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author:("Sood, sakshat")
1.  The vitamin E isoforms α-tocopherol and γ-tocopherol have opposite associations with spirometric parameters: the CARDIA study 
Respiratory Research  2014;15(1):31.
Clinical studies of the associations of vitamin E with lung function have reported conflicting results. However, these reports primarily examine the α-tocopherol isoform of vitamin E and have not included the isoform γ-tocopherol which we recently demonstrated in vitro opposes the function of α-tocopherol. We previously demonstrated, in vitro and in animal studies, that the vitamin E isoform α-tocopherol protects, but the isoform γ-tocopherol promotes lung inflammation and airway hyperresponsiveness.
To translate these findings to humans, we conducted analysis of 4526 adults in the Coronary Artery Risk Development in Young Adults (CARDIA) multi-center cohort with available spirometry and tocopherol data in blacks and whites. Spirometry was obtained at years 0, 5, 10, and 20 and serum tocopherol was from years 0, 7 and 15 of CARDIA.
In cross-sectional regression analysis at year 0, higher γ-tocopherol associated with lower FEV1 (p = 0.03 in blacks and p = 0.01 in all participants) and FVC (p = 0.01 in blacks, p = 0.05 in whites, and p = 0.005 in all participants), whereas higher α-tocopherol associated with higher FVC (p = 0.04 in blacks and whites and p = 0.01 in all participants). In the lowest quartile of α-tocopherol, higher γ-tocopherol associated with a lower FEV1 (p = 0.05 in blacks and p = 0.02 in all participants). In contrast, in the lowest quartile of γ-tocopherol, higher α-tocopherol associated with a higher FEV1 (p = 0.03) in blacks. Serum γ-tocopherol >10 μM was associated with a 175–545 ml lower FEV1 and FVC at ages 21–55 years.
Increasing serum concentrations of γ-tocopherol were associated with lower FEV1 or FVC, whereas increasing serum concentrations of α-tocopherol was associated with higher FEV1 or FVC. Based on the prevalence of serum γ-tocopherol >10 μM in adults in CARDIA and the adult U.S. population in the 2011 census, we expect that the lower FEV1 and FVC at these concentrations of serum γ-tocopherol occur in up to 4.5 million adults in the population.
PMCID: PMC4003816  PMID: 24629024
α-tocopherol; γ-tocopherol; FEV1; FVC; Human
2.  Utilization and perioperative outcomes of robotic vaginal vault suspension compared to abdominal or vaginal approaches for pelvic organ prolapse 
Robot-assisted vaginal vault suspension (RAVVS) for pelvic organ prolapse (POP) represents a minimally-invasive alternative to abdominal sacrocolpopexy. We measured perioperative outcomes and utilization rates of RAVVS.
RAVVS (n = 2381) and open VVS (OVVS, n = 11080) data were extracted from the 2009–2010 Nationwide Inpatient Sample. Propensity score-matched analysis compared patients undergoing RAVVS or OVVS for complications, mortality, prolonged length-of-stay, and elevated hospital charges.
Use of RAVVS for POP increased from 2009 to 2010 (16.3% to 19.2%). Patients undergoing RAVVS were more likely to be white (77.2% vs. 69.6%), to carry private insurance (52.8% vs. 46.0%) and to have fewer comorbidities (Charlson Comorbidity Index [CCI] ≥1 = 17.5% vs. 26.6%). They were more likely to undergo surgery at urban (98.2% vs. 93.7%) and academic centres (75.7% vs. 56.7%). Patients undergoing RAVVS were less likely to receive a blood-transfusion (0.7% vs. 1.8%, p < 0.001) or experience prolonged length-of-stay (9.3% vs. 25.1%, p < 0.001). They had more intraoperative complications (6.0% vs. 4.2%, p < 0.001), and higher median hospital charges ($32 402 vs. $24 136, p < 0.001). Overall postoperative complications were equivalent (17.9%, p = 1.0), though there were differences in wound (0.4% vs. 1.3%, p < 0.001), genitourinary (4.9% vs. 6.5%, p = 0.009), and surgical (6.6% vs. 4.9%, p = 0.007) complications.
The increasing use of RAVVS from 2009 to 2010 suggests a growth in the adoption of robotics to manage POP. We show that RAVVS is associated with decreased length of stay, fewer blood transfusions, as well as lower postoperative wound, genitourinary and vascular complications. The benefits of RAVVS are mitigated by higher hospital charges and higher rates of intra-operative complications.
PMCID: PMC4001629  PMID: 24839477
3.  mTOR Signaling Feedback Modulates Mammary Epithelial Differentiation and Restrains Invasion Downstream of PTEN Loss 
Cancer research  2013;73(16):5218-5231.
