Page>287</End_Page><Periodical>Epidemiol.Rev.</Periodical><Volume>23</Volume><Issue>2</Issue><Address>Pan American Health Organization and National Institute of Public Health, Center for Population Studies, Cuernavaca, Morelos, Mexico. iromieu@correo.insp.mx</Address><Web_URL>PM:12192737</Web_URL><ZZ_JournalStdAbbrev><f name="System">Epidemiol.Rev.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>4,6,7] Observational studies of diet or nutritional status biomarkers and randomised trials of diet or nutritional supplements have investigated the relation of antioxidants, notably vitamin E, and lung outcomes. Observational studies investigating the association of dietary intake and pulmonary function consistently report that higher intake of nutrients with antioxidant properties is associated with better pulmonary outcomes, but causal inferences are limited by concerns about confounding and other biases. ADDIN REFMGR.CITE <Refman><Cite><Author>Hu</Author><Year>2000</Year><RecNum>61</RecNum><IDText>Antioxidant nutrients and pulmonary function: the Third National Health and Nutrition Examination Survey (NHANES III)</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>61</Ref_ID><Title_Primary>Antioxidant nutrients and pulmonary function: the Third National Health and Nutrition Examination Survey (NHANES III)</Title_Primary><Authors_Primary>Hu,G.</Authors_Primary><Authors_Primary>Cassano,P.A.</Authors_Primary><Date_Primary>2000/5/15</Date_Primary><Keywords>Adult</Keywords><Keywords>adverse effects</Keywords><Keywords>Aged</Keywords><Keywords>analysis</Keywords><Keywords>Antioxidants</Keywords><Keywords>Ascorbic Acid</Keywords><Keywords>beta Carotene</Keywords><Keywords>blood</Keywords><Keywords>Diet</Keywords><Keywords>Disease</Keywords><Keywords>drug effects</Keywords><Keywords>etiology</Keywords><Keywords>Female</Keywords><Keywords>Forced Expiratory Volume</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Linear Models</Keywords><Keywords>Lung</Keywords><Keywords>Lung Diseases,Obstructive</Keywords><Keywords>Male</Keywords><Keywords>Middle Aged</Keywords><Keywords>Nutrition Assessment</Keywords><Keywords>Nutrition Surveys</Keywords><Keywords>Predictive Value of Tests</Keywords><Keywords>prevention &amp; control</Keywords><Keywords>Questionnaires</Keywords><Keywords>Regression Analysis</Keywords><Keywords>Selenium</Keywords><Keywords>Smoking</Keywords><Keywords>Spirometry</Keywords><Keywords>statistics &amp; numerical data</Keywords><Keywords>therapeutic use</Keywords><Keywords>United States</Keywords><Keywords>Vitamin E</Keywords><Reprint>Not in File</Reprint><Start_Page>975</Start_Page><End_Page>981</End_Page><Periodical>Am.J.Epidemiol.</Periodical><Volume>151</Volume><Issue>10</Issue><Address>Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA</Address><Web_URL>PM:10853636</Web_URL><ZZ_JournalStdAbbrev><f name="System">Am.J.Epidemiol.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Grievink</Author><Year>1998</Year><RecNum>62</RecNum><IDText>Dietary intake of antioxidant (pro)-vitamins, respiratory symptoms and pulmonary function: the MORGEN study</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>62</Ref_ID><Title_Primary>Dietary intake of antioxidant (pro)-vitamins, respiratory symptoms and pulmonary function: the MORGEN study</Title_Primary><Authors_Primary>Grievink,L.</Authors_Primary><Authors_Primary>Smit,H.A.</Authors_Primary><Authors_Primary>Ocke,M.C.</Authors_Primary><Authors_Primary>van&apos;t Veer,P.</Authors_Primary><Authors_Primary>Kromhout,D.</Authors_Primary><Date_Primary>1998/3</Date_Primary><Keywords>administration &amp; dosage</Keywords><Keywords>Adult</Keywords><Keywords>analysis</Keywords><Keywords>Antioxidants</Keywords><Keywords>Ascorbic Acid</Keywords><Keywords>beta Carotene</Keywords><Keywords>Cough</Keywords><Keywords>Cross-Sectional Studies</Keywords><Keywords>Data Collection</Keywords><Keywords>Disease</Keywords><Keywords>epidemiology</Keywords><Keywords>Food</Keywords><Keywords>Forced Expiratory Volume</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Lung</Keywords><Keywords>methods</Keywords><Keywords>Middle Aged</Keywords><Keywords>Netherlands</Keywords><Keywords>Odds Ratio</Keywords><Keywords>physiology</Keywords><Keywords>physiopathology</Keywords><Keywords>Prevalence</Keywords><Keywords>Public Health</Keywords><Keywords>Regression Analysis</Keywords><Keywords>Respiration Disorders</Keywords><Keywords>Respiratory Sounds</Keywords><Keywords>Vital Capacity</Keywords><Keywords>Vitamin E</Keywords><Keywords>Vitamins</Keywords><Reprint>Not in File</Reprint><Start_Page>166</Start_Page><End_Page>171</End_Page><Periodical>Thorax</Periodical><Volume>53</Volume><Issue>3</Issue><Address>Department of Chronic Diseases and Environmental Epidemiology, National Institute of Public Health and the Environment (RIVM), Bilthoven, The Netherlands</Address><Web_URL>PM:9659349</Web_URL><ZZ_JournalStdAbbrev><f name="System">Thorax</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>[8,9] Studies comparing COPD patients to healthy individuals report lower plasma and peripheral skeletal muscle vitamin E (?-tocopherol) concentrations in patients, and a lower risk of death from respiratory disease with higher serum ?-tocopherol concentration, but whether nutrition contributed to the onset of COPD is less clear.[ ADDIN REFMGR.CITE <Refman><Cite><Author>McKeever</Author><Year>2008</Year><RecNum>14</RecNum><IDText>A multivariate analysis of serum nutrient levels and lung function</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>14</Ref_ID><Title_Primary>A multivariate analysis of serum nutrient levels and lung function</Title_Primary><Authors_Primary>McKeever,T.M.</Authors_Primary><Authors_Primary>Lewis,S.A.</Authors_Primary><Authors_Primary>Smit,H.A.</Authors_Primary><Authors_Primary>Burney,P.</Authors_Primary><Authors_Primary>Cassano,P.A.</Authors_Primary><Authors_Primary>Britton,J.</Authors_Primary><Date_Primary>2008</Date_Primary><Keywords>analysis</Keywords><Keywords>Antioxidants</Keywords><Keywords>blood</Keywords><Keywords>Cross-Sectional Studies</Keywords><Keywords>epidemiology</Keywords><Keywords>Female</Keywords><Keywords>Food</Keywords><Keywords>Forced Expiratory Volume</Keywords><Keywords>Humans</Keywords><Keywords>Incidence</Keywords><Keywords>Male</Keywords><Keywords>Middle Aged</Keywords><Keywords>Nutritional Status</Keywords><Keywords>Public Health</Keywords><Keywords>Pulmonary Disease,Chronic Obstructive</Keywords><Keywords>Respiratory Function Tests</Keywords><Keywords>Smoking</Keywords><Keywords>statistics &amp; numerical data</Keywords><Keywords>United States</Keywords><Reprint>Not in File</Reprint><Start_Page>67</Start_Page><End_Page>76</End_Page><Periodical>Respir.Res.</Periodical><Volume>9</Volume><Address>Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK. Tricia.McKeever@nottingham.ac.uk</Address><Web_URL>PM:18823528</Web_URL><ZZ_JournalStdAbbrev><f name="System">Respir.Res.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Gosker</Author><Year>2005</Year><RecNum>26</RecNum><IDText>Altered antioxidant status in peripheral skeletal muscle of patients with COPD</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>26</Ref_ID><Title_Primary>Altered antioxidant status in peripheral skeletal muscle of patients with COPD</Title_Primary><Authors_Primary>Gosker,H.R.</Authors_Primary><Authors_Primary>Bast,A.</Authors_Primary><Authors_Primary>Haenen,G.R.</Authors_Primary><Authors_Primary>Fischer,M.A.</Authors_Primary><Authors_Primary>van,der,V</Authors_Primary><Authors_Primary>Wouters,E.F.</Authors_Primary><Authors_Primary>Schols,A.M.</Authors_Primary><Date_Primary>2005/1</Date_Primary><Keywords>Aged</Keywords><Keywords>Antioxidants</Keywords><Keywords>Body Composition</Keywords><Keywords>enzymology</Keywords><Keywords>Exercise Tolerance</Keywords><Keywords>Female</Keywords><Keywords>Glutathione</Keywords><Keywords>Glutathione Peroxidase</Keywords><Keywords>Glutathione Transferase</Keywords><Keywords>Humans</Keywords><Keywords>Lipid Peroxidation</Keywords><Keywords>Male</Keywords><Keywords>Malondialdehyde</Keywords><Keywords>metabolism</Keywords><Keywords>Middle Aged</Keywords><Keywords>Muscle Contraction</Keywords><Keywords>Muscle,Skeletal</Keywords><Keywords>Oxidative Stress</Keywords><Keywords>physiopathology</Keywords><Keywords>Pulmonary Disease,Chronic Obstructive</Keywords><Keywords>Reactive Oxygen Species</Keywords><Keywords>Superoxide Dismutase</Keywords><Keywords>Uric Acid</Keywords><Keywords>Vitamin E</Keywords><Reprint>Not in File</Reprint><Start_Page>118</Start_Page><End_Page>125</End_Page><Periodical>Respir.Med.</Periodical><Volume>99</Volume><Issue>1</Issue><Address>Department of Respiratory Medicine, Nutrition Toxicology and Environment Research Institute, Maastricht University, Maastricht, The Netherlands. h.gosker@pul.unimaas.nl</Address><Web_URL>PM:15672860</Web_URL><ZZ_JournalStdAbbrev><f name="System">Respir.Med.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Wright</Author><Year>2006</Year><RecNum>68</RecNum><IDText>Higher baseline serum concentrations of vitamin E are associated with lower total and cause-specific mortality in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>68</Ref_ID><Title_Primary>Higher baseline serum concentrations of vitamin E are associated with lower total and cause-specific mortality in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study</Title_Primary><Authors_Primary>Wright,M.E.</Authors_Primary><Authors_Primary>Lawson,K.A.</Authors_Primary><Authors_Primary>Weinstein,S.J.</Authors_Primary><Authors_Primary>Pietinen,P.</Authors_Primary><Authors_Primary>Taylor,P.R.</Authors_Primary><Authors_Primary>Virtamo,J.</Authors_Primary><Authors_Primary>Albanes,D.</Authors_Primary><Date_Primary>2006/11</Date_Primary><Keywords>adverse effects</Keywords><Keywords>Aged</Keywords><Keywords>alpha-Tocopherol</Keywords><Keywords>analysis</Keywords><Keywords>beta Carotene</Keywords><Keywords>blood</Keywords><Keywords>Cardiovascular Diseases</Keywords><Keywords>Cause of Death</Keywords><Keywords>Chromatography,High Pressure Liquid</Keywords><Keywords>Cohort Studies</Keywords><Keywords>Confidence Intervals</Keywords><Keywords>Diet</Keywords><Keywords>Dietary Supplements</Keywords><Keywords>Disease</Keywords><Keywords>Dose-Response Relationship,Drug</Keywords><Keywords>epidemiology</Keywords><Keywords>Fasting</Keywords><Keywords>Finland</Keywords><Keywords>Follow-Up Studies</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Male</Keywords><Keywords>Meta-Analysis as Topic</Keywords><Keywords>methods</Keywords><Keywords>Middle Aged</Keywords><Keywords>mortality</Keywords><Keywords>Neoplasms</Keywords><Keywords>Odds Ratio</Keywords><Keywords>Proportional Hazards Models</Keywords><Keywords>Prospective Studies</Keywords><Keywords>Risk</Keywords><Keywords>Smoking</Keywords><Keywords>Vitamin E</Keywords><Reprint>Not in File</Reprint><Start_Page>1200</Start_Page><End_Page>1207</End_Page><Periodical>Am.J.Clin.Nutr.</Periodical><Volume>84</Volume><Issue>5</Issue><Address>Nutritional Epidemiology Branch and the Genetic Epidemiology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. wrighmar@mail.</Address><Web_URL>PM:17093175</Web_URL><ZZ_JournalStdAbbrev><f name="System">Am.J.Clin.Nutr.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>10-12] Randomised trials of diet change or vitamin E supplements in clinical populations have reported mixed results. COPD patients who increased intake of antioxidant-rich foods had improved pulmonary function over three years while those on usual diets experienced continuous lung function decline. ADDIN REFMGR.CITE <Refman><Cite><Author>Keranis</Author><Year>2010</Year><RecNum>72</RecNum><IDText>Impact of dietary shift to higher antioxidant foods in COPD: A Randomized Trial</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>72</Ref_ID><Title_Primary>Impact of dietary shift to higher antioxidant foods in COPD: A Randomized Trial</Title_Primary><Authors_Primary>Keranis,E.</Authors_Primary><Authors_Primary>Makris,D.</Authors_Primary><Authors_Primary>Rodopoulou,P.</Authors_Primary><Authors_Primary>Martinou,H.</Authors_Primary><Authors_Primary>Papamakarios,G.</Authors_Primary><Authors_Primary>Daniil,Z.</Authors_Primary><Authors_Primary>Zintzaras,E.</Authors_Primary><Authors_Primary>Gourgoulianis,K.I.</Authors_Primary><Date_Primary>2010/2/11</Date_Primary><Keywords>Antioxidants</Keywords><Keywords>Diet</Keywords><Keywords>Disease</Keywords><Keywords>Food</Keywords><Keywords>Fruit</Keywords><Keywords>Lung</Keywords><Keywords>Oxidative Stress</Keywords><Keywords>Prospective Studies</Keywords><Keywords>Vegetables</Keywords><Reprint>Not in File</Reprint><Start_Page>774</Start_Page><End_Page>780</End_Page><Periodical>Eur.Respir.J.</Periodical><Volume>36</Volume><Issue>4</Issue><Address>University of Thessaly School of Medicine, Larissa, Greece</Address><Web_URL>PM:20150206</Web_URL><ZZ_JournalStdAbbrev><f name="System">Eur.Respir.J.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>[13] Studies of ?