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1.  Comorbidities of COPD have a major impact on clinical outcomes, particularly in African Americans 
COPD patients have a great burden of comorbidity. However, it is not well established whether this is due to shared risk factors such as smoking, if they impact patients exercise capacity and quality of life, or whether there are racial disparities in their impact on COPD.
We analyzed data from 10,192 current and ex-smokers with (cases) and without COPD (controls) from the COPDGene® cohort to establish risk for COPD comorbidities adjusted for pertinent covariates. In adjusted models, we examined comorbidities prevalence and impact in African-Americans (AA) and Non-Hispanic Whites (NHW).
Comorbidities are more common in COPD compared to those with normal spirometry (controls), and the risk persists after adjustments for covariates including pack-years smoked. After adjustment for confounders, eight conditions were independently associated with worse exercise capacity, quality of life and dyspnea. There were racial disparities in the impact of comorbidities on exercise capacity, dyspnea and quality of life, presence of osteoarthritis and gastroesophageal reflux disease having a greater negative impact on all three outcomes in AAs than NHWs (p<0.05 for all interaction terms).
Individuals with COPD have a higher risk for comorbidities than controls, an important finding shown for the first time comprehensively after accounting for confounders. Individual comorbidities are associated with worse exercise capacity, quality of life, and dyspnea, in African-Americans compared to non-Hispanic Whites.
PMCID: PMC4329763
COPD; Comorbidities; Race
2.  Allele-Selective Inhibition of Huntingtin and Ataxin-3 Expression by RNA Duplexes Containing Unlocked Nucleic Acid (UNA) Substitutions 
Biochemistry  2013;52(51):9329-9338.
Unlocked nucleic acid (UNA) is an acyclic analog of RNA that can be introduced into RNA or DNA oligonucleotides. The increased flexibility conferred by the acyclic structure fundamentally affects the strength of base-pairing, createing opportunities for improved applications and new insights into molecular recognition. Here we test how UNA substitutions affect allele-selective inhibition of trinucleotide-repeat genes Huntingtin (HTT) and Ataxin-3 (ATX-3) expression. We find that the either the combination of mismatched bases and UNA substitutions or UNA substitutions alone can improve potency and selectivity. Inhibition is potent and selectivities of > 40-fold for inhibiting mutant versus wild-type expression can be achieved. Surprisingly, even though UNA preserves the potential for complete base-pairing, the introduction of UNA substitutions at central positions within fully complementary duplexes leads to >19-fold selectivity. Like mismatched bases, the introduction of central UNA bases disrupts the potential for cleavage of substrate by Argonaute 2 (AGO2) during gene silencing. UNA-substituted duplexes are as effective as other strategies for allele-selective silencing of trinucleotide repeat disease genes. Modulation of AGO2 activity by the introduction of UNA substitutions demonstrates that backbone flexibility is as important as base-pairing for catalysis of fully complementary duplex substrates. UNA can be used to tailor RNA silencing for optimal properties and allele-selective action.
PMCID: PMC3893079  PMID: 24266403
3.  A Simplified Score to Quantify Comorbidity in COPD 
PLoS ONE  2014;9(12):e114438.
Comorbidities are common in COPD, but quantifying their burden is difficult. Currently there is a COPD-specific comorbidity index to predict mortality and another to predict general quality of life. We sought to develop and validate a COPD-specific comorbidity score that reflects comorbidity burden on patient-centered outcomes.
Materials and Methods
Using the COPDGene study (GOLD II-IV COPD), we developed comorbidity scores to describe patient-centered outcomes employing three techniques: 1) simple count, 2) weighted score, and 3) weighted score based upon statistical selection procedure. We tested associations, area under the Curve (AUC) and calibration statistics to validate scores internally with outcomes of respiratory disease-specific quality of life (St. George's Respiratory Questionnaire, SGRQ), six minute walk distance (6MWD), modified Medical Research Council (mMRC) dyspnea score and exacerbation risk, ultimately choosing one score for external validation in SPIROMICS.
Associations between comorbidities and all outcomes were comparable across the three scores. All scores added predictive ability to models including age, gender, race, current smoking status, pack-years smoked and FEV1 (p<0.001 for all comparisons). Area under the curve (AUC) was similar between all three scores across outcomes: SGRQ (range 0·7624–0·7676), MMRC (0·7590–0·7644), 6MWD (0·7531–0·7560) and exacerbation risk (0·6831–0·6919). Because of similar performance, the comorbidity count was used for external validation. In the SPIROMICS cohort, the comorbidity count performed well to predict SGRQ (AUC 0·7891), MMRC (AUC 0·7611), 6MWD (AUC 0·7086), and exacerbation risk (AUC 0·7341).
Quantifying comorbidity provides a more thorough understanding of the risk for patient-centered outcomes in COPD. A comorbidity count performs well to quantify comorbidity in a diverse population with COPD.