Oncogenic signaling pathways are tightly regulated by negative feedback circuits and relief of these circuits represents a common mechanism of tumor drug resistance. Although the significance of these feedback pathways for signal transduction is evident, their relevance for cellular differentiation and morphogenesis in a genetically-defined context is unclear. In this study, we used isogenic benign mammary organotypic cultures to interrogate the role of mTOR-mediated negative feedback in the specific setting of PTEN inactivation. We found that mTOR signaling promoted basal-like differentiation and repressed nuclear hormone receptor expression after short-term PTEN loss in murine cell cultures analyzed ex vivo. Unexpectedly, we found that PTEN inactivation inhibited growth factor-induced epithelial invasion, and that downstream mTOR-mediated signaling feedback was both necessary and sufficient for this effect. Mechanistically, using isogenic MCF10A cells with and without somaticPTEN deletion, we showed that mTOR inhibition promoted EGF-mediated epithelial invasion by de-repressing upstream EGFR, SRC and PI3K signaling. In addition to offering new signal transduction insights, these results bring to light a number of important and potentially clinically relevant cellular consequences of mTOR inhibition in the specific context of PTEN loss, including modulation of hormone and growth factor responsiveness and promotion of epithelial invasion. Our findings prompt future investigations of the possibility that mTOR inhibitor therapy may not only be ineffective but even deleterious in tumors with PTEN loss.
PMCID: PMC3767295  PMID: 23774212
PTEN; mTORC1; feedback; invasion; breast
4.  Indoor fuel exposure and the lung in both developing and developed countries: An update 
Clinics in chest medicine  2012;33(4):649-665.
Almost 3 billion people worldwide burn solid fuels indoors. These fuels include biomass and coal. Although indoor solid fuel smoke is likely a greater problem in developing countries, wood burning populations in developed countries may also be at risk from these exposures. Despite the large population at risk worldwide, the effect of exposure to indoor solid fuel smoke has not been adequately studied. Indoor air pollution from solid fuel use is strongly associated with COPD (both emphysema and chronic bronchitis), acute respiratory tract infections, and lung cancer (primarily coal use) and weakly associated with asthma, tuberculosis, and interstitial lung disease. Tobacco use further potentiates the development of respiratory disease among subjects exposed to solid fuel smoke. There is a need to perform additional interventional studies in this field. It is also important to increase awareness about the health effects of solid fuel smoke inhalation among physicians and patients as well as trigger preventive actions through education, research, and policy change in both developing and developed countries.
PMCID: PMC3500516  PMID: 23153607
Biomass; Solid fuel; COPD; Asthma; Lung cancer; Respiratory tract infection
6.  Adiponectin, Leptin, and Resistin in Asthma: Basic Mechanisms through Population Studies 
Journal of Allergy  2013;2013:785835.
Adipokines, factors produced by adipose tissue, may be proinflammatory (such as leptin and resistin) or anti-inflammatory (such as adiponectin). Effects of these adipokines on the lungs have the potential to evoke or exacerbate asthma. This review summarizes basic mechanistic data through population-based and clinical studies addressing the potential role of adipokines in asthma. Augmenting circulating concentrations of adiponectin attenuates allergic airway inflammation and airway hyperresponsiveness in mice. Murine data is supported by human data that suggest that low serum adiponectin is associated with greater risk for asthma among women and peripubertal girls. Further, higher serum total adiponectin may be associated with lower clinical asthma severity among children and women with asthma. In contrast, exogenous administration of leptin results in augmented allergic airway hyperresponsiveness in mice. Alveolar macrophages obtained from obese asthmatics are uniquely sensitive to leptin in terms of their potential to augment inflammation. Consistent with this basic mechanistic data, epidemiologic studies demonstrate that higher serum leptin is associated with greater asthma prevalence and/or severity and that these associations may be stronger among women, postpubertal girls, and prepubertal boys. The role of adipokines in asthma is still evolving, and it is not currently known whether modulation of adipokines may be helpful in asthma prevention or treatment.
PMCID: PMC3832971  PMID: 24288549
7.  Leptin, Adiponectin and Pulmonary Diseases 
Biochimie  2012;94(10):2180-2189.
PMCID: PMC3399062  PMID: 22445899
Adipokines; Leptin; Adiponectin; Asthma; Chronic Obstructive Pulmonary Disease
8.  Low Serum Adiponectin Predicts Future Risk for Asthma in Women 
Rationale: Our previous cross-sectional study showed that serum adiponectin is inversely associated with asthma among women. However, it is not known if serum adiponectin predicts future development of asthma or if asthma affects subsequent serum adiponectin concentrations among women.
