Biomedical subjects

John E Connett

Publications and source records attributed to John E Connett.

At least 19 recordsLinked to original sources

PubMed2006

Transforming growth factor-beta1 polymorphisms, airway responsiveness and lung function decline in smokers.

Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation in the airways, parenchyma and vessels, which can cause a structural remodeling with increased fibrosis that narrows and fixes the airway lumen. Transforming growth factor-beta1 (TGF-beta1), a multifunctional growth factor, was reported to be increased in the airways of COPD patients. In this study, we hypothesized that polymorphisms in the TGF-beta1 gene would be associated with an accelerated rate of decline of forced expiratory volume in 1s (FEV(1)). Three polymorphisms, -509 (C-->T), +869 (T-->C) and +915 (G-->C), located in TGF-beta1 gene were genotyped. We determined the prevalence of these polymorphisms in 590 continuing smokers who had the fastest (n=283) and slowest (n=307) rate of decline of lung function from the NHLBI Lung Health Study. There was no association between these TGF-beta1 polymorphisms and the rate of decline of FEV(1), but in a post-hoc analysis the genotype distribution at +869 was significantly different between high and low responders to methacholine (P=0.04). These data suggest that the T-C polymorphism at position +869 in the TGF-beta1 gene contributes to airway hyperresponsiveness, but not to rapid decline of lung function.

Bronchoconstrictor Agents↗

PubMed2006

Association of Hck genetic polymorphisms with gene expression and COPD.

Polymorphonuclear leukocytes (PMNs) are major effector cells in the chronic airway inflammation in chronic obstructive pulmonary disease (COPD). PMN degranulation is associated with degradation of extracellular matrix and tissue damage. Hck is an essential molecule in the signaling pathway regulating PMN degranulation. We hypothesized that polymorphisms affect the expression level of Hck, which, in turn, modulates PMN mediator release and tissue damage and influences the development of COPD. Here we systematically investigated genetic tag polymorphisms of the Hck gene, Hck mRNA and protein expression pattern in PMNs, and PMN mediator release (myeloperoxidase) in 60 healthy white subjects, and assessed their association with the use of several genetic models. The association of genetic polymorphisms with COPD-related phenotypes was determined in the lung healthy study cohort (LHS). We identified a novel 15 bp insertion/deletion polymorphism (8,656 L/S) in intron 1 of the Hck gene, which was associated with differential expression of Hck protein and PMN myeloperoxidase release. In the LHS cohort, there was significant interaction between the 8,656 L/S polymorphism and smoking on baseline lung function and 8,656 L/S was associated with bronchodilator response. These data suggest that the insertion/deletion polymorphism could be a functional polymorphism of the Hck gene, may contribute to COPD pathogenesis and modify COPD-related phenotypes.

Adult↗

PubMed2006

Predictors of attendance and dropout at the Lung Health Study 11-year follow-up.

Participant attrition and attendance at follow-up were examined in a multicenter, randomized, clinical trial. The Lung Health Study (LHS) enrolled a total of 5887 adults to examine the impact of smoking cessation coupled with the use of an inhaled bronchodilator on chronic obstructive pulmonary disease (COPD). Of the initial LHS 1 volunteers still living at the time of enrolment in LHS 3 (5332), 4457 (84%) attended the LHS 3 clinic visit, a follow-up session to determine current smoking status and lung function. The average period between the beginning of LHS 1 and baseline interview for LHS 3 was 11 years. In univariate analyses, attenders were older, more likely female, more likely to be married, smoked fewer cigarettes per day, and were more likely to have children who smoked at the start of LHS 1 than non-attenders. Attenders were also less likely to experience respiratory symptoms, such as cough, but had decreased baseline lung function compared with non-attenders. Volunteers recruited via mass mailing were more likely to attend the long-term follow-up visit. Those recruited by public site, worksite, or referral methods were less likely to attend. In multivariate models, age, gender, cigarettes smoked per day, married status, and whether participants' children smoked were identified as significant predictors of attendance versus non-attendance at LHS 3 using stepwise logistic regression. Treatment condition (smoking intervention or usual care) was not a significant predictor of attendance at LHS 3. Older females who smoked less heavily were most likely to participate. These findings may be applied to improve participant recruitment and retention in future clinical trials.

