Publications by authors named "Brooks Morgan"

18 Publications

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Understanding how social norms affect modern contraceptive use.

BMC Public Health 2021 06 4;21(1):1061. Epub 2021 Jun 4.

The University of Washington, Seattle, USA.

Background: An aim of this study is to introduce a practitioner-friendly behavior model. Few theories of health behavior explicitly take the effect of social norms on behavior into account. Generally, theories that do take social norms into account assume that the effect of social norms on behavior operates through motivation. We use the Fogg Behavior Model (FBM), a behavior model that is new to public health, to explore whether social norms are associated with modern contraceptive use among Nigerian women, and whether they affect behavior through motivation or through ability. In other words, do social norms that discourage contraception lower women's motivation to use contraception or do they lower women's ability to use contraception.

Methods: This study uses data from a cross-sectional household survey of Nigerian women, ages 14-24. The survey collected data on socio-economic and demographic characteristics of women, whether they were sexually experienced, and whether they used contraception. Modern contraceptive use was the outcome of interest for the study. The survey also collected data on social norms around premarital sex and contraceptive use. Multivariate logistic regression was used for the analysis.

Results: After adjusting for a range of socio-economic and demographic variables, we found that social norms that discourage contraception had a statistically significant negative association with contraceptive use (aOR = 0.90, p < 0.001). The analysis found that the negative association between social norms and contraceptive use remained statistically significant after controlling for motivation but did not remain statistically significant after controlling for ability.

Conclusion: These findings suggest that social norms may affect contraceptive use in Nigeria through ability rather than motivation. In terms of programmatic implications, these finding suggest that public health interventions may be able to counter the negative effects of social norms that discourage contraceptive use by increasing women's ability to practice contraception.
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http://dx.doi.org/10.1186/s12889-021-11110-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178889PMC
June 2021

Factors associated with head circumference and indices of cognitive development in early childhood.

BMJ Glob Health 2020 10;5(10)

Division of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA

Background: While head circumference (HC) has been related to intracranial volume and brain size, its association with cognitive function remains unclear. We sought to understand the relationship among various biological and socioeconomic risk factors, HC and cognitive development.

Methods: We analysed data across resource-poor settings in Bangladesh, India, Nepal, Peru, South Africa and Tanzania from the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development longitudinal birth cohort study. Participating children were enrolled and followed up between 2009 and 2014. A final sample of 1210 children aged 0-24 months were included in the analyses. The main outcomes were HC for age Z-score and cognitive, gross motor and language scores from Bayley Scales of Infant Development-III tests. Length, weight and HC were measured monthly, and cognitive tests were administered at 6, 15 and 24 months of age. To disentangle the associations between risk factors and HC from linear growth and to distinguish the direct and indirect effects of these risk factors on cognitive function, we conducted mediation analysis using longitudinal models to account for all data measured during follow-up.

Results: Average HC-for-age Z-score (HCAZ) was -0.54 (95% CI -0.47 to -0.62) near birth and -1.01 (95% CI -0.94 to -1.08) at 24 months. Children with higher enrolment weight (p<0.0001), higher socioeconomic score (p=0.00037) and taller mothers (p=0.00084) had higher HCAZ at all ages, while enteropathogen infection (p=0.013) and more febrile episodes (p=0.013) were associated with lower HCAZ. The associations between HCAZ and enrolment weight-for-age, maternal height, socioeconomic status or pathogen burden were partly mediated through their associations with length-for-age. HCAZ showed no association with cognitive, gross motor or language skills at 6, 15 and 24 months of age.

Conclusions: The main risk factors associated with HC are similar to those associated with body length, and HC is not related to cognitive function.
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http://dx.doi.org/10.1136/bmjgh-2020-003427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594357PMC
October 2020

Mean Airway Pressure As a Predictor of 90-Day Mortality in Mechanically Ventilated Patients.

Crit Care Med 2020 05;48(5):688-695

Division of Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD.

Objectives: To determine the association between mean airway pressure and 90-day mortality in patients with acute respiratory failure requiring mechanical ventilation and to compare the predictive ability of mean airway pressure compared with inspiratory plateau pressure and driving pressure.

Design: Prospective observational cohort.

Setting: Five ICUs in Lima, Peru.

Subjects: Adults requiring invasive mechanical ventilation via endotracheal tube for acute respiratory failure.

Interventions: None.