Objectives: To determine longitudinal association between serum adiponectin and incident asthma among women.
Methods: We used data from examinations at Years 10, 15, and 20 of the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. In our primary analysis, the association of CARDIA Year 15 serum adiponectin concentration with Year 20 incident asthma was evaluated. In our secondary analysis, the converse direction, that is, the association of CARDIA Year 10 prevalent asthma with Year 15 serum adiponectin, was evaluated, using logistic regression techniques.
Measurements and Main Results: Our primary analysis included 1,450 women, mostly premenopausal. Multivariable analyses demonstrated that the lowest tertile of Year 15 serum adiponectin concentration (<7 mg/L) predicted significantly higher risk for incident asthma at Year 20 among women (odds ratio, 2.07; 95% confidence interval, 1.05, 4.10), and particularly among current smokers (interaction P = 0.051). Further, low serum adiponectin was more important than body mass index in predicting the risk for incident asthma among women. We also showed that the converse relationship was not true; that is, Year 10 prevalent asthma did not predict Year 15 serum adiponectin concentrations in women.
Conclusions: Serum adiponectin affects future risk for asthma in women and not vice versa. Measures that raise systemic adiponectin concentrations may lead to newer ways to prevent asthma among women, particularly among those who smoke.
PMCID: PMC3400996  PMID: 22492987
incident asthma; obesity; adiponectin; adipokine; women
9.  Effect of Specific Allergen Inhalation on Serum Adiponectin in Human Asthma 
Chest  2008;135(2):287-294.
Adiponectin is associated with asthma. The direction of this association is not known in humans. In mice, this association is bidirectional - allergen inhalation affects serum adiponectin and exogenous adiponectin administration affects asthma. We sought to evaluate whether allergen inhalation affects serum adiponectin in human asthma.
This study included eight sensitized mild asthmatics and six healthy controls. Asthmatics were challenged with inhaled specific allergen (positive allergen skin test), methacholine, and irrelevant allergen (negative allergen skin test). Controls were challenged with irrelevant allergen. Sequential serum samples were obtained before and nine times after each challenge. Serum adiponectin (primary outcome), leptin, adiponectin-to-leptin ratio, eotaxin, and tumor necrosis factor-alpha - response curves, area under the curves, baseline and peak concentrations, were evaluated. Statistical analysis used repeated measures ANOVA and paired t-tests.
There were no significant differences in outcome measures among the challenges in asthmatics or when compared to controls. Type II error is an unlikely explanation for these findings since the study was adequately powered to detect changes in serum adiponectin, as reported in the literature. Further, pooled data showed that serum adiponectin diurnal variation curves were lower in asthma than in controls.
Serum adiponectin concentrations are lower in asthma than controls. Specific allergen inhalation in asthma does not acutely affect serum adiponectin concentrations. The reverse association i.e. effect of adiponectin on asthma needs further study. If future studies prove adiponectin to be a protective factor for asthma, modulating adiponectin may open a new approach towards managing asthma.
PMCID: PMC3623933  PMID: 18812451
Adipokine; Adiponectin; Allergen inhalation challenge; Asthma; Leptin
10.  Association between Asthma and Serum Adiponectin Concentration in Women 
Thorax  2008;63(10):877-882.
The association of murine asthma with adiposity may be mediated by adiponectin, an anti-inflammatory adipokine with reduced serum concentrations in the obese. We studied whether serum adiponectin concentration was associated with human asthma and explained the association between adiposity and asthma, particularly in women and in pre-menopausal women.
A cross-sectional analysis of 2,890 eligible subjects at year 15 of the Coronary Artery Risk Development in Young Adults (CARDIA) cohort and its YALTA ancillary study, and had either current asthma or never asthma at that evaluation, was performed. Obesity was defined as body mass index (BMI) ≥ 30 kg/m2. Multivariable logistic regression analysis was performed with dependent variable current asthma status.
Women, but not men, with current asthma had lower mean unadjusted serum adiponectin concentration than those with never asthma (p < 0.001; p for sex interaction < 0.001). Similarly, current asthma was related to obese status only in women (OR 3.31, 95% CI 2.00, 5.46, p for sex interaction 0.004); this association was little affected by adjusting for serum adiponectin. Prevalence of current asthma in pre-menopausal women was reduced in the highest vs. lowest tertile of serum adiponectin concentration (OR 0.46, 95% CI 0.26, 0.84, p 0.03), after adjusting for BMI. However, the interaction between serum adiponectin concentration and BMI category on current asthma status was not significant in pre-menopausal women or women overall.