PMCID: PMC4267736  PMID: 25514500
4.  The Use of the Edinburgh Postpartum Depression Scale in a Population of Teenager Pregnant Women in Mexico: A Validation Study 
:Depression may occur in teenager pregnant women. The use of a validated tool for screening depression is highly recommended. The Edinburgh postnatal depression scale (EPDS) is a screening tool for depression used in women during the postnatal period and pregnancy. However, the EPDS has not been validated in teenager pregnant women. Therefore, we sought to validate a Spanish translated Mexican version of the EPDS in a population of teenager pregnant women. Methods: One hundred and twenty teenager pregnant women attending routine prenatal consultations in a public hospital in Durango City, Mexico participated in the study. All participants submitted a revised Spanish translated Mexican version of the EPDS and were examined by a psychiatrist to evaluate the presence of depression by using DSM-IV criteria. Results: Of the 120 teenager pregnant women studied, 2 had major depression and 25 had minor depression according to the DSM-IV criteria. The optimal EPDS cut-off for screening combined major and minor depression in teenager pregnant women was 8/9. At this threshold, we found a sensitivity of 70.4%, a specificity of 84.9%, a positive predictive value of 47.6%, a negative predictive value of 91.0%, and an area under the curve of 0.81 (95% confidence interval: 0.56-1.07). Conclusion: The EPDS can be used for screening depression in Mexican teenager pregnant women whenever a cut-off score of 8/9 is used.
PMCID: PMC4258699  PMID: 25493092
Cut off; depression scale; epidemiology; pregnancy; screening; validation.
5.  Effect of APE1 T2197G (Asp148Glu) Polymorphism on APE1, XRCC1, PARP1 and OGG1 Expression in Patients with Colorectal Cancer 
It has been hypothesized that genetic variation in base excision repair (BER) might modify colorectal adenoma risk. Thus, we evaluated the influence of APE1 T2197G (Asp148Glu) polymorphism on APE1, XRCC1, PARP1 and OGG1 expression in normal and tumor samples from patients with colorectal cancer. The results indicate a downregulation of OGG1 and an upregulation of XRCC1 expression in tumor tissue. Regarding the anatomical location of APE1, OGG1 and PARP-1, a decrease in gene expression was observed among patients with cancer in the rectum. In patients with or without some degree of tumor invasion, a significant downregulation in OGG1 was observed in tumor tissue. Interestingly, when taking into account the tumor stage, patients with more advanced grades (III and IV) showed a significant repression for APE1, OGG1 and PARP-1. XRCC1 expression levels were significantly enhanced in tumor samples and were correlated with all clinical and histopathological data. Concerning the polymorphism T2197G, GG genotype carriers exhibited a significantly reduced expression of genes of the BER repair system (APE1, XRCC1 and PARP1). In summary, our data show that patients with colorectal cancer present expression changes in several BER genes, suggesting a role for APE1, XRCC1, PARP1 and OGG1 and APE1 polymorphism in colorectal carcinogenesis.
PMCID: PMC4227165  PMID: 25268610
colorectal cancer; DNA repair; APE1 polymorphism; BER
6.  2’f-OMe-phosphorodithioate modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity 
Nature communications  2014;5:3459.
Improving small interfering RNA (siRNA) efficacy in target cell populations remains a challenge to its clinical implementation. Here, we report a chemical modification, consisting of phosphorodithioate (PS2) and 2’-O-Methyl (2’-OMe) MePS2 on one nucleotide that significantly enhances potency and resistance to degradation for various siRNAs. We find enhanced potency stems from an unforeseen increase in siRNA loading to the RNA-induced silencing complex, likely due to the unique interaction mediated by 2’-OMe and PS2. We demonstrate the therapeutic utility of MePS2 siRNAs in chemoresistant ovarian cancer mouse models via targeting GRAM Domain Containing 1B (GRAMD1B), a protein involved in chemoresistance. GRAMD1B silencing is achieved in tumors following MePS2-modified siRNA treatment, leading to a synergistic anti-tumor effect in combination with paclitaxel. Given the previously limited success in enhancing siRNA potency with chemically modified siRNAs, our findings represent an important advance in siRNA design with the potential for application in numerous cancer types.
PMCID: PMC4112501  PMID: 24619206
7.  Validation of the Edinburgh Postpartum Depression Scale in a Population of Adult Pregnant Women in Mexico 
The Edinburgh postnatal depression scale (EPDS) is useful for screening depression in puerperal women as well as women during pregnancy. However, such instrument should be validated in a given language before it can be used. There is not validated Mexican version of the EPDS for use in adult pregnant women. Therefore, we sought to validate a Spanish translated Mexican version of the EPDS in a population of adult pregnant women.
One hundred fifty-eight adult women (mean age: 28 ± 6.8 years; range: 18 - 45 years) within their 2 - 9 months of pregnancy attending routine prenatal consultations in a public hospital in Durango City, Mexico were studied. All pregnant women submitted a Spanish translated Mexican version of the EPDS. In addition, participants were assessed for major and minor depression by using the DSM-IV criteria.
Of the 158 pregnant women studied, 11 had major depression and 26 had minor depression by the DSM-IV criteria. The best EPDS score for screening combined major and minor depression in adult pregnant women was 9/10. This threshold showed a sensitivity of 75.7%, a specificity of 74.4%, a positive predictive value of 50.8%, a negative predictive value of 94.7% and an area under the curve of 0.89 (95% confidence interval: 0.71 - 1.06).