-tocopherol treatment in COPD patients report mainly negative results, although conclusions are limited by an incomplete understanding of potential to benefit, the short duration of studies, and case heterogeneity. ADDIN REFMGR.CITE <Refman><Cite><Author>Daga</Author><Year>2003</Year><RecNum>24</RecNum><IDText>Effects of exogenous vitamin E supplementation on the levels of oxidants and antioxidants in chronic obstructive pulmonary disease</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>24</Ref_ID><Title_Primary>Effects of exogenous vitamin E supplementation on the levels of oxidants and antioxidants in chronic obstructive pulmonary disease</Title_Primary><Authors_Primary>Daga,M.K.</Authors_Primary><Authors_Primary>Chhabra,R.</Authors_Primary><Authors_Primary>Sharma,B.</Authors_Primary><Authors_Primary>Mishra,T.K.</Authors_Primary><Date_Primary>2003/2</Date_Primary><Keywords>administration &amp; dosage</Keywords><Keywords>Adult</Keywords><Keywords>alpha-Tocopherol</Keywords><Keywords>Antioxidants</Keywords><Keywords>blood</Keywords><Keywords>Dietary Supplements</Keywords><Keywords>Double-Blind Method</Keywords><Keywords>Female</Keywords><Keywords>Humans</Keywords><Keywords>Male</Keywords><Keywords>Malondialdehyde</Keywords><Keywords>metabolism</Keywords><Keywords>Oxidants</Keywords><Keywords>Oxidative Stress</Keywords><Keywords>Prospective Studies</Keywords><Keywords>Pulmonary Disease,Chronic Obstructive</Keywords><Keywords>Spirometry</Keywords><Keywords>Superoxide Dismutase</Keywords><Keywords>Vitamin E</Keywords><Reprint>Not in File</Reprint><Start_Page>7</Start_Page><End_Page>11</End_Page><Periodical>J.Biosci.</Periodical><Volume>28</Volume><Issue>1</Issue><Address>Department of Medicine, Maulana Azad Medical College and Associated Hospitals, New Delhi 110 002, India. mkdaga@</Address><Web_URL>PM:12682418</Web_URL><ZZ_JournalStdAbbrev><f name="System">J.Biosci.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Nadeem</Author><Year>2008</Year><RecNum>21</RecNum><IDText>Effect of vitamin E supplementation with standard treatment on oxidant-antioxidant status in chronic obstructive pulmonary disease</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>21</Ref_ID><Title_Primary>Effect of vitamin E supplementation with standard treatment on oxidant-antioxidant status in chronic obstructive pulmonary disease</Title_Primary><Authors_Primary>Nadeem,A.</Authors_Primary><Authors_Primary>Raj,H.G.</Authors_Primary><Authors_Primary>Chhabra,S.K.</Authors_Primary><Date_Primary>2008/12</Date_Primary><Keywords>administration &amp; dosage</Keywords><Keywords>Adrenal Cortex Hormones</Keywords><Keywords>Adult</Keywords><Keywords>Aged</Keywords><Keywords>Antioxidants</Keywords><Keywords>blood</Keywords><Keywords>Bronchodilator Agents</Keywords><Keywords>Dietary Supplements</Keywords><Keywords>drug therapy</Keywords><Keywords>Forced Expiratory Volume</Keywords><Keywords>Glutathione</Keywords><Keywords>Humans</Keywords><Keywords>Lung</Keywords><Keywords>metabolism</Keywords><Keywords>Middle Aged</Keywords><Keywords>Pulmonary Disease,Chronic Obstructive</Keywords><Keywords>Single-Blind Method</Keywords><Keywords>Spirometry</Keywords><Keywords>therapeutic use</Keywords><Keywords>Vitamin E</Keywords><Reprint>Not in File</Reprint><Start_Page>705</Start_Page><End_Page>711</End_Page><Periodical>Indian J.Med.Res.</Periodical><Volume>128</Volume><Issue>6</Issue><Address>Department of Biochemistry, Vallabhbhai Patel Chest Institute University of Delhi, Delhi, India</Address><Web_URL>PM:19246793</Web_URL><ZZ_JournalStdAbbrev><f name="System">Indian J.Med.Res.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Rautalahti</Author><Year>1997</Year><RecNum>76</RecNum><IDText>The effect of alpha-tocopherol and beta-carotene supplementation on COPD symptoms</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>76</Ref_ID><Title_Primary>The effect of alpha-tocopherol and beta-carotene supplementation on COPD symptoms</Title_Primary><Authors_Primary>Rautalahti,M.</Authors_Primary><Authors_Primary>Virtamo,J.</Authors_Primary><Authors_Primary>Haukka,J.</Authors_Primary><Authors_Primary>Heinonen,O.P.</Authors_Primary><Authors_Primary>Sundvall,J.</Authors_Primary><Authors_Primary>Albanes,D.</Authors_Primary><Authors_Primary>Huttunen,J.K.</Authors_Primary><Date_Primary>1997/11</Date_Primary><Keywords>administration &amp; dosage</Keywords><Keywords>Aged</Keywords><Keywords>alpha-Tocopherol</Keywords><Keywords>Antioxidants</Keywords><Keywords>beta Carotene</Keywords><Keywords>blood</Keywords><Keywords>Bronchitis</Keywords><Keywords>complications</Keywords><Keywords>Cough</Keywords><Keywords>Dietary Supplements</Keywords><Keywords>Disease</Keywords><Keywords>Dyspnea</Keywords><Keywords>Finland</Keywords><Keywords>Fruit</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Incidence</Keywords><Keywords>Lung</Keywords><Keywords>Lung Diseases,Obstructive</Keywords><Keywords>Male</Keywords><Keywords>Middle Aged</Keywords><Keywords>physiopathology</Keywords><Keywords>Prevalence</Keywords><Keywords>Public Health</Keywords><Keywords>Recurrence</Keywords><Keywords>therapy</Keywords><Keywords>Vegetables</Keywords><Keywords>Vitamin A</Keywords><Keywords>Vitamin E</Keywords><Reprint>Not in File</Reprint><Start_Page>1447</Start_Page><End_Page>1452</End_Page><Periodical>Am.J.Respir.Crit Care Med.</Periodical><Volume>156</Volume><Issue>5</Issue><Address>National Public Health Institute, Helsinki, Finland. Matti.Rautalahti@ktl.fi</Address><Web_URL>PM:9372659</Web_URL><ZZ_JournalStdAbbrev><f name="System">Am.J.Respir.Crit Care Med.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>[14-16] Very few large, randomised studies of non-diseased individuals have been completed. In the Heart Protection Study (HPS), which included participants with coronary disease, other occlusive arterial disease, or diabetes, a post-hoc analysis found no effect of vitamin E supplements on the occurrence of respiratory-related death, on COPD/asthma hospitalization rates, or on pulmonary function measured by spirometry at the end of the study. ADDIN REFMGR.CITE <Refman><Cite><Year>2002</Year><RecNum>69</RecNum><IDText>MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>69</Ref_ID><Title_Primary>MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial</Title_Primary><Date_Primary>2002/7/6</Date_Primary><Keywords>Adult</Keywords><Keywords>Aged</Keywords><Keywords>Aged,80 and over</Keywords><Keywords>alpha-Tocopherol</Keywords><Keywords>Antioxidants</Keywords><Keywords>Ascorbic Acid</Keywords><Keywords>beta Carotene</Keywords><Keywords>blood</Keywords><Keywords>Cardiovascular Diseases</Keywords><Keywords>Cause of Death</Keywords><Keywords>Cholesterol</Keywords><Keywords>classification</Keywords><Keywords>Coronary Disease</Keywords><Keywords>Diabetes Mellitus</Keywords><Keywords>Disease</Keywords><Keywords>drug therapy</Keywords><Keywords>Female</Keywords><Keywords>Follow-Up Studies</Keywords><Keywords>Great Britain</Keywords><Keywords>Humans</Keywords><Keywords>Incidence</Keywords><Keywords>Male</Keywords><Keywords>methods</Keywords><Keywords>Middle Aged</Keywords><Keywords>mortality</Keywords><Keywords>Myocardial Infarction</Keywords><Keywords>Neoplasms</Keywords><Keywords>prevention &amp; control</Keywords><Keywords>Severity of Illness Index</Keywords><Keywords>Stroke</Keywords><Keywords>therapeutic use</Keywords><Keywords>Vitamin E</Keywords><Keywords>Vitamins</Keywords><Reprint>Not in File</Reprint><Start_Page>23</Start_Page><End_Page>33</End_Page><Periodical>Lancet</Periodical><Volume>360</Volume><Issue>9326</Issue><Web_URL>PM:12114037</Web_URL><ZZ_JournalStdAbbrev><f name="System">Lancet</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>[17] In the Alpha-Tocopherol and Beta-Carotene (ATBC) study, a study of male cigarette smokers, there was no effect of ?-tocopherol on the incidence of chronic bronchitis or COPD symptoms. ADDIN REFMGR.CITE <Refman><Cite><Author>Rautalahti</Author><Year>1997</Year><RecNum>76</RecNum><IDText>The effect of alpha-tocopherol and beta-carotene supplementation on COPD symptoms</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>76</Ref_ID><Title_Primary>The effect of alpha-tocopherol and beta-carotene supplementation on COPD symptoms</Title_Primary><Authors_Primary>Rautalahti,M.</Authors_Primary><Authors_Primary>Virtamo,J.</Authors_Primary><Authors_Primary>Haukka,J.</Authors_Primary><Authors_Primary>Heinonen,O.P.</Authors_Primary><Authors_Primary>Sundvall,J.</Authors_Primary><Authors_Primary>Albanes,D.</Authors_Primary><Authors_Primary>Huttunen,J.K.</Authors_Primary><Date_Primary>1997/11</Date_Primary><Keywords>administration &amp; dosage</Keywords><Keywords>Aged</Keywords><Keywords>alpha-Tocopherol</Keywords><Keywords>Antioxidants</Keywords><Keywords>beta Carotene</Keywords><Keywords>blood</Keywords><Keywords>Bronchitis</Keywords><Keywords>complications</Keywords><Keywords>Cough</Keywords><Keywords>Dietary Supplements</Keywords><Keywords>Disease</Keywords><Keywords>Dyspnea</Keywords><Keywords>Finland</Keywords><Keywords>Fruit</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Incidence</Keywords><Keywords>Lung</Keywords><Keywords>Lung Diseases,Obstructive</Keywords><Keywords>Male</Keywords><Keywords>Middle Aged</Keywords><Keywords>physiopathology</Keywords><Keywords>Prevalence</Keywords><Keywords>Public Health</Keywords><Keywords>Recurrence</Keywords><Keywords>therapy</Keywords><Keywords>Vegetables</Keywords><Keywords>Vitamin A</Keywords><Keywords>Vitamin E</Keywords><Reprint>Not in File</Reprint><Start_Page>1447</Start_Page><End_Page>1452</End_Page><Periodical>Am.J.Respir.Crit Care Med.</Periodical><Volume>156</Volume><Issue>5</Issue><Address>National Public Health Institute, Helsinki, Finland. Matti.Rautalahti@ktl.fi</Address><Web_URL>PM:9372659</Web_URL><ZZ_JournalStdAbbrev><f name="System">Am.J.Respir.Crit Care Med.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>[16]Using data from the Women’s Health Study (WHS), a large study of apparently healthy women aged > 45 years, we tested the hypothesis that supplementation with 600 IUs of ?-tocopherol every other day decreases the occurrence rate of chronic lung disease.METHODSAdditional details in the online supplement.Study DesignThe WHS, a randomised, double-blind, placebo-controlled, two-by-two factorial trial assessed risks and benefits of vitamin E supplements (600 IU every other day; Natural Source Vitamin E Association, Washington, DC, USA) and/or aspirin (100 mg every other day; Bayer AG, Leverkusen, Germany) in the primary prevention of cardiovascular disease and cancer. Full details of the study design are published elsewhere. ADDIN REFMGR.CITE <Refman><Cite><Author>Rexrode</Author><Year>2000</Year><RecNum>38</RecNum><IDText>Baseline characteristics of participants in the Women&apos;s Health Study</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>38</Ref_ID><Title_Primary>Baseline characteristics of participants in the Women&apos;s Health Study</Title_Primary><Authors_Primary>Rexrode,K.M.</Authors_Primary><Authors_Primary>Lee,I.M.</Authors_Primary><Authors_Primary>Cook,N.R.</Authors_Primary><Authors_Primary>Hennekens,C.H.</Authors_Primary><Authors_Primary>Buring,J.E.</Authors_Primary><Date_Primary>2000/1</Date_Primary><Keywords>administration &amp; dosage</Keywords><Keywords>Aged</Keywords><Keywords>Anti-Inflammatory Agents</Keywords><Keywords>Anti-Inflammatory Agents,Non-Steroidal</Keywords><Keywords>Aspirin</Keywords><Keywords>Cardiovascular Diseases</Keywords><Keywords>Confounding Factors (Epidemiology)</Keywords><Keywords>Double-Blind Method</Keywords><Keywords>epidemiology</Keywords><Keywords>Female</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Middle Aged</Keywords><Keywords>Neoplasms</Keywords><Keywords>Obesity</Keywords><Keywords>prevention &amp; control</Keywords><Keywords>Risk</Keywords><Keywords>therapeutic use</Keywords><Keywords>Vitamin E</Keywords><Keywords>Women&apos;s Health</Keywords><Reprint>Not in File</Reprint><Start_Page>19</Start_Page><End_Page>27</End_Page><Periodical>J.Womens Health Gend.Based.Med.</Periodical><Volume>9</Volume><Issue>1</Issue><Address>Department of Medicine, Brigham and Women&apos;s Hospital and Harvard Medical School, Boston, Massachusetts 02215, USA</Address><Web_URL>PM:10718501</Web_URL><ZZ_JournalStdAbbrev><f name="System">J.Womens Health Gend.Based.Med.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>[18] The study was registered with (NCT00000479).Eligibility criteria included: age ≥45 years, healthcare professional, U.S. residence, no previous history of coronary heart disease, cerebrovascular disease, cancer (except non-melanoma skin cancer), or other major chronic illness; no more than weekly use of vitamins E, A, or ?