High serum adiponectin concentration may protect against current asthma in pre-menopausal women, but does not explain the association between asthma and adiposity.
PMCID: PMC3616883  PMID: 18390629
Asthma; Adiposity; Body mass index; Waist circumference; Adiponectin
11.  Difference in airflow obstruction between Hispanic and non-Hispanic white female smokers 
COPD  2008;5(5):274-281.
Smoking-related respiratory diseases are a major cause of morbidity and mortality. However, the relationship between smoking and respiratory disease has not been well-studied among ethnic minorities in general and among women in particular.
The objective of this cross-sectional study was to evaluate the risk of airflow obstruction and to assess lung function among Hispanic and non-Hispanic white (NHW) female smokers in a New Mexico cohort.
Participants completed a questionnaire detailing smoking history and underwent spirometry testing. Outcomes studied included airflow obstruction, selected lung function parameters, and chronic mucus hyper-secretion. Chi square, logistic, and linear regression techniques were utilized.
Main findings
Of the 1,433 eligible women participants, 248 (17.3%) were Hispanic; and 319 had airflow obstruction (22.3%). Hispanic smokers were more likely to be current smokers, and report lower pack-years of smoking, compared to NHW smokers (p < 0.05 for all analyses). Further, Hispanic smokers were at a reduced risk of airflow obstruction compared to NHW smokers, with an O.R. of 0.51, 95% C.I. 0.34, 0.78 (p = 0.002) after adjustment for age, BMI, pack-years and duration of smoking, and current smoking status. Following adjustment for covariates, Hispanic smokers also had a higher mean absolute and percent predicted post-bronchodilator FEV1/FVC ratio, as well as higher mean percent predicted FEV1 (p < 0.05 for all analyses).
Principal conclusions
Hispanic female smokers in this New Mexico-based cohort had lower risk of airflow obstruction and better lung function than NHW female smokers. Further, smoking history did not completely explain these associations.
PMCID: PMC3616889  PMID: 18972275
Hispanic ethnicity; Smokers; Airflow obstruction; Pulmonary function; Chronic mucus hyper-secretion; Women
12.  Adiponectin in pulmonary disease and critically ill patients 
Current medicinal chemistry  2012;19(32):5493-5500.
Adiponectin is a predominantly anti-inflammatory protein produced by adipose tissue with possible signalling activity in the lung. It is increasingly associated with inflammatory pulmonary diseases, such as asthma and chronic obstructive pulmonary disease (COPD), and in critical illness. Although mouse studies indicate causative associations between adiponectin and asthma and COPD, the human literature in this regard is inconclusive. Some, but not all, studies demonstrate that serum adiponectin concentrations are inversely associated with asthma prevalence among premenopausal women and peripubertal girls. On the other hand, serum adiponectin concentrations are associated with lower asthma severity among boys but greater severity among men. Further, case-control studies demonstrate higher systemic and airway adiponectin concentrations in primarily male COPD patients than controls. Systemic adiponectin is positively associated with lung function in healthy adults but inversely associated in studies of male subjects with COPD. Murine and human studies further show contradictory associations of systemic adiponectin with critical illness. Higher premorbid systemic adiponectin concentrations are associated with improved survival from sepsis in mice. On the other hand, higher systemic adiponectin concentrations on day 1 of critical illness are associated with lower survival in critically ill patients with respiratory failure. In the absence of adequate longitudinal data, it is not possible to determine whether the adiponectin derangements are the consequence or the cause of the disease studied. Future research will determine whether modulation of adiponectin, independent of BMI, may be helpful in the prevention or treatment of asthma, COPD or critical illness.