The Mexican version of the EPDS can be considered for screening depression in Mexican adult pregnant women whenever a cut-off score of 9/10 is used.
PMCID: PMC4125333  PMID: 25110542
Pregnancy; Depression; Validation study; Mexico
8.  A synthetic biology approach to the development of transcriptional regulatory models and custom enhancer design☆,☆☆ 
Methods (San Diego, Calif.)  2013;62(1):91-98.
Synthetic biology offers novel opportunities for elucidating transcriptional regulatory mechanisms and enhancer logic. Complex cis-regulatory sequences—like the ones driving expression of the Drosophila even-skipped gene—have proven difficult to design from existing knowledge, presumably due to the large number of protein-protein interactions needed to drive the correct expression patterns of genes in multicellular organisms. This work discusses two novel computational methods for the custom design of enhancers that employ a sophisticated, empirically validated transcriptional model, optimization algorithms, and synthetic biology. These synthetic elements have both utilitarian and academic value, including improving existing regulatory models as well as evolutionary questions. The first method involves the use of simulated annealing to explore the sequence space for synthetic enhancers whose expression output fit a given search criterion. The second method uses a novel optimization algorithm to find functionally accessible pathways between two enhancer sequences. These paths describe a set of mutations wherein the predicted expression pattern does not significantly vary at any point along the path. Both methods rely on a predictive mathematical framework that maps the enhancer sequence space to functional output.
PMCID: PMC3924567  PMID: 23732772
modeling; transcriptional regulation; synthetic biology
9.  Impact of self-reported Gastroesophageal reflux disease in subjects from COPDGene cohort 
Respiratory Research  2014;15(1):62.
The coexistence of gastroesophageal reflux disease (GERD) and COPD has been recognized, but there has been no comprehensive evaluation of the impact of GERD on COPD-related health status and patient-centered outcomes.
Cross-sectional and longitudinal study of 4,483 participants in the COPDGene cohort who met GOLD criteria for COPD. Physician-diagnosed GERD was ascertained by questionnaire. Clinical features, spirometry and imaging were compared between COPD subjects without versus with GERD. We evaluated the relationship between GERD and symptoms, exacerbations and markers of microaspiration in univariate and multivariate models. Associations were additionally tested for the confounding effect of covariates associated with a diagnosis of GERD and the use of proton-pump inhibitor medications (PPIs). To determine whether GERD is simply a marker for the presence of other conditions independently associated with worse COPD outcomes, we also tested models incorporating a GERD propensity score.
GERD was reported by 29% of subjects with female predominance. Subjects with GERD were more likely to have chronic bronchitis symptoms, higher prevalence of prior cardiovascular events (combined myocardial infarction, coronary artery disease and stroke 21.3% vs. 13.4.0%, p < 0.0001). Subjects with GERD also had more severe dyspnea (MMRC score 2.2 vs. 1.8, p < 0.0001), and poorer quality of life (QOL) scores (St. George’s Respiratory Questionnaire (SGRQ) total score 41.8 vs. 34.9, p < 0.0001; SF36 Physical Component Score 38.2 vs. 41.4, p < 0.0001). In multivariate models, a significant relationship was detected between GERD and SGRQ (3.4 points difference, p < 0.001) and frequent exacerbations at baseline (≥2 exacerbation per annum at inclusion OR 1.40, p = 0.006). During a mean follow-up time of two years, GERD was also associated with frequent (≥2/year exacerbations OR 1.40, p = 0.006), even in models in which PPIs, GERD-PPI interactions and a GERD propensity score were included. PPI use was associated with frequent exacerbator phenotype, but did not meaningfully influence the GERD-exacerbation association.
In COPD the presence of physician-diagnosed GERD is associated with increased symptoms, poorer QOL and increased frequency of exacerbations at baseline and during follow-up. These associations are maintained after controlling for PPI use. The PPI-exacerbations association could result from confounding-by-indication.
PMCID: PMC4049804  PMID: 24894541
COPD; Gastroesophageal reflux; Comorbidity; Exacerbations; Quality-of-life; Chronic bronchitis
10.  Modeling of nanotherapeutics delivery based on tumor perfusion 
New journal of physics  2012;15:055004.
Heterogeneities in the perfusion of solid tumors prevent optimal delivery of nanotherapeutics. Clinical imaging protocols to obtain patient-specific data have proven difficult to implement. It is challenging to determine which perfusion features hold greater prognostic value and to relate measurements to vessel structure and function. With the advent of systemically administered nanotherapeutics, whose delivery is dependent on overcoming diffusive and convective barriers to transport, such knowledge is increasingly important. We describe a framework for the automated evaluation of vascular perfusion curves measured at the single vessel level. Primary tumor fragments, collected from triple-negative breast cancer patients and grown as xenografts in mice, were injected with fluorescence contrast and monitored using intravital microscopy. The time to arterial peak and venous delay, two features whose probability distributions were measured directly from time-series curves, were analyzed using a Fuzzy C-mean (FCM) supervised classifier in order to rank individual tumors according to their perfusion characteristics. The resulting rankings correlated inversely with experimental nanoparticle accumulation measurements, enabling modeling of nanotherapeutics delivery without requiring any underlying assumptions about tissue structure or function, or heterogeneities contained within. With additional calibration, these methodologies may enable the study of nanotherapeutics delivery strategies in a variety of tumor models.