Measurements And Main Results: Of potentially eligible participants (n = 1,500), 65 (4%) were missing baseline mean airway pressure, while 352 (23.5%) were missing baseline plateau pressure and driving pressure. Ultimately, 1,429 participants were included in the analysis with an average age of 59 ± 19 years, 45% female, and a mean PaO2/FIO2 ratio of 248 ± 147 mm Hg at baseline. Overall, 90-day mortality was 50.4%. Median baseline mean airway pressure was 13 cm H2O (interquartile range, 10-16 cm H2O) in participants who died compared to a median mean airway pressure of 12 cm H2O (interquartile range, 10-14 cm H2O) in participants who survived greater than 90 days (p < 0.001). Mean airway pressure was independently associated with 90-day mortality (odds ratio, 1.38 for difference comparing the 75th to the 25th percentile for mean airway pressure; 95% CI, 1.10-1.74) after adjusting for age, sex, baseline Acute Physiology and Chronic Health Evaluation III, baseline PaO2/FIO2 (modeled with restricted cubic spline), baseline positive end-expiratory pressure, baseline tidal volume, and hospital site. In predicting 90-day mortality, baseline mean airway pressure demonstrated similar discriminative ability (adjusted area under the curve = 0.69) and calibration characteristics as baseline plateau pressure and driving pressure.

Conclusions: In a multicenter prospective cohort, baseline mean airway pressure was independently associated with 90-day mortality in mechanically ventilated participants and predicts mortality similarly to plateau pressure and driving pressure. Because mean airway pressure is readily available on all mechanically ventilated patients and all ventilator modes, it is a potentially more useful predictor of mortality in acute respiratory failure.
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http://dx.doi.org/10.1097/CCM.0000000000004268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273919PMC
May 2020

Premature, Opportune, and Delayed Weaning in Mechanically Ventilated Patients: A Call for Implementation of Weaning Protocols in Low- and Middle-Income Countries.

Crit Care Med 2020 05;48(5):673-679

Division of Pulmonary and Critical Care, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD.

Objectives: Weaning protocols establish readiness-to-wean criteria to determine the opportune moment to conduct a spontaneous breathing trial. Weaning protocols have not been widely adopted or evaluated in ICUs in low- and middle-income countries. We sought to compare clinical outcomes between participants whose weaning trials were retrospectively determined to have been premature, opportune, or delayed based on when they met readiness-to-wean criteria.

Design: Prospective, multicenter observational study.

Setting: Five medical ICUs in four public hospitals in Lima, Perú.

Subjects: Adults with acute respiratory failure and at least 24 hours of invasive mechanical ventilation (n = 1,657).

Interventions: None.

Measurements And Main Results: We established six readiness-to-wean criteria and retrospectively categorized our sample into three weaning groups: 1) premature: if the weaning trial took place before fulfilling all criteria, 2) opportune: if the weaning trial took place within 24 hours after fulfilling the criteria, and 3) delayed: if the weaning trial took place over 24 hours after fulfilling criteria. We compared 90-day mortality, ventilator-free days, ICU-free days, and hospital-free days between premature, opportune, and delayed weaning groups. In our sample, 761 participants (60.8%) were classified as having a premature weaning trial, 196 underwent opportune weaning (15.7%), and 295 experienced delayed weaning (23.6%). There was no significant difference in 90-day mortality between the groups. Both the premature and delayed weaning groups had poorer clinical outcomes with fewer ventilator-free days (-2.18, p = 0.008) and (-3.49, p < 0.001), ICU-free days (-2.25, p = 0.001) and (-3.72, p < 0.001), and hospital-free days (-2.76, p = 0.044) and (-4.53, p = 0.004), respectively, compared with the opportune weaning group.

Conclusions: Better clinical outcomes occur with opportune weaning compared with premature and delayed weaning. If readiness-to-wean criteria can be applied in resource-limited settings, it may improve ICU outcomes associated with opportune weaning.
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http://dx.doi.org/10.1097/CCM.0000000000004220DOI Listing
May 2020

Lack of an Association Between Household Air Pollution Exposure and Previous Pulmonary Tuberculosis.

Lung 2019 12 3;197(6):793-801. Epub 2019 Oct 3.

Division of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, USA.

Context: Observational studies investigating household air pollution (HAP) exposure to biomass fuel smoke as a risk factor for pulmonary tuberculosis have reported inconsistent results.

Objective: To evaluate the association between HAP exposure and the prevalence of self-reported previous pulmonary tuberculosis.

Design: We analyzed pooled data including 12,592 individuals from five population-based studies conducted in Latin America, East Africa, and Southeast Asia from 2010 to 2015. We used multivariable logistic regression to model the association between HAP exposure and self-reported previous pulmonary tuberculosis adjusted for age, sex, tobacco smoking, body mass index, secondary education, site and country of residence.

Results: Mean age was 54.6 years (range of mean age across settings 43.8-59.6 years) and 48.6% were women (range of % women 38.3-54.5%). The proportion of participants reporting HAP exposure was 38.8% (range in % HAP exposure 0.48-99.4%). Prevalence of previous pulmonary tuberculosis was 2.7% (range of prevalence 0.6-6.9%). While participants with previous pulmonary tuberculosis had a lower pre-bronchodilator FEV (mean - 0.7 SDs, 95% CI - 0.92 to - 0.57), FVC (- 0.52 SDs, 95% CI - 0.69 to - 0.33) and FEV/FVC (- 0.59 SDs, 95% CI - 0.76 to - 0.43) as compared to those who did not, we did not find an association between HAP exposure and previous pulmonary tuberculosis (adjusted odds ratio = 0.86; 95% CI 0.56-1.32).