Adult↗

PubMed2006

Contribution of alpha- and beta-defensins to lung function decline and infection in smokers: an association study.

BACKGROUND: Alpha-defensins, which are major constituents of neutrophil azurophilic granules, and beta-defensins, which are expressed in airway epithelial cells, could contribute to the pathogenesis of chronic obstructive pulmonary disease by amplifying cigarette smoke-induced and infection-induced inflammatory reactions leading to lung injury. In Japanese and Chinese populations, two different beta-defensin-1 polymorphisms have been associated with chronic obstructive pulmonary disease phenotypes. We conducted population-based association studies to test whether alpha-defensin and beta-defensin polymorphisms influenced smokers' susceptibility to lung function decline and susceptibility to lower respiratory infection in two groups of white participants in the Lung Health Study (275 = fast decline in lung function and 304 = no decline in lung function). METHODS: Subjects were genotyped for the alpha-defensin-1/alpha-defensin-3 copy number polymorphism and four beta-defensin-1 polymorphisms (G-20A, C-44G, G-52A and Val38Ile). RESULTS: There were no associations between individual polymorphisms or imputed haplotypes and rate of decline in lung function or susceptibility to infection. CONCLUSION: These findings suggest that, in a white population, the defensin polymorphisms tested may not be of importance in determining who develops abnormally rapid lung function decline or is susceptible to developing lower respiratory infections.

Adult↗

PubMed2006

Variability of spirometry in chronic obstructive pulmonary disease: results from two clinical trials.

OBJECTIVE: Our goal is to determine short-term intraindividual biologic and measurement variability in spirometry of patients with a wide range of stable chronic obstructive pulmonary disease severity, using datasets from the National Emphysema Treatment Trial (NETT) and the Lung Health Study (LHS). This may be applied to determine criteria that can be used to assess a clinically meaningful change in spirometry. METHODS: A total of 5,886 participants from the LHS and 1,215 participants from the NETT performed prebronchodilator spirometry during two baseline sessions. We analyzed varying criteria for absolute and percent change of FEV(1) and FVC to determine which criterion was met by 90% of the participants. RESULTS: The mean +/- SD FEV(1) for the initial session was 2.64 +/- 0.60 L (75.1 +/- 8.8% predicted) for the LHS and 0.68 +/- 0.22 L (23.7 +/- 6.5% predicted) for the NETT. The mean +/- SD number of days between test sessions was 24.9 +/- 17.1 for the LHS and 85.7 +/- 21.7 for the NETT. As the degree of obstruction increased, the intersession percent difference of FEV(1) increased. However, the absolute difference between tests remained relatively constant despite the severity of obstruction (0.106 +/- 0.10 L). Over 90% of participants had an intersession FEV(1) difference of less than 225 ml irrespective of the severity of obstruction. CONCLUSIONS: Absolute changes in FEV(1) rather than percent change should be used to determine whether patients with chronic obstructive pulmonary disease have improved or worsened between test sessions.

Aged↗

PubMed2006

Interferon gamma polymorphisms and their interaction with smoking are associated with lung function.

Interactions between genetic and environmental determinants are likely to be important in the pathogenesis of chronic obstructive pulmonary disease. We hypothesized that interferon gamma (IFNG) single nucleotide polymorphisms (SNPs) and their interaction with smoking are associated with the rate of decline or level of lung function in smokers. We studied four SNPs in IFNG in 585 non-Hispanic whites (NHW) who had the fastest (n =280) or the slowest (n=305) decline of FEV(1)% predicted selected from among continuous smokers followed for 5 years in the NHLBI Lung Health Study. We also studied 1061 NHW with the lowest (n=530) or the highest (n=531) baseline lung function at the beginning of the LHS. Two SNPs were associated with baseline levels of lung function and the p values were 0.008 for +2197T/C in a dominant model and 0.002 for +5171A/G in a recessive model. However, after adjusting for confounding factors, only +5171A/G was still significant (p=0.001 for the recessive model). In addition, there was a significant genotype and smoking interaction with p=0.006 for the +5171A/G (GG vs.GA + AA) for the baseline lung function. When comparing individuals with GG versus individuals with AG + AA for low lung function, the adjusted odds ratios decreased significantly as pack-years increased. No association was found in the rate of decline study. There was an association between IFNG genotype and baseline of lung function and this association was modified by cigarette smoking.