PMCID: PMC3770306  PMID: 24039540
nanoparticles; intravital microscopy; cancer; data classifier; vasculature
11.  Characterization of Cytomegalovirus Lung Infection in Non-HIV Infected Children 
Viruses  2014;6(5):2038-2051.
Cytomegalovirus (CMV) is a prevalent pathogen in the immunocompromised host and invasive pneumonia is a feared complication of the virus in this population. In this pediatric case series we characterized CMV lung infection in 15 non-HIV infected children (median age 3 years; IQR 0.2–4.9 years), using current molecular and imaging diagnostic modalities, in combination with respiratory signs and symptoms. The most prominent clinical and laboratory findings included cough (100%), hypoxemia (100%), diffuse adventitious breath sounds (100%) and increased respiratory effort (93%). All patients had abnormal lung images characterized by ground glass opacity/consolidation in 80% of cases. CMV was detected in the lung either by CMV PCR in bronchoalveolar lavage (82% detection rate) or histology/immunohistochemistry in lung biopsy (100% detection rate). CMV caused respiratory failure in 47% of children infected and the overall mortality rate was 13.3%. Conclusion: CMV pneumonia is a potential lethal disease in non-HIV infected children that requires a high-index of suspicion. Common clinical and radiological patterns such as hypoxemia, diffuse adventitious lung sounds and ground-glass pulmonary opacities may allow early identification of CMV lung infection in the pediatric population, which may lead to prompt initiation of antiviral therapy and better clinical outcomes.
PMCID: PMC4036547  PMID: 24811320
CMV; lung; pneumonia; children; ground glass
12.  Predictors of Severity and Mortality in Children Hospitalized With Respiratory Syncytial Virus Infection in a Tropical Region 
Pediatric pulmonology  2013;49(3):269-276.
Respiratory syncytial virus (RSV) is one of the leading causes of acute lower respiratory infection (ALRI) in infants and young children. Although ALRI is a major public health problem in developing countries located in tropical areas, studies about RSV epidemiology in these regions are scarce.
In a retrospective cohort study, we investigated the epidemiology and predictive variables that reflect disease severity and mortality in young children hospitalized with ALRI due to RSV in Colombia, South-America, during a 2-year period (2009–2011).
Of a total of 6,344 children with a diagnosis of ALRI, we selected 2,147 (33.8%) that were positive for RSV. After controlling for pre-existing conditions, we found that independent predictors of severe disease in our population included age <6 months (RR 2.01; CI 95% 1.70–2.38; P < 0.001), prematurity (RR 1.61; CI 95% 1.20–2.17; P = 0.001), congenital heart disease (RR 2.03; CI 95% 1.16–3.54; P = 0.013), and mixed RSV-adenovirus infection (RR 2.09; CI 95% 1.60–2.73; P < 0.001). Multivariate analysis identified that cancer (RR 31.60; CI 95% 5.97–167.13; P < 0.001) is a predictor of mortality in our RSV-infected pediatric population independently of age and other co-morbidities.
RSV is an important cause of ALRI in infants and young children living in tropical regions, especially during the rainy season. The identified predictors of severe disease and mortality should be taken into account when planning interventions to reduce the burden of ALRI in young children living in these regions.
PMCID: PMC4002290  PMID: 23401345
respiratory syncytial virus; acute respiratory infection; pediatrics
13.  Clinical and computed tomographic predictors of chronic bronchitis in COPD: a cross sectional analysis of the COPDGene study 
Respiratory Research  2014;15(1):52.
Chronic bronchitis (CB) has been related to poor outcomes in Chronic Obstructive Pulmonary Disease (COPD). From a clinical standpoint, we have shown that subjects with CB in a group with moderate to severe airflow obstruction were younger, more likely to be current smokers, male, Caucasian, had worse health related quality of life, more dyspnea, and increased exacerbation history compared to those without CB. We sought to further refine our clinical characterization of chronic bronchitics in a larger cohort and analyze the CT correlates of CB in COPD subjects. We hypothesized that COPD patients with CB would have thicker airways and a greater history of smoking, acute bronchitis, allergic rhinitis, and occupational exposures compared to those without CB.
We divided 2703 GOLD 1–4 subjects in the Genetic Epidemiology of COPD (COPDGene®) Study into two groups based on symptoms: chronic bronchitis (CB+, n = 663, 24.5%) and no chronic bronchitis (CB-, n = 2040, 75.5%). Subjects underwent extensive clinical characterization, and quantitative CT analysis to calculate mean wall area percent (WA%) of 6 segmental airways was performed using VIDA PW2 ( Square roots of the wall areas of bronchi with internal perimeters 10 mm and 15 mm (Pi10 and Pi15, respectively), % emphysema, %gas trapping, were calculated using 3D Slicer (
There were no differences in % emphysema (11.4 ± 12.0 vs. 12.0 ± 12.6%, p = 0.347) or % gas trapping (35.3 ± 21.2 vs. 36.3 ± 20.6%, p = 0.272) between groups. Mean segmental WA% (63.0 ± 3.2 vs. 62.0 ± 3.1%, p < 0.0001), Pi10 (3.72 ± 0.15 vs. 3.69 ± 0.14 mm, p < 0.0001), and Pi15 (5.24 ± 0.22 vs. 5.17 ± 0.20, p < 0.0001) were greater in the CB + group. Greater percentages of gastroesophageal reflux, allergic rhinitis, histories of asthma and acute bronchitis, exposures to dusts and occupational exposures, and current smokers were seen in the CB + group. In multivariate binomial logistic regression, male gender, Caucasian race, a lower FEV1%, allergic rhinitis, history of acute bronchitis, current smoking, and increased airway wall thickness increased odds for having CB.