PMCID: PMC3607498  PMID: 22876927
Asthma; COPD; Sepsis; Respiratory Failure; Adiponectin; Lung function
13.  Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function 
Hancock, Dana B. | Artigas, María Soler | Gharib, Sina A. | Henry, Amanda | Manichaikul, Ani | Ramasamy, Adaikalavan | Loth, Daan W. | Imboden, Medea | Koch, Beate | McArdle, Wendy L. | Smith, Albert V. | Smolonska, Joanna | Sood, Akshay | Tang, Wenbo | Wilk, Jemma B. | Zhai, Guangju | Zhao, Jing Hua | Aschard, Hugues | Burkart, Kristin M. | Curjuric, Ivan | Eijgelsheim, Mark | Elliott, Paul | Gu, Xiangjun | Harris, Tamara B. | Janson, Christer | Homuth, Georg | Hysi, Pirro G. | Liu, Jason Z. | Loehr, Laura R. | Lohman, Kurt | Loos, Ruth J. F. | Manning, Alisa K. | Marciante, Kristin D. | Obeidat, Ma'en | Postma, Dirkje S. | Aldrich, Melinda C. | Brusselle, Guy G. | Chen, Ting-hsu | Eiriksdottir, Gudny | Franceschini, Nora | Heinrich, Joachim | Rotter, Jerome I. | Wijmenga, Cisca | Williams, O. Dale | Bentley, Amy R. | Hofman, Albert | Laurie, Cathy C. | Lumley, Thomas | Morrison, Alanna C. | Joubert, Bonnie R. | Rivadeneira, Fernando | Couper, David J. | Kritchevsky, Stephen B. | Liu, Yongmei | Wjst, Matthias | Wain, Louise V. | Vonk, Judith M. | Uitterlinden, André G. | Rochat, Thierry | Rich, Stephen S. | Psaty, Bruce M. | O'Connor, George T. | North, Kari E. | Mirel, Daniel B. | Meibohm, Bernd | Launer, Lenore J. | Khaw, Kay-Tee | Hartikainen, Anna-Liisa | Hammond, Christopher J. | Gläser, Sven | Marchini, Jonathan | Kraft, Peter | Wareham, Nicholas J. | Völzke, Henry | Stricker, Bruno H. C. | Spector, Timothy D. | Probst-Hensch, Nicole M. | Jarvis, Deborah | Jarvelin, Marjo-Riitta | Heckbert, Susan R. | Gudnason, Vilmundur | Boezen, H. Marike | Barr, R. Graham | Cassano, Patricia A. | Strachan, David P. | Fornage, Myriam | Hall, Ian P. | Dupuis, Josée | Tobin, Martin D. | London, Stephanie J. | Gibson, Greg
PLoS Genetics  2012;8(12):e1003098.
Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest PJMA = 5.00×10−11), HLA-DQB1 and HLA-DQA2 (smallest PJMA = 4.35×10−9), and KCNJ2 and SOX9 (smallest PJMA = 1.28×10−8) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.
Author Summary
Measures of pulmonary function provide important clinical tools for evaluating lung disease and its progression. Genome-wide association studies have identified numerous genetic risk factors for pulmonary function but have not considered interaction with cigarette smoking, which has consistently been shown to adversely impact pulmonary function. In over 50,000 study participants of European descent, we applied a recently developed joint meta-analysis method to simultaneously test associations of gene and gene-by-smoking interactions in relation to two major clinical measures of pulmonary function. Using this joint method to incorporate genetic main effects plus gene-by-smoking interaction, we identified three novel gene regions not previously related to pulmonary function: (1) DNER, (2) HLA-DQB1 and HLA-DQA2, and (3) KCNJ2 and SOX9. Expression analyses in human lung tissue from ours or prior studies indicate that these regions contain genes that are plausibly involved in pulmonary function. This work highlights the utility of employing novel methods for incorporating environmental interaction in genome-wide association studies to identify novel genetic regions.
PMCID: PMC3527213  PMID: 23284291
14.  New Mexican Hispanic Smokers Have Lower Odds of Chronic Obstructive Pulmonary Disease and Less Decline in Lung Function Than Non-Hispanic Whites 
Rationale: The epidemiology of cigarette smoking–related chronic obstructive pulmonary disease (COPD) is not well characterized in Hispanics in the United States. Understanding how ethnicity influences COPD is important for a number of reasons, from informing public health policies to dissecting the genetic and environmental effects that contribute to disease.
Objectives: The present study assessed differences in risk between Hispanics and non-Hispanic whites for longitudinal and cross-sectional COPD phenotypes. Genetic ancestry was used to verify findings based on self-reported ethnicity. Hispanics in New Mexico are primarily differentiated from non-Hispanic whites by their proportion of Native American ancestry.
Methods: The study was performed in a New Mexican cohort of current and former smokers. Self-reported Hispanic and non-Hispanic white ethnicity was validated by defining genetic ancestry proportions at the individual level using 48 single-nucleotide polymorphism markers. Self-reported ethnicity and genetic ancestry were independently used to assess associations with cross-sectional and longitudinal measures of lung function. Multivariable models were adjusted for indicators of smoking behavior.
Measurements and Main Results: Self-reported Hispanic ethnicity was significantly associated with lower odds of COPD (odds ratio, 0.49; 95% confidence interval, 0.35–0.71; P = 0.007), and this protection was validated by the observation that Hispanic smokers have reduced risk of rapid decline in lung function (odds ratio, 0.48; 95% confidence interval, 0.30–0.78; P = 0.003). Similar findings were noted when Native American genetic ancestry proportions were used as predictors instead of self-report of Hispanic ethnicity.