Conclusions: There was no association between HAP exposure and self-reported previous pulmonary tuberculosis in five population-based studies conducted worldwide.
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http://dx.doi.org/10.1007/s00408-019-00275-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254569PMC
December 2019

Prevalence of chronic respiratory disease in urban and rural Uganda.

Bull World Health Organ 2019 May 26;97(5):318-327. Epub 2019 Mar 26.

Division of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University, 1830 E. Monument Street, Room 555, Baltimore, Maryland, MD 21287, United States of America.

Objective: To determine the prevalence of chronic respiratory diseases in urban and rural Uganda and to identify risk factors for these diseases.

Methods: The population-based, cross-sectional study included adults aged 35 years or older. All participants were evaluated by spirometry according to standard guidelines and completed questionnaires on respiratory symptoms, functional status and demographic characteristics. The presence of four chronic respiratory conditions was monitored: chronic obstructive pulmonary disease (COPD), asthma, chronic bronchitis and a restrictive spirometry pattern.

Findings: In total, 1502 participants (average age: 46.9 years) had acceptable, reproducible spirometry results: 837 (56%) in rural Nakaseke and 665 (44%) in urban Kampala. Overall, 46.5% (698/1502) were male. The age-adjusted prevalence of any chronic respiratory condition was 20.2%. The age-adjusted prevalence of COPD was significantly greater in rural than urban participants (6.1 versus 1.5%, respectively;  < 0.001), whereas asthma was significantly more prevalent in urban participants: 9.7% versus 4.4% in rural participants ( < 0.001). The age-adjusted prevalence of chronic bronchitis was similar in rural and urban participants (3.5 versus 2.2%, respectively;  = 0.62), as was that of a restrictive spirometry pattern (10.9 versus 9.4%;  = 0.82). For COPD, the population attributable risk was 51.5% for rural residence, 19.5% for tobacco smoking, 16.0% for a body mass index < 18.5 kg/m and 13.0% for a history of treatment for pulmonary tuberculosis.

Conclusion: The prevalence of chronic respiratory disease was high in both rural and urban Uganda. Place of residence was the most important risk factor for COPD and asthma.
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http://dx.doi.org/10.2471/BLT.18.216523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747035PMC
May 2019

Stress-induced neural activation is altered during early withdrawal from chronic methamphetamine.

Behav Brain Res 2019 07 19;366:67-76. Epub 2019 Mar 19.

University at Albany, Department of Psychology, Albany, NY 12222, United States. Electronic address:

Chronic methamphetamine (MA) use can lead to increased symptoms of depression and anxiety during abstinence. Less is known about the specific brain regions that are altered following repeated MA that may be associated with these behavioral perturbations. Furthermore, MA has been reported to recruit and activate microglia in the brain, which may exacerbate stress-associated behavioral changes. In the present study, male and female mice were injected with MA (5 mg/kg) or saline once daily for 10 days, and during early withdrawal were assessed for alterations in immediate early gene (c-Fos) responses to a forced swim stressor. Chronic MA exposure increased floating and decreased swim time in the forced swim test in male and female mice tested 48 h after the final dose, indicating elevated depressive-like behavior. Furthermore, assessment of nest building, a measure of distress or despair-like behavior, revealed a sex-specific effect with only MA-treated females showing impairments. The c-Fos response to forced swim was attenuated by prior MA exposure in the central amygdala, CA3 hippocampal region, prefrontal cortex, and bed nucleus of the stria terminalis (BST). In the BST this attenuation occurred only in males. Neither the total number of microglia or activated microglia were altered by chronic MA exposure in regions examined. The primary findings indicate that chronic MA exposure attenuates activation of select stress-associated brain regions, a dysregulation that might contribute to alterations in mood-related behaviors.
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http://dx.doi.org/10.1016/j.bbr.2019.03.034DOI Listing
July 2019

Epidemiology and risk factors of asthma-chronic obstructive pulmonary disease overlap in low- and middle-income countries.

J Allergy Clin Immunol 2019 04 4;143(4):1598-1606. Epub 2018 Oct 4.

Division of Pulmonary and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, Md; Center for Global Non-Communicable Diseases, School of Medicine, Johns Hopkins University, Baltimore, Md. Electronic address:

Background: Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) represents the confluence of bronchial airway hyperreactivity and chronic airflow limitation and has been described as leading to worse lung function and quality of life than found with either singular disease process.

Objective: We aimed to describe the prevalence and risk factors for ACO among adults across 6 low- and middle-income countries (LMICs).

Methods: We compiled cross-sectional data for 11,923 participants aged 35 to 92 years from 4 population-based studies in 12 settings. We defined COPD as postbronchodilator FEV/forced vital capacity ratio below the lower limit of normal, asthma as wheeze or medication use in 12 months or self-reported physician diagnosis, and ACO as having both.