Histories of asthma, allergic rhinitis, acute bronchitis, current smoking, a lower FEV1%, Caucasian race, male gender, and increased airway wall thickness are associated with CB. These data provide clinical and radiologic correlations to the clinical phenotype of CB.
PMCID: PMC4067738  PMID: 24766722
Chronic bronchitis; Chronic obstructive pulmonary disease; Airway thickening; Asthma
14.  Validation of a scale to assess the severity of bronchiolitis in a population of hospitalized infants 
Although assessment of the severity of bronchiolitis using severity scores is important both in daily practice and as an outcome measure in clinical trials, many of these scores have not been formally validated or have been only partially validated.
We conducted a prospective cohort study on a sample of children diagnosed with bronchiolitis. Two physicians independently assessed all of the children on the modified Wood’s Clinical Asthma Score (M-WCAS) and on the Tal et al. severity score and collected the information required to assess the criterion validity, construct validity, inter-rater agreement, sensitivity to change, and usability of the M-WCAS.
The median (interquartilic range [IQR]) of the age of the 54 patients included in the study was 5 (2–9) months. Thirty (55.6%) of the patients were males and 24 (44.4%) were female. The scores of the M-WCAS correlated positively with the scores of the Tal et al. severity score (ρ = 0.761, p < 0.001). The scores of the M-WCAS in patients who required subsequent admission to the PICU were significantly higher than those in patients who required admission only to the pediatric medical floor (PMF) [4.5 (3.6–5.2) vs. 2.5 (1.5–2.5), p < 0.001]. The inter-rater agreement for the raters was found to be κ = 0.897 (p < 0.001), 95% CI (0.699–1.000). The scores of the M-WCAS in patients at admission to the PMF were significantly higher than those obtained immediately before discharge from the hospital [2.5 (1.9–2.5) vs. 1.0 (0.5–1.6), p < 0.001).
Our results suggest that the M-WCAS severity score has adequate criterion validity, adequate construct validity, adequate inter-rater agreement, adequate sensitivity to change, and appropriate usability for infants hospitalized for acute bronchiolitis.
PMCID: PMC4000565  PMID: 24000783
Bronchiolitis; infants; reliability; severity assessment tool; validity
15.  Internet access and use by COPD patients in the National Emphysema/COPD Association Survey 
Technology offers opportunities to improve healthcare, but little is known about Internet use by COPD patients. We tested two hypotheses: Internet access is associated with socio-demographic disparities and frequency of use is related to perceived needs.
We analyzed data from a 2007–2008 national convenience sample survey of COPD patients to determine the relationship between Internet access and frequency of use with demographics, socio-economic status, COPD severity, and satisfaction with healthcare.
Among survey respondents (response rate 7.2%; n = 914, 59.1% women, mean age 71.2 years), 34.2% reported lack of Internet access, and an additional 49% had access but used the Internet less than weekly. Multivariate models showed association between lack of access and older age (OR 1.10, 95% CI 1.07, 1.13), lower income (income below $30,000 OR 2.47, 95% CI 1.63, 3.73), less education (high school highest attainment OR 2.30, 95% CI 1.54, 3.45), comorbid arthritis or mobility-related disease (OR 1.56, 95% CI 1.05, 2.34). More frequent use (at least weekly) was associated with younger age (OR 0.95, 95% CI 0.93, 0.98), absence of cardiovascular disease (OR 0.48, 95% CI 0.29, 0.78), but with perception of needs insufficiently met by the healthcare system, including diagnostic delay (OR 1.72, 95% CI 1.06, 2.78), feeling treated poorly (OR 2.46, 95% CI 1.15, 5.24), insufficient physician time (OR 2.29, 95% CI 1.02, 5.13), and feeling their physician did not listen (OR 3.14, 95% CI 1.42, 6.95).
An analysis of the characteristics associated with Internet access and use among COPD patients identified two different patient populations. Lack of Internet access was a marker of socioeconomic disparity and mobility-associated diseases, while frequent Internet use was associated with less somatic disease but dissatisfaction with care.