Case-Control Studies↗

PubMed2006

Feasibility of retinoids for the treatment of emphysema study.

BACKGROUND: Retinoids promote alveolar septation in the developing lung and stimulate alveolar repair in some animal models of emphysema. METHODS: One hundred forty-eight subjects with moderate-to-severe COPD and a primary component of emphysema, defined by diffusing capacity of the lung for carbon monoxide (Dlco) [37.1 +/- 12.0% of predicted] and CT density mask (38.5 +/- 12.8% of voxels <- 910 Hounsfield units) [mean +/- SD] were enrolled into a randomized, double-blind, feasibility study at five university hospitals. Participants received all-trans retinoic acid (ATRA) at either a low dose (LD) [1 mg/kg/d] or high dose (HD) [2 mg/kg/d], 13-cis retinoic acid (13-cRA) [1 mg/kg/d], or placebo for 6 months followed by a 3-month crossover period. RESULTS: No treatment was associated with an overall improvement in pulmonary function, CT density mask score, or health-related quality of life (QOL) at the end of 6 months. However, time-dependent changes in Dlco (initial decrease with delayed recovery) and St. George Respiratory Questionnaire (delayed improvement) were observed in the HD-ATRA cohort and correlated with plasma drug levels. In addition, 5 of 25 participants in the HD-ATRA group had delayed improvements in their CT scores that also related to ATRA levels. Retinoid-related side effects were common but generally mild. CONCLUSIONS: No definitive clinical benefits related to the administration of retinoids were observed in this feasibility study. However, time- and dose-dependent changes in Dlco, CT density mask score, and health-related QOL were observed in subjects treated with ATRA, suggesting the possibility of exposure-related biological activity that warrants further investigation.

Aged↗

PubMed2005

Small-sample performance of the robust score test and its modifications in generalized estimating equations.

The sandwich variance estimator of generalized estimating equations (GEE) may not perform well when the number of independent clusters is small. This could jeopardize the validity of the robust Wald test by causing inflated type I error and lower coverage probability of the corresponding confidence interval than the nominal level. Here, we investigate the small-sample performance of the robust score test for correlated data and propose several modifications to improve the performance. In a simulation study, we compare the robust score test to the robust Wald test for correlated Bernoulli and Poisson data, respectively. It is confirmed that the robust Wald test is too liberal whereas the robust score test is too conservative for small samples. To explain this puzzling operating difference between the two tests, we consider their applications to two special cases, one-sample and two-sample comparisons, thus motivating some modifications to the robust score test. A modification based on a simple adjustment to the usual robust score statistic by a factor of J/(J - 1) (where J is the number of clusters) reduces the conservativeness of the generalized score test. Simulation studies mimicking group-randomized clinical trials with binary and count responses indicated that it may improve the small-sample performance over that of the generalized score and Wald tests with test size closer to the nominal level. Finally, we demonstrate the utility of our proposal by applying it to a group-randomized clinical trial, trying alternative cafeteria options in schools (TACOS).

Adolescent↗

PubMed2005

Lack of association of human leukocyte antigen-B7 with COPD and rate of decline in lung function.

BACKGROUND: Although variation in the human leukocyte antigen (HLA) locus is associated with various diseases, there have been a limited number of studies that have examined the possible role of HLA in chronic obstructive pulmonary disease (COPD). Only HLA-B7 has been shown to be correlated with low forced expiratory volume in 1s (FEV1) in Caucasians; however, this finding has not been replicated. The aim of this study was to investigate the contribution of the HLA-B7 allele to COPD and to rate of decline of lung function. METHODS: We determined the prevalence of HLA-B7 in a group of COPD patients and a non-obstructed control group of smokers by using a polymerase chain reaction-based genotyping assay. We also determined the prevalence of HLA-B7 in smokers selected from the National Heart Lung and Blood Institute, Lung Health Study for having the fastest and slowest decline of lung function. RESULTS: No significant difference was found in the frequency of HLA-B7 between the COPD and non-obstructed groups. There was also no significant association of HLA-B7 with rate of decline of lung function. CONCLUSION: These data indicate that HLA-B7 does not contribute to COPD or rate of decline of FEV1 in smokers.