Results: The prevalence of ACO was 3.8% (0% in rural Puno, Peru, to 7.8% in Matlab, Bangladesh). The odds of having ACO were higher with household exposure to biomass fuel smoke (odds ratio [OR], 1.48; 95% CI, 0.98-2.23), smoking tobacco (OR, 1.28 per 10 pack-years; 95% CI, 1.22-1.34), and having primary or less education (OR, 1.35; 95% CI, 1.07-1.70) as compared to nonobstructed nonasthma individuals. ACO was associated with severe obstruction (FEV %, <50; 31.6% of ACO vs 10.9% of COPD alone) and severe spirometric deficits compared with participants with asthma (-1.61 z scores FEV; 95% CI, -1.48 to -1.75) or COPD alone (-0.94 z scores; 95% CI, -0.78 to -1.10).

Conclusions: ACO may be as prevalent and more severe in LMICs than has been reported in high-income settings. Exposure to biomass fuel smoke may be an overlooked risk factor, and we favor diagnostic criteria for ACO that include environmental exposures common to LMICs.
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http://dx.doi.org/10.1016/j.jaci.2018.06.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079232PMC
April 2019

Validation of the Saint George's Respiratory Questionnaire in Uganda.

BMJ Open Respir Res 2018 11;5(1):e000276. Epub 2018 Jul 11.

Division of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

Introduction: Chronic obstructive pulmonary disease (COPD) will soon be the third leading global cause of death and is increasing rapidly in low/middle-income countries. There is a need for local validation of the Saint George's Respiratory Questionnaire (SGRQ), which can be used to identify those experiencing lifestyle impairment due to their breathing.

Methods: The SGRQ was professionally translated into Luganda and reviewed by our field staff and a local pulmonologist. Participants included a COPD-confirmed clinic sample and COPD-positive and negative members of the community who were enrolled in the Lung Function in Nakaseke and Kampala (LiNK) Study. SGRQs were assembled from all participants, while demographic and spirometry data were additionally collected from LiNK participants.

Results: In total, 103 questionnaires were included in analysis: 49 with COPD from clinic, 34 community COPD-negative and 20 community COPD-positive. SGRQ score varied by group: 53.5 for clinic, 34.4 for community COPD-positive and 4.1 for community COPD-negative (p<0.001). The cross-validated statistic for SGRQ total score predicting COPD was 0.87 (95% CI 0.75 to 1.00). SGRQ total score was associated with COPD severity (forced expiratory volume in 1 s per cent of predicted), with an coefficient of -0.60 (-0.75, -0.39). SGRQ score was associated with dyspnoea (OR 1.05/point; 1.01, 1.09) and cough (1.07; 1.03, 1.11).

Conclusion: Our Luganda language SGRQ accurately distinguishes between COPD-positive and negative community members in rural Uganda. Scores were correlated with COPD severity and were associated with odds of dyspnoea and cough. We find that it can be successfully used as a respiratory questionnaire for obstructed adults in Uganda.
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http://dx.doi.org/10.1136/bmjresp-2018-000276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045769PMC
July 2018

Asthma and Allergic Disorders in Uganda: A Population-Based Study Across Urban and Rural Settings.

J Allergy Clin Immunol Pract 2018 Sep - Oct;6(5):1580-1587.e2. Epub 2018 Feb 1.

Division of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, Md; Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md. Electronic address:

Background: Allergic diseases are increasing in sub-Saharan Africa, but few studies have characterized the burden among adults.

Objective: We conducted a study to evaluate the prevalence and risk factors of allergic disorders in urban and rural Uganda.

Methods: We present a cross-sectional analysis of enrollment data from a population-based cohort study of adults aged ≥35 years in urban and rural Uganda. Sociodemographic and both lifetime and 12-month respiratory symptoms data were collected and spirometry was conducted following standard guidelines.

Results: In 1,308 adults (median age 43.8 years and 52.3% female), we found an age-adjusted prevalence of 6.8% for asthma (9.8% urban, 4.3% rural; P < .001), 11.9% for allergic rhinitis (16.4% urban, 7.8% rural; P < .001), and 8.2% for eczema (9.9% urban, 7.8% rural; P = .15). Urbanization was the primary driver of asthma, accounting for 61.4% of cases (95% confidence interval [CI] 22.0% to 83.4%), and was the strongest risk factor for any allergic illness (odds ratio [OR] = 1.87, 95% CI 1.39-2.51). Parental asthma was not associated with allergic illness. Asthma was associated with a lower forced expiratory volume in 1 second (FEV) by 0.56 z scores (95% CI 0.33-0.80). We found a dose-response association between lower quintiles of the FEV/forced vital capacity ratio and both hospitalization (OR = 1.77, 95% CI 1.21-2.59) and impairment in daily activities (1.65, 1.20-2.27).