Conclusions: Hispanic ethnicity is inversely associated with cross-sectional and longitudinal spirometric COPD phenotypes even after adjustment for smoking. Native American genetic ancestry may account for this “Hispanic protection.”
PMCID: PMC3262041  PMID: 21908412
15.  Sex Differences: Implications for the Obesity-Asthma Association 
We have demonstrated in several studies that obesity and adipokines are more strongly associated with asthma in women than in men. The reason for this controversial sex difference is not known. Based on our prior studies, we hypothesize that sex-related difference in ectopic fat may explain the obesity-asthma association in women.
PMCID: PMC3019137  PMID: 21088605
adipokine; leptin; adiponectin; physical activity; gonadal hormones; obesity
16.  Wood Smoke Exposure and Gene Promoter Methylation Are Associated with Increased Risk for COPD in Smokers 
Rationale: Wood smoke–associated chronic obstructive pulmonary disease (COPD) is common in women in developing countries but has not been adequately described in developed countries.
Objectives: Our objective was to determine whether wood smoke exposure was a risk factor for COPD in a population of smokers in the United States and whether aberrant gene promoter methylation in sputum may modify this association.
Methods: For this cross-sectional study, 1,827 subjects were drawn from the Lovelace Smokers' Cohort, a predominantly female cohort of smokers. Wood smoke exposure was self-reported. Postbronchodilator spirometry was obtained, and COPD outcomes studied included percent predicted FEV1, airflow obstruction, and chronic bronchitis. Effect modification of wood smoke exposure with current cigarette smoke, ethnicity, sex, and promoter methylation of lung cancer-related genes in sputum on COPD outcomes were separately explored. Multivariable logistic and poisson regression models were used for binary and rate-based outcomes, respectively.
Measurements and Main Results: Self-reported wood smoke exposure was independently associated with a lower percent predicted FEV1 (point estimate [± SE] −0.03 ± 0.01) and a higher prevalence of airflow obstruction and chronic bronchitis (odds ratio, 1.96; 95% confidence interval, 1.52–2.52 and 1.64 (95% confidence interval, 1.31–2.06, respectively). These associations were stronger among current cigarette smokers, non-Hispanic whites, and men. Wood smoke exposure interacted in a multiplicative manner with aberrant promoter methylation of the p16 or GATA4 genes on lower percent predicted FEV1.
Conclusions: These studies identify a novel link between wood smoke exposure and gene promoter methylation that synergistically increases the risk for reduced lung function in cigarette smokers.
PMCID: PMC3001253  PMID: 20595226
wood smoke; cigarette smokers; airflow obstruction; gene promoter methylation in sputum DNA
17.  Serum Adiponectin is Associated with Adverse Outcomes of Asthma in Men but Not in Women 
Background: Murine studies suggest a beneficial effect of systemic adiponectin on asthma. Our objective was to determine the association between serum adiponectin concentrations and asthma control/severity outcomes in men and women separately. Methods: Cross-sectional and longitudinal analyses of data from years 10, 15, and 20 examinations of the prospective coronary artery risk development in young adults study in the United States were performed. Asthma was defined by self-reported provider diagnosis at or prior to year 15 examination. Outcomes included presence of active disease, number of respiratory symptoms, and number of asthma medications; as well as longitudinal decline in absolute FEV1. Year 15 serum adiponectin concentration was the predictor variable. Results: In a multivariable analysis of 411 eligible subjects, after adjusting for body mass index and covariates, higher serum adiponectin concentrations were associated with more frequent active disease (including more frequent use of any asthma medication), and greater number of respiratory symptoms and asthma medications among men but not among women with asthma (p for interactions between sex and adiponectin for all analyses < 0.05). Conclusions: Higher serum adiponectin concentrations may be independently associated with adverse clinical outcomes of asthma in men but not in women. If biological effect is confirmed in future studies, modification of systemic adiponectin concentrations may open up newer ways to treat asthma in men.
PMCID: PMC3186942  PMID: 22007173
asthma control and severity; obesity; sex differences; serum adiponectin
18.  Principles of Physics in Surgery: The Laws of Mechanics and Vectors Physics for Surgeons—Part 2 
The Indian Journal of Surgery  2010;72(5):355-361.
In this sequel, to an earlier article, we discuss the laws of Mechanics, Thermodynamics and Vectors as they apply to soft and bony tissues. These include the Laplace’s Law as applied to colonic perforation, compression therapy, parturition, variceal rupture, disc herniations etc. The Pascal’s Law finds use in hernia repair and the Heimlich maneuver. Trigonometrically derived components of forces, acting after suturing, show ways to reduce cut-through; the thickness and the bite of suture determines the extent of tissue reaction. The heating effect of current explains the optimum gap between the prongs of a bipolar cautery and the use of law of transfer of heat in determining relation between healthy wound healing and ambient temperature.