PMCID: PMC4021217  PMID: 24755090
Chronic obstructive pulmonary disease; Internet; Elderly adults; Chronic disease management; Multimorbidity; Health information seeking; Digital divide
16.  Robust Spectral Analysis of Thoraco-Abdominal Motion and Oxymetry in Obstructive Sleep Apnea 
Standard PSG montage involves the use of nasal-oral airflow sensors to visualize cyclic episodes of upper airflow interruption, which are considered diagnostic of sleep apnea. Given the high-cost and discomfort associated with in-laboratory PSG, there is an emergent need for novel technology that simplifies OSA screening and diagnosis with less expensive methods. The main goal of this project was to identify novel OSA signatures based on the spectral analysis of thoraco-abdominal motion channels. Our main hypothesis was that proper spectral analysis can detect OSA cycles in adults using simultaneous recording of SaO2 and either, chest or abdominal motion. The impact of this new approach is that it may allow the design of more comfortable and reliable portable devices for screening, diagnosis and monitoring of OSA, functioning only with oximetry and airflow-independent (abdominal or chest) breathing sensors.
PMCID: PMC3992998  PMID: 24110335
17.  Blue Rubber Bleb Nevus Syndrome as a Cause of Lower Digestive Bleeding 
Case Reports in Surgery  2014;2014:683684.
Introduction. Blue rubber bleb nevus syndrome is a rare disorder that is characterized by multiple recurrent vascular malformations that involve the skin and the gastrointestinal tract. The disease can present chronic anemia and severe episodes of gastrointestinal bleeding. Case Report. A 41-year-old man was admitted with recurrent episodes of lower gastrointestinal bleeding and anemia that had worsened over the last 3 months. The physical examination showed soft, diffuse, compressible, bluish nodules on all of the skin surfaces of the body. A biopsy from one of these skin lesions allowed a histological diagnosis of cavernous hemangioma. He submitted to a colonoscopy, which showed hemorrhoids and a plane vascular lesion mainly located on the right colon with recent signs of bleeding; this lesion was treated by local excision and sclerosis. The pathological study of the colon specimens also reflected the presence of cavernous hemangioma. The cutaneous hemangiomas and the presence of colonic venous malformations were compatible with blue rubber bleb nevus syndrome. The patient presented a favorable follow-up with clinical control of the anemia and without relapse of the gastrointestinal bleeding two years after the procedure. Conclusion. Although rarely diagnosed, blue rubber bleb nevus syndrome may be responsible for lower digestive bleeding.
PMCID: PMC3932640  PMID: 24653853
18.  Taking Healthy Steps: rationale, design and baseline characteristics of a randomized trial of a pedometer-based internet-mediated walking program in veterans with chronic obstructive pulmonary disease 
Low levels of physical activity are common in patients with chronic obstructive pulmonary disease (COPD), and a sedentary lifestyle is associated with poor outcomes including increased mortality, frequent hospitalizations, and poor health-related quality of life. Internet-mediated physical activity interventions may increase physical activity and improve health outcomes in persons with COPD.
This manuscript describes the design and rationale of a randomized controlled trial that tests the effectiveness of Taking Healthy Steps, an Internet-mediated walking program for Veterans with COPD. Taking Healthy Steps includes an uploading pedometer, a website, and an online community. Eligible and consented patients wear a pedometer to obtain one week of baseline data and then are randomized on a 2:1 ratio to Taking Healthy Steps or to a wait list control. The intervention arm receives iterative step-count feedback; individualized step-count goals, motivational and informational messages, and access to an online community. Wait list controls are notified that they are enrolled, but that their intervention will start in one year; however, they keep the pedometer and have access to a static webpage.
Participants include 239 Veterans (mean age 66.7 years, 93.7% male) with 155 randomized to Taking Healthy Steps and 84 to the wait list control arm; rural-living (45.2%); ever-smokers (93.3%); and current smokers (25.1%). Baseline mean St. George’s Respiratory Questionnaire Total Score was 46.0; 30.5% reported severe dyspnea; and the average number of comorbid conditions was 4.9. Mean baseline daily step counts was 3497 (+/- 2220).
Veterans with COPD can be recruited to participate in an online walking program. We successfully recruited a cohort of older Veterans with a significant level of disability including Veterans who live in rural areas using a remote national recruitment strategy.
Trial registration
Clinical NCT01102777
PMCID: PMC3946238  PMID: 24491137
COPD; Chronic bronchitis; Emphysema; Quality of life; Exercise; Physical activity; Internet; Pedometer; Walking; Veterans
19.  The link between rhinitis and rapid-eye-movement sleep breathing disturbances in children with obstructive sleep apnea 
Rhinitis and obstructive sleep apnea (OSA) often coexist during childhood. To delineate this clinical association, we examined OSA severity and polysomnogram (PSG) features in children with rhinitis and OSA. Given that rapid-eye-movement (REM) sleep is characterized by nasal congestion, we hypothesized that children with rhinitis have more REM-related breathing abnormalities.
We conducted a retrospective cross-sectional analysis of 145 children with PSG-diagnosed OSA. Outcomes included PSG parameters and obstructive apnea–hypopnea index (OAHI) during REM and non-REM. Linear multivariable models examined the joint effect of rhinitis and OSA parameters with control for potential confounders.
Rhinitis was present in 43% of children with OSA (n = 63) but overall OAHI severity was unaffected by the presence of rhinitis. In contrast, OAHI during REM sleep in children with moderate–severe OSA was significantly increased in subjects with rhinitis and OSA (44.1/hr; SE = 6.4) compared with those with OSA alone (28.2/hr; SE = 3.8).