Aged↗

PubMed2005

The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial.

BACKGROUND: Randomized clinical trials have not yet demonstrated the mortality benefit of smoking cessation. OBJECTIVE: To assess the long-term effect on mortality of a randomly applied smoking cessation program. DESIGN: The Lung Health Study was a randomized clinical trial of smoking cessation. Special intervention participants received the smoking intervention program and were compared with usual care participants. Vital status was followed up to 14.5 years. SETTING: 10 clinical centers in the United States and Canada. PATIENTS: 5887 middle-aged volunteers with asymptomatic airway obstruction. MEASUREMENTS: All-cause mortality and mortality due to cardiovascular disease, lung cancer, and other respiratory disease. INTERVENTION: The intervention was a 10-week smoking cessation program that included a strong physician message and 12 group sessions using behavior modification and nicotine gum, plus either ipratropium or a placebo inhaler. RESULTS: At 5 years, 21.7% of special intervention participants had stopped smoking since study entry compared with 5.4% of usual care participants. After up to 14.5 years of follow-up, 731 patients died: 33% of lung cancer, 22% of cardiovascular disease, 7.8% of respiratory disease other than cancer, and 2.3% of unknown causes. All-cause mortality was significantly lower in the special intervention group than in the usual care group (8.83 per 1000 person-years vs. 10.38 per 1000 person-years; P = 0.03). The hazard ratio for mortality in the usual care group compared with the special intervention group was 1.18 (95% CI, 1.02 to 1.37). Differences in death rates for both lung cancer and cardiovascular disease were greater when death rates were analyzed by smoking habit. LIMITATIONS: Results apply only to individuals with airway obstruction. CONCLUSION: Smoking cessation intervention programs can have a substantial effect on subsequent mortality, even when successful in a minority of participants.

Behavior Therapy↗

PubMed2005

Difficulty in demonstrating a risk from drinking pattern in fourteen years of coronary heart disease morbidity and mortality: the Lung Health Study.

The health effects of a binge pattern of alcohol consumption have not been widely investigated. The objective of this study is to evaluate cardiovascular consequences of drinking eight or more drinks at a sitting and of usual drinking of alcohol among 3702 men in the Lung Health Study (LHS), a clinical trial where heavy drinkers were excluded from enrollment. Using a 14-year follow-up period, survival graphs were examined. Cox proportional hazards regressions were performed on time to first event for documented hospitalizations and deaths due to coronary heart disease (CHD). The upper two quartiles of usual drinking were protective against CHD in men [hazard ratios (HRs) 0.76 and 0.69] in adjusted models. When eight or more drinks per occasion was combined with models of usual drinking quartiles, its effect was not significant. The measure of eight or more drinks in these data appears to act as a surrogate for heavy drinking, and does not provide a suitable test of the effect of drinking pattern in men, due primarily to the exclusion of heavier drinkers at baseline. The alcohol effects in women in this study were not significant.

Adult↗

PubMed2004

Loss of bone density with inhaled triamcinolone in Lung Health Study II.

Inhaled glucocorticosteroids (ICS) are commonly prescribed for chronic obstructive pulmonary disease. No adverse effect on bone mineral density (BMD) has been proven. In a randomized double-blind, placebo-controlled trial at seven centers in North America, we recruited 412 current smokers or recent quitters with mild to moderate chronic obstructive pulmonary disease. They used inhaled triamcinolone acetonide, 600 mcg, or placebo, twice daily. We measured femoral neck and lumbar spine BMD at baseline and after 1 and 3 years, and serum osteocalcin at baseline, 3 months, 1 year, and 3 years. After 3 years, BMD at the femoral neck decreased 1.78% more with ICS than with placebo (p < 0.001). More participants in the ICS group experienced 6% or more loss of femoral neck BMD (p = 0.002). Lumbar spine BMD increased in the placebo group by 0.98% but decreased by 0.35% in the ICS group (a difference of 1.33%, p = 0.007). Changes in osteocalcin did not correlate with changes in BMD. Fractures, lost height, or osteoporosis diagnoses were not increased among ICS users compared with placebo users. In summary, the use of inhaled triamcinolone acetonide was associated with loss of BMD at the femoral neck and lumbar spine after 3 years of treatment.