-carotene supplements; no history of adverse aspirin effects; less than weekly use of aspirin or non-steroidal anti-inflammatory drug (NSAID), or willingness to forgo; no use of anticoagulants or corticosteroids. A 3-month placebo-only run-in period identified likely long-term compliers. Of these, 39,876 women remained willing and eligible and were randomised into WHS between April 1993 and January 1996. ADDIN REFMGR.CITE <Refman><Cite><Author>Rexrode</Author><Year>2000</Year><RecNum>38</RecNum><IDText>Baseline characteristics of participants in the Women&apos;s Health Study</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>38</Ref_ID><Title_Primary>Baseline characteristics of participants in the Women&apos;s Health Study</Title_Primary><Authors_Primary>Rexrode,K.M.</Authors_Primary><Authors_Primary>Lee,I.M.</Authors_Primary><Authors_Primary>Cook,N.R.</Authors_Primary><Authors_Primary>Hennekens,C.H.</Authors_Primary><Authors_Primary>Buring,J.E.</Authors_Primary><Date_Primary>2000/1</Date_Primary><Keywords>administration &amp; dosage</Keywords><Keywords>Aged</Keywords><Keywords>Anti-Inflammatory Agents</Keywords><Keywords>Anti-Inflammatory Agents,Non-Steroidal</Keywords><Keywords>Aspirin</Keywords><Keywords>Cardiovascular Diseases</Keywords><Keywords>Confounding Factors (Epidemiology)</Keywords><Keywords>Double-Blind Method</Keywords><Keywords>epidemiology</Keywords><Keywords>Female</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Middle Aged</Keywords><Keywords>Neoplasms</Keywords><Keywords>Obesity</Keywords><Keywords>prevention &amp; control</Keywords><Keywords>Risk</Keywords><Keywords>therapeutic use</Keywords><Keywords>Vitamin E</Keywords><Keywords>Women&apos;s Health</Keywords><Reprint>Not in File</Reprint><Start_Page>19</Start_Page><End_Page>27</End_Page><Periodical>J.Womens Health Gend.Based.Med.</Periodical><Volume>9</Volume><Issue>1</Issue><Address>Department of Medicine, Brigham and Women&apos;s Hospital and Harvard Medical School, Boston, Massachusetts 02215, USA</Address><Web_URL>PM:10718501</Web_URL><ZZ_JournalStdAbbrev><f name="System">J.Womens Health Gend.Based.Med.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>[18] Questionnaire DataMailed questionnaires collected baseline data on anthropometric, demographic, lifestyle, and clinical characteristics. Follow-up questionnaires, completed twice during the first year and annually thereafter, assessed study supplement compliance, new disease occurrence and diagnosis date, personal characteristics and habits, non-study aspirin, vitamin and NSAID use, and side effects. Compliance, defined as taking two-thirds of study supplements, was similar (78.9% and 71.6% at 5 and 10 years, respectively) between active and placebo groups. ADDIN REFMGR.CITE <Refman><Cite><Author>Lee</Author><Year>2005</Year><RecNum>42</RecNum><IDText>Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women&apos;s Health Study: a randomized controlled trial</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>42</Ref_ID><Title_Primary>Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women&apos;s Health Study: a randomized controlled trial</Title_Primary><Authors_Primary>Lee,I.M.</Authors_Primary><Authors_Primary>Cook,N.R.</Authors_Primary><Authors_Primary>Gaziano,J.M.</Authors_Primary><Authors_Primary>Gordon,D.</Authors_Primary><Authors_Primary>Ridker,P.M.</Authors_Primary><Authors_Primary>Manson,J.E.</Authors_Primary><Authors_Primary>Hennekens,C.H.</Authors_Primary><Authors_Primary>Buring,J.E.</Authors_Primary><Date_Primary>2005/7/6</Date_Primary><Keywords>Aged</Keywords><Keywords>alpha-Tocopherol</Keywords><Keywords>Aspirin</Keywords><Keywords>Cardiovascular Diseases</Keywords><Keywords>Diet</Keywords><Keywords>Dietary Supplements</Keywords><Keywords>Double-Blind Method</Keywords><Keywords>Drug Interactions</Keywords><Keywords>epidemiology</Keywords><Keywords>Female</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Incidence</Keywords><Keywords>Lung</Keywords><Keywords>methods</Keywords><Keywords>Middle Aged</Keywords><Keywords>mortality</Keywords><Keywords>Neoplasms</Keywords><Keywords>prevention &amp; control</Keywords><Keywords>Primary Prevention</Keywords><Keywords>Risk</Keywords><Keywords>Risk Factors</Keywords><Keywords>therapeutic use</Keywords><Keywords>Vitamin E</Keywords><Keywords>Women&apos;s Health</Keywords><Reprint>Not in File</Reprint><Start_Page>56</Start_Page><End_Page>65</End_Page><Periodical>JAMA</Periodical><Volume>294</Volume><Issue>1</Issue><Address>Division of Preventive Medicine, Department of Medicine, Brigham and Women&apos;s Hospital, Harvard Medical School, Boston, MA 02215, USA. ilee@rics.bwh.harvard.edu</Address><Web_URL>PM:15998891</Web_URL><ZZ_JournalStdAbbrev><f name="System">JAMA</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>[19] Non-trial vitamin E supplement use ≥4 days/month was 10.0% and 10.9% at 5 and 10 years, respectively. ADDIN REFMGR.CITE <Refman><Cite><Author>Lee</Author><Year>2005</Year><RecNum>42</RecNum><IDText>Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women&apos;s Health Study: a randomized controlled trial</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>42</Ref_ID><Title_Primary>Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women&apos;s Health Study: a randomized controlled trial</Title_Primary><Authors_Primary>Lee,I.M.</Authors_Primary><Authors_Primary>Cook,N.R.</Authors_Primary><Authors_Primary>Gaziano,J.M.</Authors_Primary><Authors_Primary>Gordon,D.</Authors_Primary><Authors_Primary>Ridker,P.M.</Authors_Primary><Authors_Primary>Manson,J.E.</Authors_Primary><Authors_Primary>Hennekens,C.H.</Authors_Primary><Authors_Primary>Buring,J.E.</Authors_Primary><Date_Primary>2005/7/6</Date_Primary><Keywords>Aged</Keywords><Keywords>alpha-Tocopherol</Keywords><Keywords>Aspirin</Keywords><Keywords>Cardiovascular Diseases</Keywords><Keywords>Diet</Keywords><Keywords>Dietary Supplements</Keywords><Keywords>Double-Blind Method</Keywords><Keywords>Drug Interactions</Keywords><Keywords>epidemiology</Keywords><Keywords>Female</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Incidence</Keywords><Keywords>Lung</Keywords><Keywords>methods</Keywords><Keywords>Middle Aged</Keywords><Keywords>mortality</Keywords><Keywords>Neoplasms</Keywords><Keywords>prevention &amp; control</Keywords><Keywords>Primary Prevention</Keywords><Keywords>Risk</Keywords><Keywords>Risk Factors</Keywords><Keywords>therapeutic use</Keywords><Keywords>Vitamin E</Keywords><Keywords>Women&apos;s Health</Keywords><Reprint>Not in File</Reprint><Start_Page>56</Start_Page><End_Page>65</End_Page><Periodical>JAMA</Periodical><Volume>294</Volume><Issue>1</Issue><Address>Division of Preventive Medicine, Department of Medicine, Brigham and Women&apos;s Hospital, Harvard Medical School, Boston, MA 02215, USA. ilee@rics.bwh.harvard.edu</Address><Web_URL>PM:15998891</Web_URL><ZZ_JournalStdAbbrev><f name="System">JAMA</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>[19] Chronic Lung Disease AscertainmentChronic lung disease (CLD) was not a pre-specified trial endpoint. Occurrence of self-reported MD-diagnosed CLD was ascertained on questionnaires beginning 12 months after study enrolment. A multipart question asked participants “have you ever been diagnosed by a physician as having any of the following?”, and choices included “other chronic lung disease (e.g. emphysema, chronic bronchitis, bronchiectasis)” as well as “asthma.” For each diagnosis, date of diagnosis was reported. Thereafter, annual questionnaires asked about diagnoses occurring since the prior questionnaire, including diagnosis date. Incident cases were ascertained through March 31, 2004 (scheduled trial end). Prevalent CLD was defined as CLD diagnosis prior to trial enrolment. Women with prevalent CLD were excluded from the analysis (figure 1). Statistical Analysis1,279 women reported prevalent CLD (638 in vitamin E group; 641 in placebo group), thus 38,597 participants were available for analyses. All analyses followed the intention-to-treat principle. Cumulative incidence of CLD by study arm was assessed using Kaplan-Meier methods and log-rank tests to compare survival curves. Cox proportional hazards models estimated hazard ratios. Further models considered whether the effect of vitamin E on incident CLD was modified by smoking status, age, body mass index, multivitamin use, alcohol intake, baseline asthma, history of cholesterol levels ≥240mg/dL, or randomised aspirin assignment. Effect modification was tested for statistical significance using likelihood ratio tests comparing models with and without interaction terms. Data management and analyses were completed in SAS (SAS Institute Inc., Cary, NC).RESULTSBaseline characteristics in the 38,597 participants, summarized in table 1, were balanced between the vitamin E and placebo arms. Thus, participants in both arms were similar on age, smoking, body mass index, multivitamin use, dietary intake of vitamin E, alcohol intake, history of asthma diagnosis, and percent with cholesterol ≥240 mg/dL (Table 1). The mean age of study participants was 54.5 years, and women were followed on average for 9.8 years (376,710 person-years; 188,578 person-years in the vitamin E arm, 188,132 person-years in the placebo arm).Participants reported 1,606 new diagnoses of chronic lung disease, corresponding to a cumulative incidence of 4.2%. Participants in the vitamin E arm reported 760 incident CLD diagnoses (cumulative incidence, 3.9%) compared to 846 occurrences in the placebo arm (cumulative incidence, 4.4%; figure 3), corresponding to a statistically significant 10% reduction in risk among participants randomised to vitamin E supplements (hazard rate (HR) 0.90; 95% confidence interval (CI) 0.81-0.99; p = 0.029). Comparing the cumulative CLD incidence by year of follow-up in the vitamin E and placebo groups (figure 2) the curves separate at about 1.5 years on study and continue to diverge until about 5 years of supplementation, maintaining a consistent separation thereafter. In contrast, the aspirin intervention had little or no association with risk of chronic lung disease; the hazard ratio was 0.98 (95% CI 0.89-1.08).Cigarette smoking had a strong association with CLD incidence (current smoker vs. never smoker: HR 4.17; 95% CI 3.70-4.70; p = <0.0001). In addition, other known COPD risk factors were positively associated with the CLD outcome: older age at randomization (age ≥65 years vs. <55 years; HR 2.38; 95% CI 2.07-2.73; p = <0.0001), obesity (BMI ≥30.0 vs. <25.0; HR 1.60; 95% CI 1.41-1.81; p = <0.0001), asthma diagnosis prior to randomization (HR 1.94; 95% CI 1.65-2.28; p = <0.0001), and hypercholesterolemia (HR 1.42; 95% CI 1.28-1.57; p = <0.0001). TABLE 1. Baseline characteristics of Women’s Health Study participants by vitamin E randomizationVitamin E (N=19299)*Placebo(N=19298)?CharacteristicNo. (%)?No. (%)?Demographic/lifestyleAge, years?54.5 (7.0)54.6 (7.0)<5511714 (60.7)11679 (60.5)55-645654 (29.3)5677 (29.4)≥651931 (10.0)1942 (10.1)Cigarette smoking??Current2434 (12.6)2491 (12.9)Past6937 (36.0)6823 (35.4)Never9909 (51.4)9968 (51.7)Average duration, years?§18.8 (12.5)18.9 (12.6)Body mass index, kg/m2?26.0 (5.0)26.0 (5.0)<25.09598 (50.8)9670 (51.1)25.0-<30.05880 (31.1)5837 (30.8)≥30.03404 (18.0)3411 (18.0)NutritionMultivitamin Use??Never2521 (13.2)2553 (13.4)Past only10927 (57.4)10982 (57.7)Current5574 (29.3)5499 (28.9)Vitamin E intake, mg/day??Diet only?6.6 (5.0)6.6 (5.3)Diet + Supplements?63.2 (143.0)62.6 (140.9)Alcohol intakeRare/never8743 (45.3)8590 (44.5)1-3/month2531 (13.1)2553 (13.2)1-6/week6048 (31.4)6194 (32.1)1+/day1970 (10.2)1959 (10.2)Medical conditionsAsthma diagnosis1104 (5.7)1105 (5.7)Cholesterol ≥240 mg/dL5615 (29.1)5688 (29.5)Study aspirin assignment9638 (49.9)9654 (50.0)*N total for each characteristic ranges from 18,882 to 19,299, given missing data in some variables?N total for each characteristic ranges from 18,918 to 19,298, given missing data in some variables?Continuous variables are presented as means (SD)§Average smoking duration for current and past smokers onlyThere was no statistical evidence that the effect of randomised vitamin E assignment on CLD risk was modified by age (p=0.86), smoking status (p=0.96), body mass index (p=0.25), multivitamin use (p=0.67), baseline asthma history (p=0.89), cholesterol ≥240 mg/dL (p=0.84), or by study aspirin assignment (p=0.19) (figure 3). Alcohol intake was borderline statistically significant (p=0.054) as a modifier of the effect of vitamin E on CLD, and women consuming one or more alcoholic drinks per day had the strongest vitamin E protective effect. In additional analyses, there was no evidence of effect modification by race, exercise frequency, hypertension, and baseline dietary intake of either vitamin E or C. For all models, controlling for randomised aspirin assignment did not alter the effect of vitamin E supplement assignment on CLD risk. An additional sensitivity analysis was conducted, censoring women who reported incident asthma from the CLD analysis; the association of vitamin E was similar with a 9% reduction in risk of CLD (HR 0.91, 95% CI: 0.81-1.03).DISCUSSIONIn this large, randomised, double-blind, placebo-controlled trial in apparently healthy women 600 IU of vitamin E on alternate days reduced the risk of self-reported newly diagnosed chronic lung disease by approximately 10%. There was no statistically significant