Conclusions: Asthma and allergic rhinitis were twice as prevalent in urban settings. Asthma was associated with greater impairment and worse lung function outcomes. We identified a high prevalence of allergic disorders in Uganda, which can be expected to increase due to urbanization and resultant exposures throughout early development.
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http://dx.doi.org/10.1016/j.jaip.2017.11.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050146PMC
November 2019

Dilution Factor of Quantitative Bacterial Cultures Obtained by Bronchoalveolar Lavage in Patients with Ventilator-Associated Bacterial Pneumonia.

Antimicrob Agents Chemother 2018 01 21;62(1). Epub 2017 Dec 21.

Institute for Clinical Pharmacodynamics, Schenectady, New York, USA.

Ventilator-associated bacterial pneumonia (VABP) is a difficult therapeutic problem. Considerable controversy exists regarding the optimal chemotherapy for this entity. The recent guidelines of the Infectious Diseases Society of America and the American Thoracic Society recommend a 7-day therapeutic course for VABP based on the balance of no negative impact on all-cause mortality, less resistance emergence, and fewer antibiotic treatment days, counterbalanced with a higher relapse rate for patients whose pathogen is a nonfermenter. The bacterial burden causing an infection has a substantial impact on treatment outcome and resistance selection. We describe the baseline bronchoalveolar lavage (BAL) fluid burden of organisms in suspected VABP patients screened for inclusion in a clinical trial. We measured the urea concentrations in plasma and BAL fluid to provide an index of the dilution of the bacterial and drug concentrations in the lung epithelial lining fluid introduced by the BAL procedure. We were then able to calculate the true bacterial burden as the diluted colony count times the dilution factor. The median dilution factor was 28.7, with the interquartile range (IQR) being 11.9 to 53.2. Median dilution factor-corrected colony counts were 6.18 log(CFU/ml) [IQR, 5.43 to 6.46 log(CFU/ml)]. In a subset of patients, repeat BAL on day 5 showed a good stability of the dilution factor. We previously showed that large bacterial burdens reduce or stop bacterial killing by granulocytes. (This study has been registered at ClinicalTrials.gov under registration no. NCT01570192.).
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http://dx.doi.org/10.1128/AAC.01323-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740323PMC
January 2018

Low cigarette smoking prevalence in peri-urban Peru: results from a population-based study of tobacco use by self-report and urine cotinine.

Tob Induc Dis 2017 21;15:32. Epub 2017 Jul 21.

Division of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University, 1830 E. Monument St, Baltimore, Maryland 21205 USA.

Background: A recent study found lower self-reported prevalence of tobacco smoking in a peri-urban area of Lima, Peru than previously reported in urban samples. These regions encompass substantial proportions of Peru's population - ones at greater risk of disease due to reduced healthcare access - but have been less often studied. We validate low smoking prevalence with urine cotinine and characterize chronic disease and lung function outcomes between non-, occasional, and daily smokers.

Methods: Data are from the CRONICAS Cohort Study, a population-based longitudinal study in four low-resource Peruvian settings, which began in 2010. Of a baseline cohort of 2978 adults, we prospectively followed 2583 (87%) to determine prevalence of chronic illness.

Results: In a baseline sub-sample of 382 participants, median adjusted cotinine was 0.0 mcg/mg (IQR 0-0) for both self-reported non-smokers and occasional smokers compared to 172.3 mcg/mg (IQR 0-709.2) for daily smokers. Creatinine-adjusted cotinine validated daily smoking prevalence of 4.7% at a cutoff of 100 mcg/mg. Kappa statistic for daily smoking and creatinine- adjusted cotinine ≥100 mcg/mg was 0.65 (95% CI 0.47, 0.83), indicating substantial agreement. At baseline, we found 3.3% daily and 8.9% occasional smoking by self-report for the full cohort. Follow-up indicated little difference in chronic disease prevalence between groups. Daily smokers trended toward having a greater decline in FVC (-1%; 95% CI -2.9, 0.8) and FEV (-1.3%; 95% CI -3.2, 0.6) over 40 months when compared to non-smokers, whereas the decline in lung function for occasional smokers was similar compared to non-smokers (-0.2% FVC; 95% CI -1.5, 1.0) and (0% FEV; 95% CI -1.3, 1.3).

Conclusions: Our data places Peru within a previously-described pattern of smoking found in much of Latin America, favoring occasional over daily smoking and low cigarette consumption. We determine that there are not significant differences between smoking groups concerning chronic disease outcomes. We favor distinguishing between daily and occasional smokers in order to accurately characterize these low-use populations.
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http://dx.doi.org/10.1186/s12971-017-0137-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521105PMC
July 2017

Inhibition of hypoxia inducible factor-1α downregulates the expression of epithelial to mesenchymal transition early marker proteins without undermining cell survival in hypoxic lens epithelial cells.

Mol Vis 2015 1;21:1024-35. Epub 2015 Sep 1.

Department of Cell Biology and Immunology, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX.