Administration, Inhalation↗

PubMed2004

Glutathione S-transferase variants and their interaction with smoking on lung function.

We studied glutathione S-transferase (GST) polymorphisms in 1,098 whites with the lowest (n = 544, FEV(1) % predicted mean +/- SEM = 62.6 +/- 0.1) and the highest (n = 554, FEV(1) % predicted mean +/- SEM = 91.8 +/- 0.1) lung function at the beginning of the Lung Health Study. Homozygosity for GSTP1 105Val was significantly more frequent in the low- than in the high-function group (13.2 vs. 9.3%) (odds ratio = 1.69, 95% confidence interval [CI] = 1.11-2.61, p = 0.016), after adjustment for confounding variables. Subjects with 105Val homozygotes had higher rates of lung function decline in the high-function group (p = 0.017). The frequencies of GSTM1, GSTT1 null genotypes were similar between the high- and low-function groups, but subjects with the GSTT1 null genotype had a faster decline of lung function in the low-function group (p = 0.032). In addition, there was a significant interaction of GSTT1 genotype and pack-years on lung function. When comparing individuals with GSTT1 null genotype with wild type, the adjusted odds ratio was 3.49 (95% CI, 1.48-8.39, p = 0.005) in mild smokers (< or = 25 pack years). We conclude that GST genotypes are risk factors for rapid decline or low lung function in smokers with mild to moderate airflow obstruction.

Acyltransferases↗

PubMed2004

Survival and long-term neurodevelopmental outcome of extremely premature infants born at 23-26 weeks' gestational age at a tertiary center.

OBJECTIVE: Long-term outcome, including school-age function, has been infrequently reported in infants born at ages as young as 23-26 weeks' gestation. The objective of this study is to report outcome on a large cohort of these infants to understand better the risks and factors that affect survival and long-term prognosis. METHODS: Records from 1036 infants who were born between January 1, 1986, and December 31, 2000, were analyzed retrospectively by logistic regression to correlate multiple factors with both survival and long-term outcome. A total of 675 surviving infants were analyzed at a mean age of 47.5 months for developmental outcome. A subset of 147 surviving infants who were born before 1991 were followed through school-age years using the University of Vermont Achenbach Child Behavioral Checklist and Teachers Report Form. Longitudinal follow-up was performed comparing 1-year outcome with school-age performance. RESULTS: Gestational age and recent year of birth correlated highly with survival. Maternal nonwhite race, female sex, inborn status, surfactant therapy, single gestation, and secondary sepsis also correlated positively with survival. Normal cranial ultrasound results, absence of chronic lung disease, female sex, cesarean delivery, and increased birth weight correlated favorably with long-term outcome. Infants who were born at 23 weeks were more likely to have severe impairments compared with those who were born at 24-26 weeks. Early follow-up identified most subsequent physical impairments but correlated poorly with school-age function. CONCLUSIONS: Survival continues to improve for infants who are born at extremely early gestational ages, but long-term developmental concerns continue to be prevalent. Early outcomes do not reliably predict school-age performance. Strategies that reduce severe intraventricular hemorrhage and chronic lung disease will likely yield the best chances to improve long-term outlook.

Child↗

PubMed2003

Changes in smoking status affect women more than men: results of the Lung Health Study.

Lung Health Study participants were smokers aged 35-60 years with mild lung function impairment who participated in a 5-year, 10-center (nine in the United States, one in Canada) clinical trial in 1986-1994. The authors compared the relation of randomized treatment assignments and of smoking history during the study with changes in lung function between men and women. Spirometry was performed annually, and 3,348 men and 1,998 women attended the follow-up clinic visit that included spirometry at year 5. This paper reports on an analysis of changes in lung function by gender, treatment group, and three smoking history categories: sustained quitters, intermittent quitters, and continuing smokers. Among participants who quit smoking in the first year, mean forced expiratory volume in 1 second (FEV(1)) expressed as a percentage of the predicted value of FEV(1 )given the person's age, height, gender, and race (FEV(1)%) increased more in women (3.7% of predicted) than in men (1.6% of predicted) (p < 0.001). Across the 5-year follow-up period, among sustained quitters, women gained more in FEV(1)% of predicted than did men. Methacholine reactivity was more strongly related to rates of decline in women than in men (p < 0.001). Therefore, among persons at risk for chronic obstructive pulmonary disease, smoking cessation has an even clearer advantage for women than it does for men.