difference in the magnitude of the effect of vitamin E by age, smoking status, randomised aspirin assignment, multivitamin use, or asthma history, and the protective effect was slightly stronger in women consuming > 1 drink/day. Randomised assignment to aspirin had no association with the risk of CLD.Two prior randomised trials investigated vitamin E supplementation in relation to lung outcomes, and both reported no effect of intervention. ADDIN REFMGR.CITE <Refman><Cite><Year>2002</Year><RecNum>69</RecNum><IDText>MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>69</Ref_ID><Title_Primary>MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial</Title_Primary><Date_Primary>2002/7/6</Date_Primary><Keywords>Adult</Keywords><Keywords>Aged</Keywords><Keywords>Aged,80 and over</Keywords><Keywords>alpha-Tocopherol</Keywords><Keywords>Antioxidants</Keywords><Keywords>Ascorbic Acid</Keywords><Keywords>beta Carotene</Keywords><Keywords>blood</Keywords><Keywords>Cardiovascular Diseases</Keywords><Keywords>Cause of Death</Keywords><Keywords>Cholesterol</Keywords><Keywords>classification</Keywords><Keywords>Coronary Disease</Keywords><Keywords>Diabetes Mellitus</Keywords><Keywords>Disease</Keywords><Keywords>drug therapy</Keywords><Keywords>Female</Keywords><Keywords>Follow-Up Studies</Keywords><Keywords>Great Britain</Keywords><Keywords>Humans</Keywords><Keywords>Incidence</Keywords><Keywords>Male</Keywords><Keywords>methods</Keywords><Keywords>Middle Aged</Keywords><Keywords>mortality</Keywords><Keywords>Myocardial Infarction</Keywords><Keywords>Neoplasms</Keywords><Keywords>prevention &amp; control</Keywords><Keywords>Severity of Illness Index</Keywords><Keywords>Stroke</Keywords><Keywords>therapeutic use</Keywords><Keywords>Vitamin E</Keywords><Keywords>Vitamins</Keywords><Reprint>Not in File</Reprint><Start_Page>23</Start_Page><End_Page>33</End_Page><Periodical>Lancet</Periodical><Volume>360</Volume><Issue>9326</Issue><Web_URL>PM:12114037</Web_URL><ZZ_JournalStdAbbrev><f name="System">Lancet</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Rautalahti</Author><Year>1997</Year><RecNum>76</RecNum><IDText>The effect of alpha-tocopherol and beta-carotene supplementation on COPD symptoms</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>76</Ref_ID><Title_Primary>The effect of alpha-tocopherol and beta-carotene supplementation on COPD symptoms</Title_Primary><Authors_Primary>Rautalahti,M.</Authors_Primary><Authors_Primary>Virtamo,J.</Authors_Primary><Authors_Primary>Haukka,J.</Authors_Primary><Authors_Primary>Heinonen,O.P.</Authors_Primary><Authors_Primary>Sundvall,J.</Authors_Primary><Authors_Primary>Albanes,D.</Authors_Primary><Authors_Primary>Huttunen,J.K.</Authors_Primary><Date_Primary>1997/11</Date_Primary><Keywords>administration &amp; dosage</Keywords><Keywords>Aged</Keywords><Keywords>alpha-Tocopherol</Keywords><Keywords>Antioxidants</Keywords><Keywords>beta Carotene</Keywords><Keywords>blood</Keywords><Keywords>Bronchitis</Keywords><Keywords>complications</Keywords><Keywords>Cough</Keywords><Keywords>Dietary Supplements</Keywords><Keywords>Disease</Keywords><Keywords>Dyspnea</Keywords><Keywords>Finland</Keywords><Keywords>Fruit</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Incidence</Keywords><Keywords>Lung</Keywords><Keywords>Lung Diseases,Obstructive</Keywords><Keywords>Male</Keywords><Keywords>Middle Aged</Keywords><Keywords>physiopathology</Keywords><Keywords>Prevalence</Keywords><Keywords>Public Health</Keywords><Keywords>Recurrence</Keywords><Keywords>therapy</Keywords><Keywords>Vegetables</Keywords><Keywords>Vitamin A</Keywords><Keywords>Vitamin E</Keywords><Reprint>Not in File</Reprint><Start_Page>1447</Start_Page><End_Page>1452</End_Page><Periodical>Am.J.Respir.Crit Care Med.</Periodical><Volume>156</Volume><Issue>5</Issue><Address>National Public Health Institute, Helsinki, Finland. Matti.Rautalahti@ktl.fi</Address><Web_URL>PM:9372659</Web_URL><ZZ_JournalStdAbbrev><f name="System">Am.J.Respir.Crit Care Med.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>[16,17] In the Heart Protection Study (HPS) 20,536 adults aged 40-80 with prevalent coronary artery disease (CAD) were randomised to a combined intervention of 600 IUs of vitamin E, 250 mg vitamin C, and 20 mg ?-carotene or placebo daily for 5 years. ADDIN REFMGR.CITE <Refman><Cite><Year>2002</Year><RecNum>69</RecNum><IDText>MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>69</Ref_ID><Title_Primary>MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial</Title_Primary><Date_Primary>2002/7/6</Date_Primary><Keywords>Adult</Keywords><Keywords>Aged</Keywords><Keywords>Aged,80 and over</Keywords><Keywords>alpha-Tocopherol</Keywords><Keywords>Antioxidants</Keywords><Keywords>Ascorbic Acid</Keywords><Keywords>beta Carotene</Keywords><Keywords>blood</Keywords><Keywords>Cardiovascular Diseases</Keywords><Keywords>Cause of Death</Keywords><Keywords>Cholesterol</Keywords><Keywords>classification</Keywords><Keywords>Coronary Disease</Keywords><Keywords>Diabetes Mellitus</Keywords><Keywords>Disease</Keywords><Keywords>drug therapy</Keywords><Keywords>Female</Keywords><Keywords>Follow-Up Studies</Keywords><Keywords>Great Britain</Keywords><Keywords>Humans</Keywords><Keywords>Incidence</Keywords><Keywords>Male</Keywords><Keywords>methods</Keywords><Keywords>Middle Aged</Keywords><Keywords>mortality</Keywords><Keywords>Myocardial Infarction</Keywords><Keywords>Neoplasms</Keywords><Keywords>prevention &amp; control</Keywords><Keywords>Severity of Illness Index</Keywords><Keywords>Stroke</Keywords><Keywords>therapeutic use</Keywords><Keywords>Vitamin E</Keywords><Keywords>Vitamins</Keywords><Reprint>Not in File</Reprint><Start_Page>23</Start_Page><End_Page>33</End_Page><Periodical>Lancet</Periodical><Volume>360</Volume><Issue>9326</Issue><Web_URL>PM:12114037</Web_URL><ZZ_JournalStdAbbrev><f name="System">Lancet</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>[17] HPS differed from the WHS in important ways. HPS enroled participants with clinically diagnosed CAD, occlusive arterial disease, or diabetes and 75% of participants were men.[ ADDIN REFMGR.CITE <Refman><Cite><Year>2002</Year><RecNum>69</RecNum><IDText>MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>69</Ref_ID><Title_Primary>MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial</Title_Primary><Date_Primary>2002/7/6</Date_Primary><Keywords>Adult</Keywords><Keywords>Aged</Keywords><Keywords>Aged,80 and over</Keywords><Keywords>alpha-Tocopherol</Keywords><Keywords>Antioxidants</Keywords><Keywords>Ascorbic Acid</Keywords><Keywords>beta Carotene</Keywords><Keywords>blood</Keywords><Keywords>Cardiovascular Diseases</Keywords><Keywords>Cause of Death</Keywords><Keywords>Cholesterol</Keywords><Keywords>classification</Keywords><Keywords>Coronary Disease</Keywords><Keywords>Diabetes Mellitus</Keywords><Keywords>Disease</Keywords><Keywords>drug therapy</Keywords><Keywords>Female</Keywords><Keywords>Follow-Up Studies</Keywords><Keywords>Great Britain</Keywords><Keywords>Humans</Keywords><Keywords>Incidence</Keywords><Keywords>Male</Keywords><Keywords>methods</Keywords><Keywords>Middle Aged</Keywords><Keywords>mortality</Keywords><Keywords>Myocardial Infarction</Keywords><Keywords>Neoplasms</Keywords><Keywords>prevention &amp; control</Keywords><Keywords>Severity of Illness Index</Keywords><Keywords>Stroke</Keywords><Keywords>therapeutic use</Keywords><Keywords>Vitamin E</Keywords><Keywords>Vitamins</Keywords><Reprint>Not in File</Reprint><Start_Page>23</Start_Page><End_Page>33</End_Page><Periodical>Lancet</Periodical><Volume>360</Volume><Issue>9326</Issue><Web_URL>PM:12114037</Web_URL><ZZ_JournalStdAbbrev><f name="System">Lancet</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>17] WHS comprised women without cardiovascular disease history. Study duration (5 years in HPS vs. 10 yrs in WHS) and supplement formulation (HPS, combined supplement vs. WHS, vitamin E alone) also differed. Finally, the outcomes in HPS, pulmonary function measured by spirometry, death due to respiratory illness, and COPD or asthma-related hospitalizations differed from the WHS, which investigated incidence of chronic lung disease diagnosis. ADDIN REFMGR.CITE <Refman><Cite><Year>2002</Year><RecNum>69</RecNum><IDText>MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>69</Ref_ID><Title_Primary>MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial</Title_Primary><Date_Primary>2002/7/6</Date_Primary><Keywords>Adult</Keywords><Keywords>Aged</Keywords><Keywords>Aged,80 and over</Keywords><Keywords>alpha-Tocopherol</Keywords><Keywords>Antioxidants</Keywords><Keywords>Ascorbic Acid</Keywords><Keywords>beta Carotene</Keywords><Keywords>blood</Keywords><Keywords>Cardiovascular Diseases</Keywords><Keywords>Cause of Death</Keywords><Keywords>Cholesterol</Keywords><Keywords>classification</Keywords><Keywords>Coronary Disease</Keywords><Keywords>Diabetes Mellitus</Keywords><Keywords>Disease</Keywords><Keywords>drug therapy</Keywords><Keywords>Female</Keywords><Keywords>Follow-Up Studies</Keywords><Keywords>Great Britain</Keywords><Keywords>Humans</Keywords><Keywords>Incidence</Keywords><Keywords>Male</Keywords><Keywords>methods</Keywords><Keywords>Middle Aged</Keywords><Keywords>mortality</Keywords><Keywords>Myocardial Infarction</Keywords><Keywords>Neoplasms</Keywords><Keywords>prevention &amp; control</Keywords><Keywords>Severity of Illness Index</Keywords><Keywords>Stroke</Keywords><Keywords>therapeutic use</Keywords><Keywords>Vitamin E</Keywords><Keywords>Vitamins</Keywords><Reprint>Not in File</Reprint><Start_Page>23</Start_Page><End_Page>33</End_Page><Periodical>Lancet</Periodical><Volume>360</Volume><Issue>9326</Issue><Web_URL>PM:12114037</Web_URL><ZZ_JournalStdAbbrev><f name="System">Lancet</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>[17]In the Alpha-tocopherol Beta-carotene Cancer Prevention Study (ATBC) 29,133 male cigarette smokers aged 50-69 were randomised to receive 50 mg vitamin E and/or 20 mg ?-carotene or placebo daily for 4 years. ADDIN REFMGR.CITE <Refman><Cite><Author>Rautalahti</Author><Year>1997</Year><RecNum>76</RecNum><IDText>The effect of alpha-tocopherol and beta-carotene supplementation on COPD symptoms</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>76</Ref_ID><Title_Primary>The effect of alpha-tocopherol and beta-carotene supplementation on COPD symptoms</Title_Primary><Authors_Primary>Rautalahti,M.</Authors_Primary><Authors_Primary>Virtamo,J.</Authors_Primary><Authors_Primary>Haukka,J.</Authors_Primary><Authors_Primary>Heinonen,O.P.</Authors_Primary><Authors_Primary>Sundvall,J.</Authors_Primary><Authors_Primary>Albanes,D.</Authors_Primary><Authors_Primary>Huttunen,J.K.</Authors_Primary><Date_Primary>1997/11</Date_Primary><Keywords>administration &amp; dosage</Keywords><Keywords>Aged</Keywords><Keywords>alpha-Tocopherol</Keywords><Keywords>Antioxidants</Keywords><Keywords>beta Carotene</Keywords><Keywords>blood</Keywords><Keywords>Bronchitis</Keywords><Keywords>complications</Keywords><Keywords>Cough</Keywords><Keywords>Dietary Supplements</Keywords><Keywords>Disease</Keywords><Keywords>Dyspnea</Keywords><Keywords>Finland</Keywords><Keywords>Fruit</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Incidence</Keywords><Keywords>Lung</Keywords><Keywords>Lung Diseases,Obstructive</Keywords><Keywords>Male</Keywords><Keywords>Middle Aged</Keywords><Keywords>physiopathology</Keywords><Keywords>Prevalence</Keywords><Keywords>Public Health</Keywords><Keywords>Recurrence</Keywords><Keywords>therapy</Keywords><Keywords>Vegetables</Keywords><Keywords>Vitamin A</Keywords><Keywords>Vitamin E</Keywords><Reprint>Not in File</Reprint><Start_Page>1447</Start_Page><End_Page>1452</End_Page><Periodical>Am.J.Respir.Crit Care Med.</Periodical><Volume>156</Volume><Issue>5</Issue><Address>National Public Health Institute, Helsinki, Finland. Matti.Rautalahti@ktl.fi</Address><Web_URL>PM:9372659</Web_URL><ZZ_JournalStdAbbrev><f name="System">Am.J.Respir.Crit Care Med.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>[16] ATBC differed substantially from the WHS in the supplement studied, the trial duration and the population studied. ADDIN REFMGR.CITE <Refman><Cite><Author>Rautalahti</Author><Year>1997</Year><RecNum>76</RecNum><IDText>The effect of alpha-tocopherol and beta-carotene supplementation on COPD symptoms</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>76</Ref_ID><Title_Primary>The effect of alpha-tocopherol and beta-carotene supplementation on COPD symptoms</Title_Primary><Authors_Primary>Rautalahti,M.</Authors_Primary><Authors_Primary>Virtamo,J.</Authors_Primary><Authors_Primary>Haukka,J.</Authors_Primary><Authors_Primary>Heinonen,O.P.</Authors_Primary><Authors_Primary>Sundvall,J.</Authors_Primary><Authors_Primary>Albanes,D.</Authors_Primary><Authors_Primary>Huttunen,J.K.