Purpose: The purpose of this study was to identify potential therapeutic strategies to slow down or prevent the expression of early-onset epithelial to mesenchymal transition (EMT) marker proteins (fibronectin and alpha smooth muscle actin, α-SMA) without sacrificing the synthesis and accumulation of the prosurvival protein vascular endothelial growth factor (VEGF) in cultured virally transformed human lens epithelial (HLE) cells.

Methods: HLE-B3 cells, maintained in a continuous hypoxic environment (1% oxygen), were treated with SB216763, a specific inhibitor of glycogen synthase kinase-3β (GSK-3β) catalytic activity. Western blot analysis was employed to detect the cytoplasmic and nuclear levels of β-catenin, as well as the total lysate content of fibronectin and α-SMA. Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of VEGF in cell culture medium. A hypoxia-inducible factor-1α (HIF-1α) translation inhibitor and an HIF-2α translation inhibitor were independently employed to evaluate the effect of hypoxia inducible factor inhibition on EMT marker protein and VEGF expression. XAV932 was used to assess the suppression of nuclear β-catenin and its downstream effect on EMT marker proteins and VEGF expression.

Results: SB216763-treated HLE-B3 cells caused marked inhibition of GSK-3β activity prompting a significant increase in the translocation of cytoplasmic β-catenin to the nucleus. The enhancement of nuclear β-catenin looked as if it positively correlated with a significant increase in the basal expression of VEGF as well as increased expression of fibronectin and α-SMA. In conjunction with SB216763, coadministration of an HIF-1α translation inhibitor, but not an HIF-2α translation inhibitor, markedly suppressed the expression of fibronectin and α-SMA without affecting VEGF levels. Treatment with XAV932 significantly reduced the level of nuclear β-catenin, but the levels of neither the EMT marker proteins nor VEGF were changed.

Conclusions: Recently, we reported that nuclear β-catenin, but not HIF-2α, regulates the expression of fibronectin and α-SMA in atmospheric oxygen. In marked contrast, data from the hypoxic condition clearly establish that nuclear β-catenin plays little apparent role in the expression of EMT marker proteins. Instead, the loss of HIF-1α (but not HIF-2α) decreases the expression of the EMT marker proteins without sacrificing the levels of the prosurvival protein VEGF. These findings support the development of a potentially relevant therapeutic strategy to undermine the progression of normal cells to the mesenchymal phenotype in the naturally hypoxic lens without subverting cell viability.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4556159PMC
June 2016

Lenticular cytoprotection, part 2: link between glycogen synthase kinase-3β, epithelial to mesenchymal transition, and mitochondrial depolarization.

Mol Vis 2014 31;20:1758-75. Epub 2014 Dec 31.

Department of Cell Biology and Immunology, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX.

Purpose: The inhibition of GSK-3β blocks mitochondrial membrane permeability transition (mMPT) for HLE-B3 cells in atmospheric oxygen. GSK-3β, as part of a multifactorial complex, also regulates nuclear levels of β-catenin, a known coordinator of cell survival and adhesion. The purpose of these studies was to demonstrate a novel, but likely disadvantageous, link between β-catenin's influence on the expression of the pro-survival protein, vascular endothelial growth factor (VEGF), resulting in enhanced lens epithelial cell mitochondrial protection against depolarization and nuclear β-catenin as an inducer of epithelial to mesenchymal transition (EMT).

Methods: Virally transformed human lens epithelial cells (HLE-B3) were treated with SB216763, a specific inhibitor of GSK-3β catalytic activity and XAV939, a specific β-catenin inhibitor that bars the translocation of β-catenin from cytoplasm to the nucleus. Western blot analysis was employed to detect the levels of cytoplasmic and nuclear β-catenin and phospho-β-catenin, pBcl-2 and the EMT proteins, α-smooth muscle actin (α-SMA), and fibronectin. ELISA was used to measure the levels of VEGF in cell culture supernatants. JC-1 analysis was performed to analyze the influence of either SB216763 or XAV939 on mitochondrial depolarization.

Results: Cultured lens epithelial cells maintained in hypoxia (1% oxygen) and subsequently reintroduced into atmospheric oxygen and treated with the GSK-3β inhibitor SB216763 illustrated a marked inhibition of phosphorylation of glycogen synthase (downstream substrate of GSK-3β) and significant increase in nuclear translocation of β-catenin. The augmented nuclear β-catenin levels positively correlated with increased expression of α-SMA and fibronectin, both marker proteins indicative of EMT. The enhanced nuclear β-catenin activity also elicited increased VEGF and pBcl-2 expression, resulting in increased resistance to mitochondrial depolarization. Treatment of the cells with the β-catenin inhibitor XAV939 resulted in decreased expression of nuclear β-catenin, VEGF levels, pBcl-2, and EMT proteins, as well as increased mitochondrial depolarization.

Conclusions: The data support a model whereby the onset of epithelial to mesenchymal transition may circuitously benefit from the enhanced synthesis of VEGF by setting up a potentially harmful situation whereby the resulting mesenchymal cell population may be more resistant to mitochondrial depolarization than the lens epithelial cell population from which it originated. These findings support the potential therapeutic relevance of developing strategies to undermine the progression of normal cells to mesenchymal transition without subverting cell viability.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287703PMC
December 2015

Lenticular mitoprotection. Part B: GSK-3β and regulation of mitochondrial permeability transition for lens epithelial cells in atmospheric oxygen.