Adult↗

PubMed2003

Polymorphisms in the IL13, IL13RA1, and IL4RA genes and rate of decline in lung function in smokers.

Targeted expression of interleukin (IL)-13 in the adult murine lung has been shown to cause emphysema. We hypothesized that variants in the IL13, IL13RA1, and IL4RA genes would be associated with an accelerated rate of decline of lung function among smokers. We determined the allele frequencies of five polymorphisms in the IL13, IL13RA1, and IL4RA genes in 588 continuing smokers chosen from the NHLBI Lung Health Study for having the fastest (n = 282) and slowest (n = 306) 5-yr rate of decline of lung function (mean change in FEV(1) %predicted/yr = -4.1 and +1.1, respectively). The IL4RA 551RR genotype was associated with rapid decline of lung function (odds ratio, 2.24; P = 0.043). However, none of the other four polymorphisms was associated with rate of decline in lung function. The association of 551RR with rapid decline of lung function became more significant in subjects who also had either the IL13 130RR or -1112TT genotypes. However, because multiple comparisons were made and only a few individuals had the 551RR genotype, these associations may represent type 1 error. Haplotypes consisting of alleles from the IL13 polymorphisms or from the IL4RA polymorphisms were not associated with rate of decline in lung function in smokers.

Adult↗

PubMed2003

The effect of smoking intervention and an inhaled bronchodilator on airways reactivity in COPD: the Lung Health Study.

BACKGROUND: The Lung Health Study (LHS), a 5-year, randomized, prospective clinical trial, studied the effects of smoking intervention and therapy with inhaled anticholinergic bronchodilators on FEV(1) in participants who were 35 to 60 years of age and had mild COPD. Participants were randomized into the following three groups: usual care; smoking cessation plus inhaled ipratropium bromide; and smoking cessation plus placebo inhaler. This report evaluates the effects of these interventions, demographic characteristics, smoking status, and FEV(1) changes on airway responsiveness (AR). METHODS AND RESULTS: Of 5,887 participants, 4,201 underwent methacholine challenge testing both at study entry and study completion. All groups increased AR during the 5-year period. The increase in AR was greatest in continuing smokers and was associated with a greater FEV(1) decline. An intent-to-treat analysis indicated no significant differences in AR changes among the three groups. CONCLUSIONS: Changes in AR over a 5-year period in the LHS were primarily related to changes in the FEV(1). The greater the decline in FEV(1), the greater the increase in AR. Smoking cessation had a small additional benefit in AR beyond its favorable effects on FEV(1) changes.

Adult↗

PubMed2002

Smoking and lung function of Lung Health Study participants after 11 years.

Eleven years after Lung Health Study (LHS) entry, we performed spirometry in 77.4% of surviving participants who enrolled in a long-term follow-up study. Those not enrolling tended to be younger male heavy smokers who continued to smoke during the LHS. Their initial LHS lung function, after adjustment for these factors, did not differ from that of enrollees. Smoking habits by original LHS treatment groups (smoking intervention vs. usual care) tended to converge, but 93% of participants who were abstinent throughout the LHS were still abstinent at 11 years. Differences in lung function between treatment groups persisted; smoking intervention participants had less decline in FEV(1) than usual care participants. Men who quit at the beginning of the LHS had an FEV(1) rate of decline of 30.2 ml/year, whereas women who quit declined at 21.5 ml/year. Men continuing to smoke throughout the 11 years declined by 66.1 ml/year, and women continuing to smoke declined by 54.2 ml/year. When decline in FEV(1) was expressed as a percentage of predicted normal value, no significant sex-based difference was apparent among continuing smokers. At 11 years, 38% of continuing smokers had an FEV(1) less than 60% of the predicted normal value compared with 10% of sustained quitters.

Adult↗