</Authors_Primary><Date_Primary>1997/11</Date_Primary><Keywords>administration &amp; dosage</Keywords><Keywords>Aged</Keywords><Keywords>alpha-Tocopherol</Keywords><Keywords>Antioxidants</Keywords><Keywords>beta Carotene</Keywords><Keywords>blood</Keywords><Keywords>Bronchitis</Keywords><Keywords>complications</Keywords><Keywords>Cough</Keywords><Keywords>Dietary Supplements</Keywords><Keywords>Disease</Keywords><Keywords>Dyspnea</Keywords><Keywords>Finland</Keywords><Keywords>Fruit</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Incidence</Keywords><Keywords>Lung</Keywords><Keywords>Lung Diseases,Obstructive</Keywords><Keywords>Male</Keywords><Keywords>Middle Aged</Keywords><Keywords>physiopathology</Keywords><Keywords>Prevalence</Keywords><Keywords>Public Health</Keywords><Keywords>Recurrence</Keywords><Keywords>therapy</Keywords><Keywords>Vegetables</Keywords><Keywords>Vitamin A</Keywords><Keywords>Vitamin E</Keywords><Reprint>Not in File</Reprint><Start_Page>1447</Start_Page><End_Page>1452</End_Page><Periodical>Am.J.Respir.Crit Care Med.</Periodical><Volume>156</Volume><Issue>5</Issue><Address>National Public Health Institute, Helsinki, Finland. Matti.Rautalahti@ktl.fi</Address><Web_URL>PM:9372659</Web_URL><ZZ_JournalStdAbbrev><f name="System">Am.J.Respir.Crit Care Med.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>[16] ATBC reported no effect of vitamin E on COPD-related symptoms, a substantially different endpoint than incidence of chronic lung disease diagnosis. Strengths of the WHS include the large number of participants, the large number of self-reported, MD-diagnosed CLD outcomes, high adherence rate, and high follow-up rate. CLD is associated with ageing, thus the minimum age required for study enrolment, 45 years, yielded a population at risk for incident CLD risk.Several limitations deserve mention. While the size of this trial was adequate to detect a statistically significant small to moderate effect of vitamin E supplementation on incident CLD, the trial was not specifically designed to test the studied hypothesis. Thus, outcome ascertainment was based solely on self-reported MD-diagnosis, a concern that is partly mitigated by the fact that participants were female health professionals. A validation study of self-reported COPD outcomes in female nurses found that 78% of self-reported COPD cases were confirmed with medical record review, suggesting self-report of lung disease by the female health professionals comprising the WHS is likely to have excellent validity. ADDIN REFMGR.CITE <Refman><Cite><Author>Barr</Author><Year>2002</Year><RecNum>1</RecNum><IDText>Validation of self-reported chronic obstructive pulmonary disease in a cohort study of nurses</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>1</Ref_ID><Title_Primary>Validation of self-reported chronic obstructive pulmonary disease in a cohort study of nurses</Title_Primary><Authors_Primary>Barr,R.G.</Authors_Primary><Authors_Primary>Herbstman,J.</Authors_Primary><Authors_Primary>Speizer,F.E.</Authors_Primary><Authors_Primary>Camargo,C.A.,Jr.</Authors_Primary><Date_Primary>2002/5/15</Date_Primary><Keywords>Adult</Keywords><Keywords>Cohort Studies</Keywords><Keywords>epidemiology</Keywords><Keywords>Female</Keywords><Keywords>Follow-Up Studies</Keywords><Keywords>Humans</Keywords><Keywords>Medical Records</Keywords><Keywords>Middle Aged</Keywords><Keywords>Nurses</Keywords><Keywords>Pulmonary Disease,Chronic Obstructive</Keywords><Keywords>Questionnaires</Keywords><Keywords>Sensitivity and Specificity</Keywords><Keywords>Smoking Cessation</Keywords><Keywords>Spirometry</Keywords><Keywords>statistics &amp; numerical data</Keywords><Keywords>Tomography Scanners,X-Ray Computed</Keywords><Keywords>United States</Keywords><Reprint>Not in File</Reprint><Start_Page>965</Start_Page><End_Page>971</End_Page><Periodical>Am.J.Epidemiol.</Periodical><Volume>155</Volume><Issue>10</Issue><Address>Channing Laboratory, Department of Medicine, Brigham and Women&apos;s Hospital, Harvard Medical School, Boston, MA 02115, USA</Address><Web_URL>PM:11994237</Web_URL><ZZ_JournalStdAbbrev><f name="System">Am.J.Epidemiol.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>[20] While the question about outcome occurrence listed bronchiectasis, the low incidence of bronchiectasis in this age range leads to the reasonable assumption that most occurrences reported refer to COPD. Current cigarette smoking was a strong predictor of CLD in these data, providing evidence of face validity for the outcome ascertainment. Finally, if the outcome is misclassified (either by undercounting cases or by including false positives) the misclassification is likely to affect both arms of the trial equally, and the hazard ratio may therefore be an underestimate of the true effect size. Outcome definitionThe complexity of airway disease phenotypes raises substantial concern about misdiagnosis of COPD and asthma, particularly in women.[ ADDIN REFMGR.CITE <Refman><Cite><Author>Tinkelman</Author><Year>2006</Year><RecNum>105</RecNum><IDText>Misdiagnosis of COPD and asthma in primary care patients 40 years of age and over</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>105</Ref_ID><Title_Primary>Misdiagnosis of COPD and asthma in primary care patients 40 years of age and over</Title_Primary><Authors_Primary>Tinkelman,D.G.</Authors_Primary><Authors_Primary>Price,D.B.</Authors_Primary><Authors_Primary>Nordyke,R.J.</Authors_Primary><Authors_Primary>Halbert,R.J.</Authors_Primary><Date_Primary>2006/1</Date_Primary><Keywords>Adrenal Cortex Hormones</Keywords><Keywords>Adult</Keywords><Keywords>Age Factors</Keywords><Keywords>Aged</Keywords><Keywords>Asthma</Keywords><Keywords>Bronchial Provocation Tests</Keywords><Keywords>Bronchitis</Keywords><Keywords>Bronchitis,Chronic</Keywords><Keywords>Bronchodilator Agents</Keywords><Keywords>diagnosis</Keywords><Keywords>Diagnostic Errors</Keywords><Keywords>Disease</Keywords><Keywords>drug therapy</Keywords><Keywords>Female</Keywords><Keywords>Forced Expiratory Volume</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Leukotriene Antagonists</Keywords><Keywords>Lung</Keywords><Keywords>Male</Keywords><Keywords>Middle Aged</Keywords><Keywords>physiology</Keywords><Keywords>physiopathology</Keywords><Keywords>Primary Health Care</Keywords><Keywords>Prospective Studies</Keywords><Keywords>Pulmonary Disease,Chronic Obstructive</Keywords><Keywords>Pulmonary Emphysema</Keywords><Keywords>Questionnaires</Keywords><Keywords>Sex Factors</Keywords><Keywords>Smoking</Keywords><Keywords>Spirometry</Keywords><Keywords>statistics &amp; numerical data</Keywords><Keywords>therapeutic use</Keywords><Keywords>Vital Capacity</Keywords><Reprint>Not in File</Reprint><Start_Page>75</Start_Page><End_Page>80</End_Page><Periodical>J.Asthma</Periodical><Volume>43</Volume><Issue>1</Issue><Address>Health Initiatives, National Jewish Medical and Research Center, Denver, USA</Address><Web_URL>PM:16448970</Web_URL><ZZ_JournalStdAbbrev><f name="System">J.Asthma</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>21] To address the possibility that women reporting a new asthma diagnosis actually had COPD, a sensitivity analysis was conducted. When women reporting incident asthma were excluded from the analysis, vitamin E was associated with a 9% reduction in the risk of CLD (HR 0.91, 95% CI: 0.81-1.03), similar to the findings in the full study group. There was little or no effect of vitamin E supplementation on incident self-reported MD-diagnosed asthma (HR 0.99; 95% CI 0.90-1.08; p=0.83). Kurth et al (2008) investigated the effect of randomized aspirin assignment on the risk of incident adult-onset asthma in the Women’s Health Study; women in the aspirin arm had a 10% lower risk of incident asthma compared to women in the placebo arm. When women developing chronic obstructive pulmonary disease over follow-up were censored from the analysis, the findings were similar.[ ADDIN REFMGR.CITE <Refman><Cite><Author>Schurks</Author><Year>2010</Year><RecNum>114</RecNum><IDText>Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>114</Ref_ID><Title_Primary>Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials</Title_Primary><Authors_Primary>Schurks,M.</Authors_Primary><Authors_Primary>Glynn,R.J.</Authors_Primary><Authors_Primary>Rist,P.M.</Authors_Primary><Authors_Primary>Tzourio,C.</Authors_Primary><Authors_Primary>Kurth,T.</Authors_Primary><Date_Primary>2010</Date_Primary><Keywords>administration &amp; dosage</Keywords><Keywords>Adult</Keywords><Keywords>adverse effects</Keywords><Keywords>Aged</Keywords><Keywords>Brain Ischemia</Keywords><Keywords>chemically induced</Keywords><Keywords>Confidence Intervals</Keywords><Keywords>Dietary Supplements</Keywords><Keywords>Humans</Keywords><Keywords>Intracranial Hemorrhages</Keywords><Keywords>methods</Keywords><Keywords>Middle Aged</Keywords><Keywords>prevention &amp; control</Keywords><Keywords>Randomized Controlled Trials as Topic</Keywords><Keywords>Risk</Keywords><Keywords>Risk Factors</Keywords><Keywords>Stroke</Keywords><Keywords>Vitamin E</Keywords><Keywords>Vitamins</Keywords><Reprint>Not in File</Reprint><Start_Page>c5702</Start_Page><Periodical>BMJ</Periodical><Volume>341</Volume><Address>Division of Preventive Medicine, Department of Medicine; Brigham and Women&apos;s Hospital, Harvard Medical School, Boston, MA 02215-1204, USA. mschuerks@rics.bwh.harvard.edu</Address><Web_URL>PM:21051774</Web_URL><ZZ_JournalFull><f name="System">BMJ</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>22] The effect of aspirin on incident asthma, and the lack of effect of aspirin on incident CLD supports the notion of differentiation in the self-reported diagnoses. Proposed mechanismsPrior studies document the presence of vitamin E in the lung compartment and the mechanisms of delivery of vitamin E to alveolar type II cells in the lung.[ ADDIN REFMGR.CITE <Refman><Cite><Author>Kolleck</Author><Year>2002</Year><RecNum>80</RecNum><IDText>Vitamin E as an antioxidant of the lung: mechanisms of vitamin E delivery to alveolar type II cells</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>80</Ref_ID><Title_Primary>Vitamin E as an antioxidant of the lung: mechanisms of vitamin E delivery to alveolar type II cells</Title_Primary><Authors_Primary>Kolleck,I.</Authors_Primary><Authors_Primary>Sinha,P.</Authors_Primary><Authors_Primary>Rustow,B.</Authors_Primary><Date_Primary>2002/12/15</Date_Primary><Keywords>Animals</Keywords><Keywords>Antioxidants</Keywords><Keywords>Cholesterol</Keywords><Keywords>Humans</Keywords><Keywords>Lung</Keywords><Keywords>Membrane Proteins</Keywords><Keywords>metabolism</Keywords><Keywords>Oxidants</Keywords><Keywords>physiology</Keywords><Keywords>Pulmonary Alveoli</Keywords><Keywords>Receptors,Immunologic</Keywords><Keywords>Receptors,Lipoprotein</Keywords><Keywords>Receptors,Scavenger</Keywords><Keywords>Scavenger Receptors,Class B</Keywords><Keywords>secretion</Keywords><Keywords>Vitamin E</Keywords><Keywords>Vitamin E Deficiency</Keywords><Reprint>Not in File</Reprint><Start_Page>S62</Start_Page><End_Page>S66</End_Page><Periodical>Am.J.Respir.Crit Care Med.</Periodical><Volume>166</Volume><Issue>12 Pt 2</Issue><Address>Department of Neonatology and Institute of Pathobiochemistry and Laboratory Medicine, Charite Hospital, Humboldt University Berlin, Berlin, Germany</Address><Web_URL>PM:12471091</Web_URL><ZZ_JournalStdAbbrev><f name="System">Am.J.Respir.Crit Care Med.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>23] Vitamin E transport to the type II cells is hypothesised to occur via high-density lipoproteins because type II cells have no physical contact with plasma and interact only with interstitial fluid lipoproteins, which are predominantly HDL lipoproteins.[ ADDIN REFMGR.CITE <Refman><Cite><Author>Kolleck</Author><Year>2002</Year><RecNum>80</RecNum><IDText>Vitamin E as an antioxidant of the lung: mechanisms of vitamin E delivery to alveolar type II cells</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>80</Ref_ID><Title_Primary>Vitamin E as an antioxidant of the lung: mechanisms of vitamin E delivery to alveolar type II cells</Title_Primary><Authors_Primary>Kolleck,I.</Authors_Primary><Authors_Primary>Sinha,P.</Authors_Primary><Authors_Primary>Rustow,B.</Authors_Primary><Date_Primary>2002/12/15</Date_Primary><Keywords>Animals</Keywords><Keywords>Antioxidants</Keywords><Keywords>Cholesterol</Keywords><Keywords>Humans</Keywords><Keywords>Lung</Keywords><Keywords>Membrane Proteins</Keywords><Keywords>metabolism</Keywords><Keywords>Oxidants</Keywords><Keywords>physiology</Keywords><Keywords>Pulmonary Alveoli</Keywords><Keywords>Receptors,Immunologic</Keywords><Keywords>Receptors,Lipoprotein</Keywords><Keywords>Receptors,Scavenger</Keywords><Keywords>Scavenger Receptors,Class B</Keywords><Keywords>secretion</Keywords><Keywords>Vitamin E</Keywords><Keywords>Vitamin E Deficiency</Keywords><Reprint>Not in File</Reprint><Start_Page>S62</Start_Page><End_Page>S66</End_Page><Periodical>Am.J.Respir.Crit Care Med.</Periodical><Volume>166</Volume><Issue>12 Pt 2</Issue><Address>Department of Neonatology and Institute of Pathobiochemistry and Laboratory Medicine, Charite Hospital, Humboldt University Berlin, Berlin, Germany</Address><Web_URL>PM:12471091</Web_URL><ZZ_JournalStdAbbrev><f name="System">Am.J.Respir.Crit Care Med.