Mol Vis 2013 29;19:2451-67. Epub 2013 Nov 29.

Department of Cell Biology and Anatomy, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX.

Purpose: Loss of integrity of either the inner or outer mitochondrial membrane results in the dissipation of the mitochondrial electrochemical gradient that leads to mitochondrial membrane permeability transition (mMPT). This study emphasizes the role of glycogen synthase kinase 3beta (GSK-3β) in maintaining mitochondrial membrane potential, thus preventing mitochondrial depolarization (hereafter termed mitoprotection). Using 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763), an inhibitor of GSK-3β, and drawing a distinction between it and 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio] butadiene (UO126), an inhibitor of extracellular-signal-regulated kinase (ERK) phosphorylation, the means by which GSK-3β influences mitoprotection in cultured human lens epithelial (HLE-B3) cells and normal, secondary cultures of bovine lens epithelial cells, maintained in atmospheric oxygen, was investigated.

Methods: Virally transfected human lens epithelial cells (HLE-B3) and normal cultures of bovine lens epithelial cells were exposed to acute hypoxic conditions (about 1% O2) followed by exposure to atmospheric oxygen (about 21% O2). Specific antisera and western blot analysis was used to examine the state of phosphorylation of ERK and GSK-3β, as well as the phosphorylation of a downstream substrate of GSK-3β, glycogen synthase (GS, useful in monitoring GSK-3β activity). The potentiometric dye, 1H-benzimidazolium-5,6-dichloro-2-[3-(5,6-dichloro-1,3-diethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)-1-propenyl]-1,3-diethyl-iodide (JC-1), was used to monitor mitochondrial depolarization upon exposure of inhibitor treatment relative to the control cells (mock inhibition) in atmospheric oxygen. Caspase-3 activation was scrutinized to determine whether mitochondrial depolarization inevitably leads to apoptosis.

Results: Treatment of HLE-B3 cells with SB216763 (12 µM) inactivated GSK-3β activity as verified by the enzyme's inability to phosphorylate its substrate, GS. SB216763-treated cells were not depolarized relative to the control cells as demonstrated with JC-1 fluorescent dye analysis. The HLE-B3 cells treated with UO126, which similarly blocked phosphorylation of GS, were nevertheless prone to mMPT relative to the control cells. Western blot analysis determined that Bcl-2-associated X (BAX) levels were unchanged for SB216763-treated or UO126-treated HLE-B3 cells when compared to their respective control cells. However, unlike the SB216763-treated cells, the UO126-treated cells showed a marked absence of Bcl-2, as well as phosphorylated Bcl-2 relative to the controls. UO126 treatment of bovine lens epithelial cells showed similar results with pBcl-2 levels, while the Bcl-2 content appeared unchanged relative to the control cells. HLE-B3 and normal bovine lens cell cultures showed susceptibility to mMPT associated with the loss of pBcl-2 by UO126 treatment.

Conclusions: MITOCHONDRIAL DEPOLARIZATION MAY OCCUR BY ONE OF TWO KEY OCCURRENCES: interruption of the electrochemical gradient across the inner mitochondrial membrane resulting in mMPT or by disruption of the integrity of the inner or outer mitochondrial membrane. The latter scenario is generally tightly regulated by members of the Bcl-2 family of proteins. Inhibition of GSK-3β activity by SB216763 blocks mMPT by preventing the opening of the mitochondrial permeability transition pore. UO126, likewise, inhibits GSK-3β activity, but unlike SB216763, inhibition of ERK phosphorylation induces the loss of intracellular pBcl-2 levels under conditions where intracellular BAX levels remain constant. These results suggest that the lenticular mitoprotection normally afforded by the inactivation of GSK-3β activity may, however, be bypassed by a loss of pBcl-2, an anti-apoptotic member of the Bcl-2 family. Bcl-2 prevents the translocation of BAX to the mitochondrial outer membrane inhibiting depolarization by disrupting the normal electrochemical gradient leading to mMPT.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3850969PMC
July 2014

Lenticular mitoprotection. Part A: Monitoring mitochondrial depolarization with JC-1 and artifactual fluorescence by the glycogen synthase kinase-3β inhibitor, SB216763.

Mol Vis 2013 27;19:1406-12. Epub 2013 Jun 27.

Department of Cell Biology and Anatomy, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX, USA.