Rhinitis is highly prevalent in children with OSA. Although OSA is not more severe in children with rhinitis, they do have a distinct OSA phenotype characterized by more REM-related OSA. Further research is needed to delineate the link between REM-sleep and the physiology of the nose during health and disease.
PMCID: PMC3899447  PMID: 24717885
Apnea; OSA; pediatric OSA; REM; REM-related OSA; rhinitis; sleep; sleep breathing
20.  Neuromyelitis Optica in Child: Diagnostic and Therapeutic Challenges 
Case Reports in Pediatrics  2013;2013:124929.
Neuromyelitis optica (NMO) is a rare syndrome of severe inflammatory demyelination of the central nervous system, causing attacks of optic neuritis and transverse myelitis. Although uncommon, attention should be given to the proper identification and management of the affected patients. We present a case of a 13-year-old girl with severe neuromyelitis optica. The patient's initial presentation consisted of encephalopathy and optic neuritis. Approximately 2 months later, coinciding with the weaning of steroid treatment, she presented with ascending paralysis and respiratory failure. She was seropositive for NMO-IgG. Treatment included intravenous immune globulin, steroids, plasmapheresis, and rituximab and was complemented with proper nutrition, vitamins, minerals, and intense rehabilitation. Two years after the initial presentation and one short relapse, the patient has made a remarkable recovery without neurologic deficit. This report underscores the difficulty in making the initial diagnosis, choosing the best treatment, and the need for more streamlined pediatric guidelines for diagnosis, treatment, and prevention of relapses of pediatric NMO.
PMCID: PMC3874358  PMID: 24392237
21.  Gender Differences in Symptoms and Care Delivery for Chronic Obstructive Pulmonary Disease 
Journal of Women's Health  2012;21(12):1267-1274.
Morbidity and mortality for women with chronic obstructive pulmonary disease (COPD) are increasing, and little is known about gender differences in perception of COPD care.
Surveys were administered to a convenience sample of COPD patients to evaluate perceptions about symptoms, barriers to care, and sources of information about COPD.
Data on 295 female and 273 male participants were analyzed. With similar frequencies, women and men reported dyspnea and rated their health as poor/very poor. Although more women than men reported annual household income <$30,000, no significant gender differences in frequency of health insurance, physician visits, or ever having had spirometry were detected. In adjusted models (1) women were more likely to report COPD diagnostic delay (odds ratio [OR] 1.66, 95% confidence interval [CI] 1.13-2.45, p=0.01), although anxiety (OR 1.83, 95% CI 1.10-3.06, p=0.02) and history of exacerbations (OR 1.60, 95% CI 1.08-2.37, p=0.01) were also significant predictors, (2) female gender was associated with difficulty reaching one's physician (OR 2.54, 95% CI 1.33-4.86, p=0.004), as was prior history of exacerbations (OR 2.25, 95% CI 1.21-4.20, p=0.01), and (3) female gender (OR 2.15, 95% CI 1.10-4.21, p=0.02) was the only significant predictor for finding time spent with their physician as insufficient.
Significant gender-related differences in the perception of COPD healthcare delivery exist, revealing an opportunity to better understand what influences these attitudes and to improve care for both men and women.
PMCID: PMC3518541  PMID: 23210491
22.  Oximetry Signal Processing Identifies REM Sleep-Related Vulnerability Trait in Asthmatic Children 
Sleep Disorders  2013;2013:406157.
Rationale. The sleep-related factors that modulate the nocturnal worsening of asthma in children are poorly understood. This study addressed the hypothesis that asthmatic children have a REM sleep-related vulnerability trait that is independent of OSA. Methods. We conducted a retrospective cross-sectional analysis of pulse-oximetry signals obtained during REM and NREM sleep in control and asthmatic children (n = 134). Asthma classification was based on preestablished clinical criteria. Multivariate linear regression model was built to control for potential confounders (significance level P ≤ 0.05). Results. Our data demonstrated that (1) baseline nocturnal respiratory parameters were not significantly different in asthmatic versus control children, (2) the maximal % of SaO2 desaturation during REM, but not during NREM, was significantly higher in asthmatic children, and (3) multivariate analysis revealed that the association between asthma and REM-related maximal % SaO2 desaturation was independent of demographic variables. Conclusion. These results demonstrate that children with asthma have a REM-related vulnerability trait that impacts oxygenation independently of OSA. Further research is needed to delineate the REM sleep neurobiological mechanisms that modulate the phenotypical expression of nocturnal asthma in children.
PMCID: PMC3832976  PMID: 24288619
23.  Relationship between Quantitative CT Metrics and Health Status and Bode in COPD 
Thorax  2012;67(5):399-406.
The value of quantitative computed tomography (QCT) to identify chronic obstructive pulmonary disease (COPD) phenotypes is increasingly appreciated. We hypothesized that QCT-defined emphysema and airway abnormalities relate to St. George's Respiratory Questionnaire (SGRQ) and BODE.
1,200 COPDGene subjects meeting GOLD criteria for COPD with QCT analysis were included. Total lung emphysema was measured using density mask technique with a -950 HU threshold. An automated program measured mean wall thickness (WT), wall area percent (WA%) and pi10 in six segmental bronchi. Separate multivariate analyses examined the relative influence of airway measures and emphysema on SGRQ and BODE.