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>23] Thus, the concentration of HDL cholesterol in the plasma and in the interstitial fluid predicts the amount of vitamin E available to the lung compartment to combat oxidative stress. Prior studies have reported that HDL cholesterol and apolipoprotein A-I levels are positively associated with FEV1, even after adjusting for serum antioxidant concentrations, a finding that may reflect the delivery of vitamin E to lung tissues.[ ADDIN REFMGR.CITE <Refman><Cite><Author>Cirillo</Author><Year>2002</Year><RecNum>99</RecNum><IDText>Lipids and pulmonary function in the Third National Health and Nutrition Examination Survey</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>99</Ref_ID><Title_Primary>Lipids and pulmonary function in the Third National Health and Nutrition Examination Survey</Title_Primary><Authors_Primary>Cirillo,D.J.</Authors_Primary><Authors_Primary>Agrawal,Y.</Authors_Primary><Authors_Primary>Cassano,P.A.</Authors_Primary><Date_Primary>2002/5/1</Date_Primary><Keywords>Adolescent</Keywords><Keywords>Adult</Keywords><Keywords>Aged</Keywords><Keywords>Aged,80 and over</Keywords><Keywords>analysis</Keywords><Keywords>Antioxidants</Keywords><Keywords>blood</Keywords><Keywords>Body Mass Index</Keywords><Keywords>Cholesterol</Keywords><Keywords>Confounding Factors (Epidemiology)</Keywords><Keywords>Disease</Keywords><Keywords>epidemiology</Keywords><Keywords>Female</Keywords><Keywords>Forced Expiratory Volume</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Lipids</Keywords><Keywords>Male</Keywords><Keywords>Middle Aged</Keywords><Keywords>mortality</Keywords><Keywords>Nutrition Surveys</Keywords><Keywords>physiology</Keywords><Keywords>Regression Analysis</Keywords><Keywords>Serum</Keywords><Keywords>Smoking</Keywords><Keywords>United States</Keywords><Reprint>Not in File</Reprint><Start_Page>842</Start_Page><End_Page>848</End_Page><Periodical>Am.J.Epidemiol.</Periodical><Volume>155</Volume><Issue>9</Issue><Address>Division of Nutritional Sciences, Cornell University, Ithaca, NY</Address><Web_URL>PM:11978588</Web_URL><ZZ_JournalStdAbbrev><f name="System">Am.J.Epidemiol.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>24] Thus, a higher HDL cholesterol level is hypothesised to deliver a greater effective dose of vitamin E to the lung compartment.Given that HDL cholesterol levels are 20-25% higher in women compared to men in all age groups, differences in the biologically effective dose of vitamin E may contribute to the difference in findings between women in WHS and the predominantly male participants in the HPS and ATBC.[ ADDIN REFMGR.CITE <Refman><Cite><Author>Cheung</Author><Year>2009</Year><RecNum>95</RecNum><IDText>High density lipoprotein-cholesterol levels increase with age in American women but not in Hong Kong Chinese women</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>95</Ref_ID><Title_Primary>High density lipoprotein-cholesterol levels increase with age in American women but not in Hong Kong Chinese women</Title_Primary><Authors_Primary>Cheung,B.M.</Authors_Primary><Authors_Primary>Li,M.</Authors_Primary><Authors_Primary>Ong,K.L.</Authors_Primary><Authors_Primary>Wat,N.M.</Authors_Primary><Authors_Primary>Tam,S.</Authors_Primary><Authors_Primary>Pang,R.W.</Authors_Primary><Authors_Primary>Thomas,G.N.</Authors_Primary><Authors_Primary>Woo,J.</Authors_Primary><Authors_Primary>Janus,E.D.</Authors_Primary><Authors_Primary>Lau,C.P.</Authors_Primary><Authors_Primary>Lam,T.H.</Authors_Primary><Authors_Primary>Lam,K.S.</Authors_Primary><Date_Primary>2009/4</Date_Primary><Keywords>Adult</Keywords><Keywords>Aged</Keywords><Keywords>Aged,80 and over</Keywords><Keywords>Aging</Keywords><Keywords>blood</Keywords><Keywords>Body Mass Index</Keywords><Keywords>Cardiovascular Diseases</Keywords><Keywords>Cholesterol</Keywords><Keywords>Cholesterol,HDL</Keywords><Keywords>Cross-Sectional Studies</Keywords><Keywords>epidemiology</Keywords><Keywords>ethnology</Keywords><Keywords>Female</Keywords><Keywords>Health</Keywords><Keywords>Hong Kong</Keywords><Keywords>Humans</Keywords><Keywords>Hypercholesterolemia</Keywords><Keywords>Male</Keywords><Keywords>Middle Aged</Keywords><Keywords>Nutrition Surveys</Keywords><Keywords>pharmacology</Keywords><Keywords>Prevalence</Keywords><Keywords>Risk</Keywords><Keywords>Risk Factors</Keywords><Keywords>Sex Characteristics</Keywords><Keywords>Smoking</Keywords><Keywords>Triglycerides</Keywords><Keywords>United States</Keywords><Reprint>Not in File</Reprint><Start_Page>561</Start_Page><End_Page>568</End_Page><Periodical>Clin.Endocrinol.(Oxf)</Periodical><Volume>70</Volume><Issue>4</Issue><Address>Department of Clinical Pharmacology, School of Clinical and Experimental Medicine, University of Birmingham, England. b.cheung@bham.ac.uk</Address><Web_URL>PM:18715284</Web_URL><ZZ_JournalStdAbbrev><f name="System">Clin.Endocrinol.(Oxf)</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>25] Sex-related differences in the effect of vitamin E supplementation on all-cause mortality have been reported, with stronger protective effects of low-dose vitamin E supplementation evident in study populations comprised of ≥75% women.[ ADDIN REFMGR.CITE <Refman><Cite><Author>Gerss</Author><Year>2010</Year><RecNum>108</RecNum><IDText>The association of vitamin E supplementation and mortality - finally consistent results of statistical analysis. RE: The questionable association of vitamin E supplementation and mortality - inconsistent results of different meta-analytic approaches</IDText><MDL Ref_Type="Generic"><Ref_Type>Generic</Ref_Type><Ref_ID>108</Ref_ID><Title_Primary>The association of vitamin E supplementation and mortality - finally consistent results of statistical analysis. RE: The questionable association of vitamin E supplementation and mortality - inconsistent results of different meta-analytic approaches</Title_Primary><Authors_Primary>Gerss,J.</Authors_Primary><Date_Primary>2010</Date_Primary><Keywords>Vitamin E</Keywords><Keywords>mortality</Keywords><Keywords>analysis</Keywords><Reprint>Not in File</Reprint><Start_Page>OL1266</Start_Page><End_Page>OL1267</End_Page><Periodical>Cell Mol.Biol.(Noisy.-le-grand)</Periodical><Volume>56</Volume><ZZ_JournalStdAbbrev><f name="System">Cell Mol.Biol.(Noisy.-le-grand)</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>33</ZZ_WorkformID></MDL></Cite></Refman>26]Alcohol intake is proposed to reduce CVD risk by raising HDL cholesterol levels, and a threshold of > 1 drink per day is associated with both higher HDL cholesterol levels and attenuation in CVD risk.[ ADDIN REFMGR.CITE <Refman><Cite><Author>De Oliveira E Silva ER</Author><Year>2000</Year><RecNum>98</RecNum><IDText>Alcohol consumption raises HDL cholesterol levels by increasing the transport rate of apolipoproteins A-I and A-II</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>98</Ref_ID><Title_Primary>Alcohol consumption raises HDL cholesterol levels by increasing the transport rate of apolipoproteins A-I and A-II</Title_Primary><Authors_Primary>De Oliveira E Silva ER</Authors_Primary><Authors_Primary>Foster,D.</Authors_Primary><Authors_Primary>McGee,Harper M.</Authors_Primary><Authors_Primary>Seidman,C.E.</Authors_Primary><Authors_Primary>Smith,J.D.</Authors_Primary><Authors_Primary>Breslow,J.L.</Authors_Primary><Authors_Primary>Brinton,E.A.</Authors_Primary><Date_Primary>2000/11/7</Date_Primary><Keywords>Adult</Keywords><Keywords>Aged</Keywords><Keywords>Alcohol Drinking</Keywords><Keywords>Apolipoprotein A-I</Keywords><Keywords>Apolipoprotein A-II</Keywords><Keywords>Biological Transport</Keywords><Keywords>blood</Keywords><Keywords>Cholesterol</Keywords><Keywords>Cholesterol,HDL</Keywords><Keywords>Diet</Keywords><Keywords>Female</Keywords><Keywords>Humans</Keywords><Keywords>Male</Keywords><Keywords>metabolism</Keywords><Keywords>methods</Keywords><Keywords>Middle Aged</Keywords><Keywords>Risk</Keywords><Reprint>Not in File</Reprint><Start_Page>2347</Start_Page><End_Page>2352</End_Page><Periodical>Circulation</Periodical><Volume>102</Volume><Issue>19</Issue><Address>Rockefeller University, New York, NY, USA</Address><Web_URL>PM:11067787</Web_URL><ZZ_JournalStdAbbrev><f name="System">Circulation</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Foerster</Author><Year>2009</Year><RecNum>96</RecNum><IDText>Alcohol drinking and cardiovascular risk in a population with high mean alcohol consumption</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>96</Ref_ID><Title_Primary>Alcohol drinking and cardiovascular risk in a population with high mean alcohol consumption</Title_Primary><Authors_Primary>Foerster,M.</Authors_Primary><Authors_Primary>Marques-Vidal,P.</Authors_Primary><Authors_Primary>Gmel,G.</Authors_Primary><Authors_Primary>Daeppen,J.B.</Authors_Primary><Authors_Primary>Cornuz,J.</Authors_Primary><Authors_Primary>Hayoz,D.</Authors_Primary><Authors_Primary>Pecoud,A.</Authors_Primary><Authors_Primary>Mooser,V.</Authors_Primary><Authors_Primary>Waeber,G.</Authors_Primary><Authors_Primary>Vollenweider,P.</Authors_Primary><Authors_Primary>Paccaud,F.</Authors_Primary><Authors_Primary>Rodondi,N.</Authors_Primary><Date_Primary>2009/2/1</Date_Primary><Keywords>Adult</Keywords><Keywords>adverse effects</Keywords><Keywords>Aged</Keywords><Keywords>Alcohol Drinking</Keywords><Keywords>analysis</Keywords><Keywords>blood</Keywords><Keywords>Blood Pressure</Keywords><Keywords>C-Reactive Protein</Keywords><Keywords>Cardiovascular Diseases</Keywords><Keywords>Cholesterol</Keywords><Keywords>Cholesterol,HDL</Keywords><Keywords>Cholesterol,LDL</Keywords><Keywords>Disease</Keywords><Keywords>etiology</Keywords><Keywords>Female</Keywords><Keywords>Humans</Keywords><Keywords>Lipids</Keywords><Keywords>Male</Keywords><Keywords>Middle Aged</Keywords><Keywords>physiopathology</Keywords><Keywords>Risk</Keywords><Keywords>Risk Factors</Keywords><Keywords>Triglycerides</Keywords><Reprint>Not in File</Reprint><Start_Page>361</Start_Page><End_Page>368</End_Page><Periodical>Am.J.Cardiol.</Periodical><Volume>103</Volume><Issue>3</Issue><Address>Institute of Social and Preventive Medicine, University of Lausanne, Lausanne, Switzerland</Address><Web_URL>PM:19166690</Web_URL><ZZ_JournalStdAbbrev><f name="System">Am.J.Cardiol.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>27,28] Given the important role of HDL cholesterol in transporting vitamin E to the lung, exploratory analyses considered alcohol intake as a modifier of the effect of vitamin E on CLD. Among variables considered as possible effect modifiers, alcohol intake was marginally statistically significant (p=0.054), and the preventive effect of vitamin E on CLD was greatest in women consuming the highest level of alcohol (> 1 drink/day). These preliminary findings are consistent with the hypothesis that delivery of vitamin E to lung tissue may vary by plasma levels of HDL cholesterol.Under our hypothesis, the effect of antioxidant supplementation was expected to be stronger in participants with a higher oxidative burden, for example, in current cigarette smokers. Contrary to expectation, there was no evidence of effect modification by smoking. If supplementation with vitamin E acts through other systemic mechanisms, for example by improving immune system function (Meydani 2005), then a general effect of vitamin E would be supported. ADDIN REFMGR.CITE <Refman><Cite><Author>Meydani</Author><Year>2005</Year><RecNum>113</RecNum><IDText>Vitamin E and immune response in the aged: molecular mechanisms and clinical implications</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>113</Ref_ID><Title_Primary>Vitamin E and immune response in the aged: molecular mechanisms and clinical implications</Title_Primary><Authors_Primary>Meydani,S.N.</Authors_Primary><Authors_Primary>Han,S.N.</Authors_Primary><Authors_Primary>Wu,D.</Authors_Primary><Date_Primary>2005/6</Date_Primary><Keywords>Aged</Keywords><Keywords>Aging</Keywords><Keywords>Animals</Keywords><Keywords>diet therapy</Keywords><Keywords>Dinoprostone</Keywords><Keywords>drug effects</Keywords><Keywords>Humans</Keywords><Keywords>Hypersensitivity</Keywords><Keywords>Immune System</Keywords><Keywords>immunology</Keywords><Keywords>Infection</Keywords><Keywords>metabolism</Keywords><Keywords>Mice</Keywords><Keywords>Nutritional Status</Keywords><Keywords>pharmacology</Keywords><Keywords>Risk</Keywords><Keywords>T-Lymphocytes</Keywords><Keywords>therapeutic use</Keywords><Keywords>Vitamin E</Keywords><Reprint>Not in File</Reprint><Start_Page>269</Start_Page><End_Page>284</End_Page><Periodical>Immunol.Rev.</Periodical><Volume>205</Volume><Address>Nutritional Immunology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA. simin.meydani@tufts.edu</Address><Web_URL>PM:15882360</Web_URL><ZZ_JournalStdAbbrev><f name="System">Immunol.Rev.