PMCID: PMC3077132  PMID: 21966132
Mechanics; Laplace; Pascal; Vectors; Suturing; Thermodynamics; Newton; Cautery
19.  Differentiation of a Highly Tumorigenic Basal Cell Compartment in Urothelial Carcinoma 
Stem cells (Dayton, Ohio)  2009;27(7):1487-1495.
Highly tumorigenic cancer cell (HTC) populations have been identified for a variety of solid tumors and assigned stem cell properties. Strategies for identifying HTCs in solid tumors have been primarily empirical rather than rational, particularly in epithelial tumors, which are responsible for 80% of cancer deaths. We report evidence for a spatially restricted bladder epithelial (urothelial) differentiation program in primary urothelial cancers (UCs) and in UC xenografts. We identified a highly tumorigenic UC cell compartment that resembles benign urothelial stem cells (basal cells), co-expresses the 67-kDa laminin receptor and the basal cell-specific cytokeratin CK17, and lacks the carcinoembryonic antigen family member CEACAM6 (CD66c). This multipotent compartment resides at the tumor-stroma interface, is easily identified on histologic sections, and possesses most, if not all, of the engraftable tumor-forming ability in the parental xenograft. We analyzed differential expression of genes and pathways in basal-like cells versus more differentiated cells. Among these, we found significant enrichment of pathways comprising “hallmarks” of cancer, and pharmacologically targetable signaling pathways, including Janus kinase-signal transducer and activator of transcription, Notch, focal adhesion, mammalian target of rapamycin, epidermal growth factor receptor (erythroblastic leukemia viral oncogene homolog [ErbB]), and wingless-type MMTV integration site family (Wnt). The basal/HTC gene expression signature was essentially invisible within the context of nontumorigenic cell gene expression and overlapped significantly with genes driving progression and death in primary human UC. The spatially restricted epithelial differentiation program described here represents a conceptual advance in understanding cellular heterogeneity of carcinomas and identifies basal-like HTCs as attractive targets for cancer therapy.
PMCID: PMC3060766  PMID: 19544456
Differentiation; Malignancy; Stem cell microenvironment interactions; Stromal cells
20.  ‘Lean’ Mass Predicts Asthma Better than Fat Mass among Women 
The obesity phenotype associated with asthma is not known. Our objective was to define the relative contribution of various distributions of fat and lean mass to asthma prevalence.
Data were obtained from 2,525 participants (including 1,422 women) who underwent Dual-energy X-ray Absorptiometry (DEXA) at the year 20 examination in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. Total, truncal, arm, and leg distributions of fat and lean mass were adjusted to the person’s height. Self-reported asthma was the outcome.
Asthma among women was associated with greater total fat mass, arm fat mass, and total lean mass, truncal lean mass, and arm lean mass. Among men, none of the above mass measures were significantly associated with asthma. Among women, the association with asthma was stronger for total lean mass than for total fat mass. Further, among various regional distributions of lean and fat mass in women, truncal lean mass was the strongest predictor.
Total lean mass is more strongly associated than total fat mass with asthma among women. These findings are contrary to the popular perception that excess physiological fat drives the obesity-asthma association. Rather, we hypothesize that ectopic fat within the ‘lean’ tissues drives this association among women.
PMCID: PMC2978755  PMID: 20525713
Asthma; Dual energy X-ray absorptiometry; Fat mass; Lean mass
21.  Serum adiponectin is positively associated with lung function in young adults, independent of obesity: The CARDIA study 
Respiratory Research  2010;11(1):176.
Adipose tissue produces adiponectin, an anti-inflammatory protein. Adiponectin deficiency in mice is associated with abnormal post-natal alveolar development.
We hypothesized that lower serum adiponectin concentrations are associated with lower lung function in humans, independent of obesity. We explored mediation of this association by insulin resistance and systemic inflammation.
Methods and Measurements
Spirometry testing was conducted at years 10 and 20 follow-up evaluation visits in 2,056 eligible young adult participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Body mass index, serum adiponectin, serum C-reactive protein (a marker of systemic inflammation), and insulin resistance were assessed at year 15.