Purpose: Dissipation of the electrochemical gradient across the inner mitochondrial membrane results in mitochondrial membrane permeability transition (mMPT), a potential early marker for the onset of apoptosis. In this study, we demonstrate a role for glycogen synthase kinase-3β (GSK-3β) in regulating mMPT. Using direct inhibition of GSK-3β with the GSK-3β inhibitor SB216763, mitochondria may be prevented from depolarizing (hereafter referred to as mitoprotection). Cells treated with SB216763 showed an artifact of fluorescence similar to the green emission spectrum of the JC-1 dye. We demonstrate the novel use of spectral deconvolution to negate the interfering contributing fluorescence by SB216763, thus allowing an unfettered analysis of the JC-1 dye to determine the mitochondrial membrane potential.

Methods: Secondary cultures of virally transfected human lens epithelial cells (HLE-B3) were exposed to acute hypoxic conditions (approximately 1% O₂) followed by exposure to atmospheric oxygen (approximately 21% O₂). The fluorescent dye JC-1 was used to monitor the extent of mitochondrial depolarization upon exposure of inhibitor treatment relative to the control cells (mock inhibition) in atmospheric oxygen. Annexin V-fluorescein isothiocyanate/propidium iodide staining was implemented to determine cell viability.

Results: Treatment of HLE-B3 cells with SB216763 (12 µM), when challenged by oxidative stress, suppressed mitochondrial depolarization relative to control cells as demonstrated with JC-1 fluorescent dye analysis. Neither the control nor the SB216763-treated HLE-B3 cells tested positive with annexin V-fluorescein isothiocyanate/propidium iodide staining under the conditions of the experiment.

Conclusions: Inhibition of GSK-3β activity by SB216763 blocked mMPT relative to the slow but consistent depolarization observed with the control cells. We conclude that inhibition of GSK-3β activity by the GSK-3β inhibitor SB216763 provides positive protection against mitochondrial depolarization.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3695757PMC
September 2013

Lenticular cytoprotection. Part 1: the role of hypoxia inducible factors-1α and -2α and vascular endothelial growth factor in lens epithelial cell survival in hypoxia.

Mol Vis 2013 2;19:1-15. Epub 2013 Jan 2.

Department of Cell Biology and Anatomy, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107, USA.

Purpose: The prosurvival signaling cascades that mediate the unique ability of human lens epithelial cells to survive in their naturally hypoxic environment are not well defined. Hypoxia induces the synthesis of the hypoxia inducible factor HIF-1α that in turn, plays a crucial role in modulating a downstream survival scheme, where vascular endothelial growth factor (VEGF) also plays a major role. To date, no published reports in the lens literature attest to the expression and functionality of HIF-2α and the role it might play in regulating VEGF expression. The aim of this study was to identify the functional expression of the hypoxia inducible factors HIF-1α and HIF-2α and establish their role in regulating VEGF expression. Furthermore, we demonstrate a link between sustained VEGF expression and the ability of the hypoxic human lens epithelial cell to thrive in low oxygen conditions and resist mitochondrial membrane permeability transition (also referred to as lenticular cytoprotection).

Methods: Hypoxia inducible factor translation inhibitors were used to demonstrate the role of HIF-1α and HIF-2α and the simultaneous expression of both hypoxic inducible factors to determine their role in regulating VEGF expression. Axitinib, which inhibits lenticular cell autophosphorylation of its VEGF receptor, was employed to demonstrate a role for the VEGF-VEGFR2 receptor complex in regulating Bcl-2 expression. Specific antisera and western blot analysis were used to detect the protein levels of HIF-1α and HIF-2α, as well as the proapoptotic protein, BAX and the prosurvival protein, Bcl-2. VEGF levels were analyzed with enzyme-linked immunosorbent assay (ELISA). The potentiometric dye, 5,5',6,6'-tetrachloro1,1',3,3'-tetraethyl-benzimidazolylcarbocyanine iodide, was used to determine the effect of the inhibitors on mitochondrial membrane permeability transition.

Results: Cultured human lens epithelial cells (HLE-B3) maintained under hypoxic condition (1% oxygen) displayed consistent accumulation of VEGF throughout the 72 h incubation period. Using hypoxia inducible factor translation inhibitors targeting HIF-1α or HIF-2α, the specific inhibition of each protein did not diminish VEGF synthesis. The combined inhibition of HIF-1α and HIF-2α expression, using a double hypoxia inducible factor translation inhibitor, markedly decreased the level of VEGF. The inhibition of VEGF synthesis was associated with a profound deficiency in the level of the prosurvival protein, Bcl-2. Axitinib also prevented the VEGF-mediated expression of Bcl-2. The loss of VEGF coupled with the decrease in intracellular Bcl-2 correlated with marked mitochondrial depolarization, an early predictor of cellular apoptosis.

Conclusions: Our data support a model in which the sustained synthesis of VEGF in human lens epithelial cells, maintained under hypoxic condition, is regulated by a compensatory inter-relationship between HIF-1α and HIF-2α. VEGF acts as a prosurvival factor in hypoxic lens epithelial cells by maintaining consistent expression of the prosurvival protein Bcl-2, which likely prevents the translocation of cytosolic BAX to the outer mitochondrial membrane, thus preventing the initiation of mitochondrial depolarization.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3541047PMC
September 2013
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