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>[29] Efficacy and Safety ConsiderationsThere has been substantial discussion of the efficacy and safety of vitamin E supplementation in the scientific literature. ADDIN REFMGR.CITE <Refman><Cite><Author>Bell</Author><Year>2008</Year><RecNum>103</RecNum><IDText>How safe is vitamin E supplementation?</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>103</Ref_ID><Title_Primary>How safe is vitamin E supplementation?</Title_Primary><Authors_Primary>Bell,S.J.</Authors_Primary><Authors_Primary>Grochoski,G.T.</Authors_Primary><Date_Primary>2008/9</Date_Primary><Keywords>administration &amp; dosage</Keywords><Keywords>adverse effects</Keywords><Keywords>Cardiovascular Diseases</Keywords><Keywords>Dietary Supplements</Keywords><Keywords>Eye Diseases</Keywords><Keywords>Humans</Keywords><Keywords>Meta-Analysis as Topic</Keywords><Keywords>mortality</Keywords><Keywords>Neoplasms</Keywords><Keywords>Nervous System Diseases</Keywords><Keywords>pharmacology</Keywords><Keywords>Practice Guidelines as Topic</Keywords><Keywords>prevention &amp; control</Keywords><Keywords>Respiratory Tract Infections</Keywords><Keywords>Risk</Keywords><Keywords>Vitamin E</Keywords><Reprint>Not in File</Reprint><Start_Page>760</Start_Page><End_Page>774</End_Page><Periodical>Crit Rev.Food Sci.Nutr.</Periodical><Volume>48</Volume><Issue>8</Issue><Address>Research and Development, Nutritional Sciences IdeaSphere Inc., SE Grand Rapids, MI 49546, USA. staceyjbell@</Address><Web_URL>PM:18756398</Web_URL><ZZ_JournalStdAbbrev><f name="System">Crit Rev.Food Sci.Nutr.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>[30] Potential harmful effects include an increased risk of all cause mortality, susceptibility to bleeding, and haemorrhagic stroke. ADDIN REFMGR.CITE <Refman><Cite><Author>Miller</Author><Year>2005</Year><RecNum>100</RecNum><IDText>Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>100</Ref_ID><Title_Primary>Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality</Title_Primary><Authors_Primary>Miller,E.R.,III</Authors_Primary><Authors_Primary>Pastor-Barriuso,R.</Authors_Primary><Authors_Primary>Dalal,D.</Authors_Primary><Authors_Primary>Riemersma,R.A.</Authors_Primary><Authors_Primary>Appel,L.J.</Authors_Primary><Authors_Primary>Guallar,E.</Authors_Primary><Date_Primary>2005/1/4</Date_Primary><Keywords>administration &amp; dosage</Keywords><Keywords>Adult</Keywords><Keywords>adverse effects</Keywords><Keywords>analysis</Keywords><Keywords>Dietary Supplements</Keywords><Keywords>Disease</Keywords><Keywords>Dose-Response Relationship,Drug</Keywords><Keywords>epidemiology</Keywords><Keywords>Humans</Keywords><Keywords>mortality</Keywords><Keywords>Randomized Controlled Trials as Topic</Keywords><Keywords>Risk</Keywords><Keywords>Sensitivity and Specificity</Keywords><Keywords>Vitamin E</Keywords><Keywords>Vitamins</Keywords><Reprint>Not in File</Reprint><Start_Page>37</Start_Page><End_Page>46</End_Page><Periodical>Ann.Intern.Med.</Periodical><Volume>142</Volume><Issue>1</Issue><Address>The Johns Hopkins School of Medicine, and The Welch Center for Prevention, Epidemiology and Clinical Research, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205-2223, USA. ermiller@jhmi.edu</Address><Web_URL>PM:15537682</Web_URL><ZZ_JournalStdAbbrev><f name="System">Ann.Intern.Med.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Violi</Author><Year>2010</Year><RecNum>109</RecNum><IDText>Nutrition, supplements, and vitamins in platelet function and bleeding</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>109</Ref_ID><Title_Primary>Nutrition, supplements, and vitamins in platelet function and bleeding</Title_Primary><Authors_Primary>Violi,F.</Authors_Primary><Authors_Primary>Pignatelli,P.</Authors_Primary><Authors_Primary>Basili,S.</Authors_Primary><Date_Primary>2010/3/2</Date_Primary><Keywords>Atherosclerosis</Keywords><Keywords>Blood Platelets</Keywords><Keywords>Dietary Supplements</Keywords><Keywords>Hemorrhage</Keywords><Keywords>Humans</Keywords><Keywords>Nutrition Therapy</Keywords><Keywords>physiology</Keywords><Keywords>physiopathology</Keywords><Keywords>Platelet Aggregation Inhibitors</Keywords><Keywords>prevention &amp; control</Keywords><Keywords>therapeutic use</Keywords><Keywords>Vitamins</Keywords><Reprint>Not in File</Reprint><Start_Page>1033</Start_Page><End_Page>1044</End_Page><Periodical>Circulation</Periodical><Volume>121</Volume><Issue>8</Issue><Address>Divisione I Clinica Medica, Universita Sapienza, Viale del Policlinico 155, Roma, 00161, Italy. francesco.violi@uniroma1.it</Address><Web_URL>PM:20194876</Web_URL><ZZ_JournalStdAbbrev><f name="System">Circulation</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Schurks</Author><RecNum>110</RecNum><IDText>Effects of vitamin E on stoke subtypes: meta-analysis of randomised controlled trials</IDText><MDL Ref_Type="Generic"><Ref_Type>Generic</Ref_Type><Ref_ID>110</Ref_ID><Title_Primary>Effects of vitamin E on stoke subtypes: meta-analysis of randomised controlled trials</Title_Primary><Authors_Primary>Schurks,M.</Authors_Primary><Authors_Primary>Glynn,R.J.</Authors_Primary><Authors_Primary>Rist,P.M.</Authors_Primary><Authors_Primary>Tzourio,C.</Authors_Primary><Authors_Primary>Kurth,T.</Authors_Primary><Keywords>Vitamin E</Keywords><Reprint>Not in File</Reprint><Periodical>BMJ</Periodical><ZZ_JournalFull><f name="System">BMJ</f></ZZ_JournalFull><ZZ_WorkformID>33</ZZ_WorkformID></MDL></Cite></Refman>[31-33] The meta-analysis linking high-dose vitamin E supplementation to increased risk of mortality, however, has been criticised for its methodology and a recent paper suggested that vitamin E has beneficial effects on ischemic stroke risk. ADDIN REFMGR.CITE <Refman><Cite><Author>Schurks</Author><RecNum>110</RecNum><IDText>Effects of vitamin E on stoke subtypes: meta-analysis of randomised controlled trials</IDText><MDL Ref_Type="Generic"><Ref_Type>Generic</Ref_Type><Ref_ID>110</Ref_ID><Title_Primary>Effects of vitamin E on stoke subtypes: meta-analysis of randomised controlled trials</Title_Primary><Authors_Primary>Schurks,M.</Authors_Primary><Authors_Primary>Glynn,R.J.</Authors_Primary><Authors_Primary>Rist,P.M.</Authors_Primary><Authors_Primary>Tzourio,C.</Authors_Primary><Authors_Primary>Kurth,T.</Authors_Primary><Keywords>Vitamin E</Keywords><Reprint>Not in File</Reprint><Periodical>BMJ</Periodical><ZZ_JournalFull><f name="System">BMJ</f></ZZ_JournalFull><ZZ_WorkformID>33</ZZ_WorkformID></MDL></Cite><Cite><Author>Gerss</Author><Year>2009</Year><RecNum>101</RecNum><IDText>The questionable association of vitamin E supplementation and mortality--inconsistent results of different meta-analytic approaches</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>101</Ref_ID><Title_Primary>The questionable association of vitamin E supplementation and mortality--inconsistent results of different meta-analytic approaches</Title_Primary><Authors_Primary>Gerss,J.</Authors_Primary><Authors_Primary>Kopcke,W.</Authors_Primary><Date_Primary>2009</Date_Primary><Keywords>administration &amp; dosage</Keywords><Keywords>adverse effects</Keywords><Keywords>analysis</Keywords><Keywords>Clinical Trials as Topic</Keywords><Keywords>Dietary Supplements</Keywords><Keywords>Disease</Keywords><Keywords>Female</Keywords><Keywords>Humans</Keywords><Keywords>Male</Keywords><Keywords>Meta-Analysis as Topic</Keywords><Keywords>mortality</Keywords><Keywords>Odds Ratio</Keywords><Keywords>Sex Factors</Keywords><Keywords>Vitamin E</Keywords><Reprint>Not in File</Reprint><Start_Page>OL1111</Start_Page><End_Page>OL1120</End_Page><Periodical>Cell Mol.Biol.(Noisy.-le-grand)</Periodical><Volume>55 Suppl</Volume><Address>University of Munster, Department of Medical Informatics and Biomathematics, Munster, Germany. joachim.gerss@ukmuenster.de</Address><Web_URL>PM:19267994</Web_URL><ZZ_JournalStdAbbrev><f name="System">Cell Mol.Biol.(Noisy.-le-grand)</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Berry</Author><Year>2009</Year><RecNum>102</RecNum><IDText>Bayesian model averaging in meta-analysis: vitamin E supplementation and mortality</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>102</Ref_ID><Title_Primary>Bayesian model averaging in meta-analysis: vitamin E supplementation and mortality</Title_Primary><Authors_Primary>Berry,D.</Authors_Primary><Authors_Primary>Wathen,J.K.</Authors_Primary><Authors_Primary>Newell,M.</Authors_Primary><Date_Primary>2009/2</Date_Primary><Keywords>administration &amp; dosage</Keywords><Keywords>adverse effects</Keywords><Keywords>alpha-Tocopherol</Keywords><Keywords>Antioxidants</Keywords><Keywords>Bayes Theorem</Keywords><Keywords>Data Collection</Keywords><Keywords>Data Interpretation,Statistical</Keywords><Keywords>Dietary Supplements</Keywords><Keywords>Dose-Response Relationship,Drug</Keywords><Keywords>Humans</Keywords><Keywords>Meta-Analysis as Topic</Keywords><Keywords>methods</Keywords><Keywords>Monte Carlo Method</Keywords><Keywords>mortality</Keywords><Keywords>Vitamin E</Keywords><Keywords>Vitamins</Keywords><Reprint>Not in File</Reprint><Start_Page>28</Start_Page><End_Page>41</End_Page><Periodical>Clin.Trials</Periodical><Volume>6</Volume><Issue>1</Issue><Address>Department of Biostatistics, University of Texas, MD Anderson Cancer Center, Houston, TX, USA. dberry@</Address><Web_URL>PM:19254931</Web_URL><ZZ_JournalStdAbbrev><f name="System">Clin.Trials</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>[33-35] Thus, the design of future vitamin E supplementation trials must carefully consider information about risks and benefits, and recommendations may need to be tailored to specific populations.Summary and ConclusionThe WHS was comprised of female health professionals aged > 45, the majority of whom were of European descent. Healthy women taking 600 IU vitamin E supplements every other day were 10% less likely to report a new chronic lung disease diagnosis during the study period. Any decisions about use of vitamin E as a preventive must consider information about vitamin E associated risks and bioavailability. ADDIN REFMGR.CITE <Refman><Cite><Author>Gerss</Author><Year>2010</Year><RecNum>108</RecNum><IDText>The association of vitamin E supplementation and mortality - finally consistent results of statistical analysis. RE: The questionable association of vitamin E supplementation and mortality - inconsistent results of different meta-analytic approaches</IDText><MDL Ref_Type="Generic"><Ref_Type>Generic</Ref_Type><Ref_ID>108</Ref_ID><Title_Primary>The association of vitamin E supplementation and mortality - finally consistent results of statistical analysis. RE: The questionable association of vitamin E supplementation and mortality - inconsistent results of different meta-analytic approaches</Title_Primary><Authors_Primary>Gerss,J.</Authors_Primary><Date_Primary>2010</Date_Primary><Keywords>Vitamin E</Keywords><Keywords>mortality</Keywords><Keywords>analysis</Keywords><Reprint>Not in File</Reprint><Start_Page>OL1266</Start_Page><End_Page>OL1267</End_Page><Periodical>Cell Mol.Biol.(Noisy.-le-grand)</Periodical><Volume>56</Volume><ZZ_JournalStdAbbrev><f name="System">Cell Mol.Biol.(Noisy.-le-grand)</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>33</ZZ_WorkformID></MDL></Cite><Cite><Author>Bell</Author><Year>2008</Year><RecNum>103</RecNum><IDText>How safe is vitamin E supplementation?</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>103</Ref_ID><Title_Primary>How safe is vitamin E supplementation?</Title_Primary><Authors_Primary>Bell,S.J.</Authors_Primary><Authors_Primary>Grochoski,G.T.</Authors_Primary><Date_Primary>2008/9</Date_Primary><Keywords>administration &amp; dosage</Keywords><Keywords>adverse effects</Keywords><Keywords>Cardiovascular Diseases</Keywords><Keywords>Dietary Supplements</Keywords><Keywords>Eye Diseases</Keywords><Keywords>Humans</Keywords><Keywords>Meta-Analysis as Topic</Keywords><Keywords>mortality</Keywords><Keywords>Neoplasms</Keywords><Keywords>Nervous System Diseases</Keywords><Keywords>pharmacology</Keywords><Keywords>Practice Guidelines as Topic</Keywords><Keywords>prevention &amp; control</Keywords><Keywords>Respiratory Tract Infections</Keywords><Keywords>Risk</Keywords><Keywords>Vitamin E</Keywords><Reprint>Not in File</Reprint><Start_Page>760</Start_Page><End_Page>774</End_Page><Periodical>Crit Rev.Food Sci.Nutr.</Periodical><Volume>48</Volume><Issue>8</Issue><Address>Research and Development, Nutritional Sciences IdeaSphere Inc., SE Grand Rapids, MI 49546, USA. staceyjbell@</Address><Web_URL>PM:18756398</Web_URL><ZZ_JournalStdAbbrev><f name="System">Crit Rev.Food Sci.Nutr.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Violi</Author><Year>2010</Year><RecNum>109</RecNum><IDText>Nutrition, supplements, and vitamins in platelet function and bleeding</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>109</Ref_ID><Title_Primary>Nutrition, supplements, and vitamins in platelet function and bleeding</Title_Primary><Authors_Primary>Violi,F.</Authors_Primary><Authors_Primary>Pignatelli,P.</Authors_Primary><Authors_Primary>Basili,S.