Main Results
After controlling for body mass index, years 10 and 20 forced vital capacity (FVC) were 81 ml and 82 ml lower respectively (p = 0.004 and 0.01 respectively) in the lowest vs. highest adiponectin quartiles. Similarly, years 10 and 20 forced expiratory volume in one second (FEV1) were 50 ml and 38 ml lower (p = 0.01 and 0.09, respectively) in the lowest vs. highest adiponectin quartiles. These associations were no longer significant after adjustment for insulin resistance and C-reactive protein. Serum adiponectin was not associated with FEV1/FVC or peak FEV1.
Independent of obesity, lower serum adiponectin concentrations are associated with lower lung function. The attenuation of this association after adjustment for insulin resistance and systemic inflammation suggests that these covariates are on a causal pathway linking adiponectin and lung function.
PMCID: PMC3014903  PMID: 21143922
22.  Current Treatment of Chronic Beryllium Disease 
The current mainstay of management of chronic beryllium disease involves cessation of beryllium exposure and use of systemic corticosteroids. However, there are no randomized controlled trials to assess the effect of these interventions on the natural history of this disease. Despite this limitation, it is prudent to remove patients with chronic beryllium disease from further exposure and consider treating progressive disease early with long-term corticosteroids. The effect of treatment should be monitored using pulmonary function tests and high resolution computed tomography of chest. However, once pulmonary fibrosis has developed, corticosteroid therapy cannot reverse the damage.
PMCID: PMC2774897  PMID: 19894178
beryllium; chronic beryllium disease; corticosteroids
23.  Altered Resting and Exercise Respiratory Physiology in Obesity 
Clinics in chest medicine  2009;30(3):445-vii.
Obesity, particularly severe obesity, affects both resting and exercise-related respiratory physiology. Severe obesity classically produces a restrictive ventilatory abnormality, characterized by reduced expiratory reserve volume. However, obstructive ventilatory abnormality may also be associated with abdominal obesity. Decreased peak work rates are usually seen among obese subjects in a setting of normal or decreased ventilatory reserve and normal cardiovascular response to exercise. Weight loss may reverse many adverse physiological consequences of severe obesity on the respiratory system.
PMCID: PMC2765111  PMID: 19700043
Obesity; Respiratory physiology; Exercise; Expiratory Reserve Volume; Oxygen consumption.
24.  Principles of physics in surgery: the laws of flow dynamics physics for surgeons — Part 1 
The Indian Journal of Surgery  2009;71(4):182-187.
In the field of medicine and surgery many principles of physics find numerous applications. In this article we have summarized some prominent applications of the laws of fluid mechanics and hydrodynamics in surgery. Poiseuille’s law sets the limits of isovolaemic haemodilution, enumerates limiting factors during fluid resuscitation and is a guiding principle in surgery for vascular stenoses. The equation of continuity finds use in non-invasive measurement of blood flow. Bernoulli’s theorem explains the formation of post-stenotic dilatation. Reynolds number explains the origin of murmurs, haemolysis and airflow disturbances. Various forms of oxygen therapy are a direct application of the gas laws. Doppler effect is used in ultrasonography to find the direction and velocity of blood flow. In this first part of a series of articles we describe some applications of the laws of hydrodynamics governing the flow of blood and other body fluids.
PMCID: PMC3452629  PMID: 23133151
Hydrodynamics; Poiseuille’s; Equation of continuity; Bernoulli’s; Reynolds number; Doppler effect
25.  Effect of change of reference standard to NHANES III on interpretation of spirometric ‘abnormality’ 
The American Thoracic Society has recently recommended the use of NHANES III spirometric reference standard in the United States. The objective of this study was to better quantify the well-known ‘problem’ of the change in interpretation of spirometry, as a consequence of the change from the other commonly used reference standards (Morris, Kory, Crapo, Knudson 1976, and Knudson 1983) to NHANES III. This is a cross-sectional study of spirometries of 1,106 non-Hispanic Caucasian American adults, including 234 subjects with obstructive and 228 subjects with restrictive spirometric ‘abnormalities’. A weighted Kappa statistic was used to evaluate the level of agreement between NHANES III and other commonly used reference standards. The level of agreement in assessing the presence of an ‘abnormality’ was poor to moderate – values of Kappa statistic ranged from 0.13 to 0.46. There was however, good to very good level of agreement in assessing the severity of the ‘abnormality’ – values of Kappa statistic ranged from 0.61 to 0.91. This study better quantifies the well-known differences in the interpretation of spirometric ‘abnormalities’ as a consequence of the recommended change of reference standard to NHANES III, which in turn may cause confusion among patients and their treating physicians.
PMCID: PMC2695189  PMID: 18229575
Reference standard; Classification of severity; Obstructive spirometric abnormality’; Restrictive spirometric ‘abnormality’; Kappa statistic

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