In separate models predicting SGRQ score, a one unit standard deviation (SD) increase in each airway measure predicted higher SGRQ scores (for WT, 1.90 points higher, p=0.002; for WA%, 1.52 points higher, p=0.02; for pi10, 2.83 points higher p<0.001). The comparable increase in SGRQ for a one unit SD increase in percent emphysema in these models was relatively weaker, significant only in the pi10 model (for percent emphysema, 1.45 points higher, p=0.01). In separate models predicting BODE, a one unit SD increase in each airway measure predicted higher BODE scores (for WT, 1.07 fold increase, p<0.001; for WA%, 1.20 fold increase, p<0.001; for pi10, 1.16 fold increase, p<0.001). In these models, emphysema more strongly influenced BODE (range 1.24-1.26 fold increase, p<0.001).
Emphysema and airway disease both relate to clinically important parameters. The relative influence of airway disease is greater for SGRQ; the relative influence of emphysema is greater for BODE.
PMCID: PMC3719874  PMID: 22514236
Imaging; COPD; emphysema
24.  Gene Silencing Activity of siRNA Molecules Containing Phosphorodithioate Substitutions 
ACS Chemical Biology  2012;7(7):1214-1220.
Chemically synthesized small interfering RNAs (siRNAs) have been widely used to identify gene function and hold great potential in providing a new class of therapeutics. Chemical modifications are desired for therapeutic applications to improve siRNA efficacy. Appropriately protected ribonucleoside-3′-yl S-[β-(benzoylmercapto)ethyl] pyrrolidinothiophosphoramidite monomers were prepared for the synthesis of siRNA containing phosphorodithioate (PS2) substitutions in which the two non-bridging oxygen atoms are replaced by sulfur atoms. A series of siRNAs containing PS2 substitutions have been strategically designed, synthesized and evaluated for their gene silencing activities. These PS2-siRNA duplexes exhibit an A-form helical structure similar to unmodified siRNA. The effect of PS2 substitutions on gene silencing activity is position-dependent, with certain PS2-siRNAs showing significantly higher activity than unmodified siRNA. The relative gene silencing activities of siRNAs containing either PS2 or phosphoromonothioate (PS) linkages at identical positions are variable and depend on the sites of modification. 5′-Phosphorylation of PS2-siRNAs has little or no effect on gene silencing activity. Incorporation of PS2 substitutions into siRNA duplexes increases their serum stability. These results offer preliminary evidence of the potential value of PS2 modified siRNAs.
PMCID: PMC3401229  PMID: 22512638
25.  Rearrangements of 2.5 Kilobases of Noncoding DNA from the Drosophila even-skipped Locus Define Predictive Rules of Genomic cis-Regulatory Logic 
PLoS Genetics  2013;9(2):e1003243.
Rearrangements of about 2.5 kilobases of regulatory DNA located 5′ of the transcription start site of the Drosophila even-skipped locus generate large-scale changes in the expression of even-skipped stripes 2, 3, and 7. The most radical effects are generated by juxtaposing the minimal stripe enhancers MSE2 and MSE3 for stripes 2 and 3 with and without small “spacer” segments less than 360 bp in length. We placed these fusion constructs in a targeted transformation site and obtained quantitative expression data for these transformants together with their controlling transcription factors at cellular resolution. These data demonstrated that the rearrangements can alter expression levels in stripe 2 and the 2–3 interstripe by a factor of more than 10. We reasoned that this behavior would place tight constraints on possible rules of genomic cis-regulatory logic. To find these constraints, we confronted our new expression data together with previously obtained data on other constructs with a computational model. The model contained representations of thermodynamic protein–DNA interactions including steric interference and cooperative binding, short-range repression, direct repression, activation, and coactivation. The model was highly constrained by the training data, which it described within the limits of experimental error. The model, so constrained, was able to correctly predict expression patterns driven by enhancers for other Drosophila genes; even-skipped enhancers not included in the training set; stripe 2, 3, and 7 enhancers from various Drosophilid and Sepsid species; and long segments of even-skipped regulatory DNA that contain multiple enhancers. The model further demonstrated that elevated expression driven by a fusion of MSE2 and MSE3 was a consequence of the recruitment of a portion of MSE3 to become a functional component of MSE2, demonstrating that cis-regulatory “elements” are not elementary objects.
Author Summary
Metazoan genes, including those of humans, contain large noncoding regions that are required for viability. Sequence variations in these regions are statistically associated with human disease, but the mechanisms underlying these associations are not well understood. These regions regulate transcription and are frequently larger than the gene's transcript by an order of magnitude. In this paper we attempt to elucidate the regulatory code of these noncoding segments of DNA by means of quantitative spatially resolved gene expression data and a computational model. The expression data comes from the early embryo of the fruit fly Drosophila melanogaster. We chose a family of DNA constructs to analyze that drive very different patterns of expression when very small changes in DNA sequence are made, reasoning that this sensitivity would reveal important properties of the regulatory code. The model reproduced the training data with precision greater than the expected accuracy of the training data itself. It was able to correctly predict from DNA sequence the expression of 44 segments of DNA from many genes and species.
PMCID: PMC3585115  PMID: 23468638

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