</Authors_Primary><Date_Primary>2010/3/2</Date_Primary><Keywords>Atherosclerosis</Keywords><Keywords>Blood Platelets</Keywords><Keywords>Dietary Supplements</Keywords><Keywords>Hemorrhage</Keywords><Keywords>Humans</Keywords><Keywords>Nutrition Therapy</Keywords><Keywords>physiology</Keywords><Keywords>physiopathology</Keywords><Keywords>Platelet Aggregation Inhibitors</Keywords><Keywords>prevention &amp; control</Keywords><Keywords>therapeutic use</Keywords><Keywords>Vitamins</Keywords><Reprint>Not in File</Reprint><Start_Page>1033</Start_Page><End_Page>1044</End_Page><Periodical>Circulation</Periodical><Volume>121</Volume><Issue>8</Issue><Address>Divisione I Clinica Medica, Universita Sapienza, Viale del Policlinico 155, Roma, 00161, Italy. francesco.violi@uniroma1.it</Address><Web_URL>PM:20194876</Web_URL><ZZ_JournalStdAbbrev><f name="System">Circulation</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Schurks</Author><Year>2010</Year><RecNum>114</RecNum><IDText>Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>114</Ref_ID><Title_Primary>Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials</Title_Primary><Authors_Primary>Schurks,M.</Authors_Primary><Authors_Primary>Glynn,R.J.</Authors_Primary><Authors_Primary>Rist,P.M.</Authors_Primary><Authors_Primary>Tzourio,C.</Authors_Primary><Authors_Primary>Kurth,T.</Authors_Primary><Date_Primary>2010</Date_Primary><Keywords>administration &amp; dosage</Keywords><Keywords>Adult</Keywords><Keywords>adverse effects</Keywords><Keywords>Aged</Keywords><Keywords>Brain Ischemia</Keywords><Keywords>chemically induced</Keywords><Keywords>Confidence Intervals</Keywords><Keywords>Dietary Supplements</Keywords><Keywords>Humans</Keywords><Keywords>Intracranial Hemorrhages</Keywords><Keywords>methods</Keywords><Keywords>Middle Aged</Keywords><Keywords>prevention &amp; control</Keywords><Keywords>Randomized Controlled Trials as Topic</Keywords><Keywords>Risk</Keywords><Keywords>Risk Factors</Keywords><Keywords>Stroke</Keywords><Keywords>Vitamin E</Keywords><Keywords>Vitamins</Keywords><Reprint>Not in File</Reprint><Start_Page>c5702</Start_Page><Periodical>BMJ</Periodical><Volume>341</Volume><Address>Division of Preventive Medicine, Department of Medicine; Brigham and Women&apos;s Hospital, Harvard Medical School, Boston, MA 02215-1204, USA. mschuerks@rics.bwh.harvard.edu</Address><Web_URL>PM:21051774</Web_URL><ZZ_JournalFull><f name="System">BMJ</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Gerss</Author><Year>2009</Year><RecNum>101</RecNum><IDText>The questionable association of vitamin E supplementation and mortality--inconsistent results of different meta-analytic approaches</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>101</Ref_ID><Title_Primary>The questionable association of vitamin E supplementation and mortality--inconsistent results of different meta-analytic approaches</Title_Primary><Authors_Primary>Gerss,J.</Authors_Primary><Authors_Primary>Kopcke,W.</Authors_Primary><Date_Primary>2009</Date_Primary><Keywords>administration &amp; dosage</Keywords><Keywords>adverse effects</Keywords><Keywords>analysis</Keywords><Keywords>Clinical Trials as Topic</Keywords><Keywords>Dietary Supplements</Keywords><Keywords>Disease</Keywords><Keywords>Female</Keywords><Keywords>Humans</Keywords><Keywords>Male</Keywords><Keywords>Meta-Analysis as Topic</Keywords><Keywords>mortality</Keywords><Keywords>Odds Ratio</Keywords><Keywords>Sex Factors</Keywords><Keywords>Vitamin E</Keywords><Reprint>Not in File</Reprint><Start_Page>OL1111</Start_Page><End_Page>OL1120</End_Page><Periodical>Cell Mol.Biol.(Noisy.-le-grand)</Periodical><Volume>55 Suppl</Volume><Address>University of Munster, Department of Medical Informatics and Biomathematics, Munster, Germany. joachim.gerss@ukmuenster.de</Address><Web_URL>PM:19267994</Web_URL><ZZ_JournalStdAbbrev><f name="System">Cell Mol.Biol.(Noisy.-le-grand)</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Berry</Author><Year>2009</Year><RecNum>102</RecNum><IDText>Bayesian model averaging in meta-analysis: vitamin E supplementation and mortality</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>102</Ref_ID><Title_Primary>Bayesian model averaging in meta-analysis: vitamin E supplementation and mortality</Title_Primary><Authors_Primary>Berry,D.</Authors_Primary><Authors_Primary>Wathen,J.K.</Authors_Primary><Authors_Primary>Newell,M.</Authors_Primary><Date_Primary>2009/2</Date_Primary><Keywords>administration &amp; dosage</Keywords><Keywords>adverse effects</Keywords><Keywords>alpha-Tocopherol</Keywords><Keywords>Antioxidants</Keywords><Keywords>Bayes Theorem</Keywords><Keywords>Data Collection</Keywords><Keywords>Data Interpretation,Statistical</Keywords><Keywords>Dietary Supplements</Keywords><Keywords>Dose-Response Relationship,Drug</Keywords><Keywords>Humans</Keywords><Keywords>Meta-Analysis as Topic</Keywords><Keywords>methods</Keywords><Keywords>Monte Carlo Method</Keywords><Keywords>mortality</Keywords><Keywords>Vitamin E</Keywords><Keywords>Vitamins</Keywords><Reprint>Not in File</Reprint><Start_Page>28</Start_Page><End_Page>41</End_Page><Periodical>Clin.Trials</Periodical><Volume>6</Volume><Issue>1</Issue><Address>Department of Biostatistics, University of Texas, MD Anderson Cancer Center, Houston, TX, USA. dberry@</Address><Web_URL>PM:19254931</Web_URL><ZZ_JournalStdAbbrev><f name="System">Clin.Trials</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>[22,26,30,32,34,35] Given that there are few prevention strategies for emphysema and chronic bronchitis, further study of vitamin E in relation to chronic obstructive pulmonary disease is of public health interest. ACKNOWLEDGEMENTSWe are indebted to the participants in the Women’s Health Study for their outstanding commitment and cooperation, to the entire staff of the Women’s Health Study for their expert assistance, and to the Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. ETHICS APPROVALThe Women’s Health Study was approved by the institutional review board of Brigham and Women’s Hospital and monitored by an external data and safety monitoring board. COMPETING INTERESTSNoneFUNDINGThis study was funded by grants from the National Institutes for Health, USA, grants NIH HL071022 (PAC); NIH HL043851 and CA47988 (Women’s Health Study). Funding sources had no involvement in study design, data collection, analyses, or interpretation, writing of the report, or decision to submit the report for publication.COPYRIGHTThe Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence on a worldwide basis to the BMJ Publishing Group Ltd, and its Licensees to permit this article (if accepted) to be published in Thorax and any other BMJPGL products and to exploit all subsidiary rights, as set out in our licence, . ADDIN REFMGR.REFLIST Reference List1 Lopez AD, Shibuya K, Rao C, Mathers CD, Hansell AL, Held LS, et al. Chronic obstructive pulmonary disease: current burden and future projections. Eur Respir J 2006;27:397-412.2 Buist AS, Vollmer WM, McBurnie MA. Worldwide burden of COPD in high- and low-income countries. Part I. The burden of obstructive lung disease (BOLD) initiative. Int J Tuberc Lung Dis 2008;12:703-8.3 Lopez AD, Murray CC. The global burden of disease, 1990-2020. Nat Med 1998;4:1241-3.4 Varraso R, Fung TT, Barr RG, Hu FB, Willett W, Camargo CA, Jr. Prospective study of dietary patterns and chronic obstructive pulmonary disease among US women. Am J Clin Nutr 2007;86:488-95.5 Sood A, Qualls C, Arynchyn A, Beckett WS, Gross MD, Steffes MW, et al. Obesity-Asthma Association: Is It Explained by Systemic Oxidant Stress? Chest 2009;108:744-53.6 Smit HA, Grievink L, Tabak C. Dietary influences on chronic obstructive lung disease and asthma: a review of the epidemiological evidence. Proc Nutr Soc 1999;58:309-19.7 Romieu I, Trenga C. Diet and obstructive lung diseases. Epidemiol Rev 2001;23:268-87.8 Hu G, Cassano PA. Antioxidant nutrients and pulmonary function: the Third National Health and Nutrition Examination Survey (NHANES III). Am J Epidemiol;151:975-81.9 Grievink L, Smit HA, Ocke MC, van't Veer P, Kromhout D. Dietary intake of antioxidant (pro)-vitamins, respiratory symptoms and pulmonary function: the MORGEN study. Thorax 1998;53:166-71.10 McKeever TM, Lewis SA, Smit HA, Burney P, Cassano PA, Britton J. A multivariate analysis of serum nutrient levels and lung function. Respir Res 2008;9:67-76.11 Gosker HR, Bast A, Haenen GR, Fischer MA, van d, V, Wouters EF, et al. Altered antioxidant status in peripheral skeletal muscle of patients with COPD. Respir Med 2005;99:118-25.12 Wright ME, Lawson KA, Weinstein SJ, Pietinen P, Taylor PR, Virtamo J, et al. Higher baseline serum concentrations of vitamin E are associated with lower total and cause-specific mortality in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Am J Clin Nutr 2006;84:1200-7.13 Keranis E, Makris D, Rodopoulou P, Martinou H, Papamakarios G, Daniil Z, et al. Impact of dietary shift to higher antioxidant foods in COPD: A Randomized Trial. Eur Respir J 2010;36:774-80.14 Daga MK, Chhabra R, Sharma B, Mishra TK. Effects of exogenous vitamin E supplementation on the levels of oxidants and antioxidants in chronic obstructive pulmonary disease. J Biosci 2003;28:7-11.15 Nadeem A, Raj HG, Chhabra SK. Effect of vitamin E supplementation with standard treatment on oxidant-antioxidant status in chronic obstructive pulmonary disease. Indian J Med Res 2008;128:705-11.16 Rautalahti M, Virtamo J, Haukka J, Heinonen OP, Sundvall J, Albanes D, et al. The effect of alpha-tocopherol and beta-carotene supplementation on COPD symptoms. Am J Respir Crit Care Med 1997;156:1447-52.17 MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:23-33.18 Rexrode KM, Lee IM, Cook NR, Hennekens CH, Buring JE. Baseline characteristics of participants in the Women's Health Study. J Womens Health Gend Based Med 2000;9:19-27.19 Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE, et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. JAMA 2005;294:56-65.20 Barr RG, Herbstman J, Speizer FE, Camargo CA, Jr. Validation of self-reported chronic obstructive pulmonary disease in a cohort study of nurses. Am J Epidemiol 2002;155:965-71.21 Tinkelman DG, Price DB, Nordyke RJ, Halbert RJ. Misdiagnosis of COPD and asthma in primary care patients 40 years of age and over. J Asthma 2006;43:75-80.22 Schurks M, Glynn RJ, Rist PM, Tzourio C, Kurth T. Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials. BMJ 2010;341:c5702.23 Kolleck I, Sinha P, Rustow B. Vitamin E as an antioxidant of the lung: mechanisms of vitamin E delivery to alveolar type II cells. Am J Respir Crit Care Med 2002;166:S62-S66.24 Cirillo DJ, Agrawal Y, Cassano PA. Lipids and pulmonary function in the Third National Health and Nutrition Examination Survey. Am J Epidemiol 2002;155:842-8.25 Cheung BM, Li M, Ong KL, Wat NM, Tam S, Pang RW, et al. High density lipoprotein-cholesterol levels increase with age in American women but not in Hong Kong Chinese women. Clin Endocrinol (Oxf) 2009;70:561-8.26 Gerss J. The association of vitamin E supplementation and mortality - finally consistent results of statistical analysis. RE: The questionable association of vitamin E supplementation and mortality - inconsistent results of different meta-analytic approaches. Cell Mol.Biol.(Noisy.-le-grand) 2010;56:OL1266-OL1267.27 De Oliveira E Silva ER, Foster D, McGee HM, Seidman CE, Smith JD, Breslow JL, et al. Alcohol consumption raises HDL cholesterol levels by increasing the transport rate of apolipoproteins A-I and A-II. Circulation 2000;102:2347-52.28 Foerster M, Marques-Vidal P, Gmel G, Daeppen JB, Cornuz J, Hayoz D, et al. Alcohol drinking and cardiovascular risk in a population with high mean alcohol consumption. Am J Cardiol 2009;103:361-8.29 Meydani SN, Han SN, Wu D. Vitamin E and immune response in the aged: molecular mechanisms and clinical implications. Immunol Rev 2005;205:269-84.30 Bell SJ, Grochoski GT. How safe is vitamin E supplementation? Crit Rev Food Sci Nutr 2008;48:760-74.31 Miller ER, III, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37-46.32 Violi F, Pignatelli P, Basili S. Nutrition, supplements, and vitamins in platelet function and bleeding. Circulation 2010;121:1033-44.33 Schurks M, Glynn RJ, Rist PM, Tzourio C, Kurth T. Effects of vitamin E on stoke subtypes: meta-analysis of randomised controlled trials. BMJ 2010;341:C5702. 34 Gerss J, Kopcke W. The questionable association of vitamin E supplementation and mortality--inconsistent results of different meta-analytic approaches. Cell Mol Biol (Noisy -le-grand) 2009;55Suppl:OL1111-OL1120.35 Berry D, Wathen JK, Newell M. Bayesian model averaging in meta-analysis: vitamin E supplementation and mortality. Clin Trials 2009;6:28-41.Figure LegendsFigure 1 Flow diagram of the vitamin E component of the Women’s Health Study chronic lung disease analysisFigure 2 Cumulative incidence of chronic lung disease during the randomized component of the Women’s Health StudyFigure 3 Effect modification of the vitamin E / chronic lung disease effect in the Women’s Health Study ................
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