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PLoS Genet ; 19(1): e1010594, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36638096

ABSTRACT

Impaired lung function in early life is associated with the subsequent development of chronic respiratory disease. Most genetic associations with lung function have been identified in adults of European descent and therefore may not represent those most relevant to pediatric populations and populations of different ancestries. In this study, we performed genome-wide association analyses of lung function in a multiethnic cohort of children (n = 1,035) living in low-income urban neighborhoods. We identified one novel locus at the TDRD9 gene in chromosome 14q32.33 associated with percent predicted forced expiratory volume in one second (FEV1) (p = 2.4x10-9; ßz = -0.31, 95% CI = -0.41- -0.21). Mendelian randomization and mediation analyses revealed that this genetic effect on FEV1 was partially mediated by DNA methylation levels at this locus in airway epithelial cells, which were also associated with environmental tobacco smoke exposure (p = 0.015). Promoter-enhancer interactions in airway epithelial cells revealed chromatin interaction loops between FEV1-associated variants in TDRD9 and the promoter region of the PPP1R13B gene, a stimulator of p53-mediated apoptosis. Expression of PPP1R13B in airway epithelial cells was significantly associated the FEV1 risk alleles (p = 1.3x10-5; ß = 0.12, 95% CI = 0.06-0.17). These combined results highlight a potential novel mechanism for reduced lung function in urban youth resulting from both genetics and smoking exposure.


Subject(s)
Genome-Wide Association Study , Lung , Adult , Adolescent , Humans , Child , Lung/metabolism , DNA Methylation/genetics , Forced Expiratory Volume/genetics , Genotype , Smoking
3.
Front Immunol ; 13: 1056417, 2022.
Article in English | MEDLINE | ID: mdl-36618392

ABSTRACT

Introduction: Progranulin (PGRN) is a secreted glycoprotein, the expression of which is linked to several neurodegenerative diseases. Although its specific function is still unclear, several studies have linked it with lysosomal functions and immune system regulation. Here, we have explored the role of PGRN in peripheral and central immune system homeostasis by investigating the consequences of PGRN deficiency on adaptive and innate immune cell populations. Methods: First, we used gene co-expression network analysis of published data to test the hypothesis that Grn has a critical role in regulating the activation status of immune cell populations in both central and peripheral compartments. To investigate the extent to which PGRN-deficiency resulted in immune dysregulation, we performed deep immunophenotyping by flow cytometry of 19-24-month old male and female Grn-deficient mice (PGRN KO) and littermate Grn-sufficient controls (WT). Results: Male PGRN KO mice exhibited a lower abundance of microglial cells with higher MHC-II expression, increased CD44 expression on monocytes in the brain, and more CNS-associated CD8+ T cells compared to WT mice. Furthermore, we observed an increase in CD44 on CD8+ T cells in the peripheral blood. Female PGRN KO mice also had fewer microglia compared to WT mice, and we also observed reduced expression of MHC-II on brain monocytes. Additionally, we found an increase in Ly-6Chigh monocyte frequency and decreased CD44 expression on CD8+ and CD4+ T cells in PGRN KO female blood. Given that Gpnmb, which encodes for the lysosomal protein Glycoprotein non-metastatic melanoma protein B, has been reported to be upregulated in PGRN KO mice, we investigated changes in GPNMB protein expression associated with PGRN deficits and found that GPNMB is modulated in myeloid cells in a sex-specific manner. Discussion: Our data suggest that PGRN and GPNMB jointly regulate the peripheral and the central immune system in a sex-specific manner; thus, understanding their associated mechanisms could pave the way for developing new neuroprotective strategies to modulate central and peripheral inflammation to lower risk for neurodegenerative diseases and possibly delay or halt progression.


Subject(s)
CD8-Positive T-Lymphocytes , Intercellular Signaling Peptides and Proteins , Male , Female , Animals , Mice , Progranulins/genetics , Intercellular Signaling Peptides and Proteins/genetics , Granulins , Mice, Knockout , Immune System
4.
J Clin Med ; 12(1)2022 Dec 23.
Article in English | MEDLINE | ID: mdl-36614910

ABSTRACT

Age-related macular degeneration (AMD) has been implicated as a risk factor for severe consequences from COVID-19. We evaluated the genetic architecture shared between AMD and COVID-19 (critical illness, hospitalization, and infections) using analyses of genetic correlations and pleiotropy (i.e., cross-phenotype meta-analysis) of AMD (n = 33,976) and COVID-19 (n ≥ 1,388,342) and subsequent analyses including expression quantitative trait locus (eQTL), differential gene expression, and Mendelian randomization (MR). We observed a significant genetic correlation between AMD and COVID-19 infection (rG = 0.10, p = 0.02) and identified novel genome-wide significant associations near PDGFB (best SNP: rs130651; p = 2.4 × 10-8) in the pleiotropy analysis of the two diseases. The disease-risk allele of rs130651 was significantly associated with increased gene expression levels of PDGFB in multiple tissues (best eQTL p = 1.8 × 10-11 in whole blood) and immune cells (best eQTL p = 7.1 × 10-20 in T-cells). PDGFB expression was observed to be higher in AMD cases than AMD controls {fold change (FC) = 1.02; p = 0.067}, as well as in the peak COVID-19 symptom stage (11-20 days after the symptom onset) compared to early/progressive stage (0-10 days) among COVID-19 patients over age 40 (FC = 2.17; p = 0.03) and age 50 (FC = 2.15; p = 0.04). Our MR analysis found that the liability of AMD risk derived from complement system dysfunction {OR (95% CI); hospitalization = 1.02 (1.01-1.03), infection = 1.02 (1.01-1.03) and increased levels of serum cytokine PDGF-BB {ß (95% CI); critical illness = 0.07 (0.02-0.11)} are significantly associated with COVID-19 outcomes. Our study demonstrated that the liability of AMD is associated with an increased risk of COVID-19, and PDGFB may be responsible for the severe COVID-19 outcomes among AMD patients.

5.
Lancet Planet Health ; 7(1): e33-e44, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36608946

ABSTRACT

BACKGROUND: Asthma prevalence and severity have markedly increased with urbanisation, and children in low-income urban centres have among the greatest asthma morbidity. Outdoor air pollution has been associated with adverse respiratory effects in children with asthma. However, the mechanisms by which air pollution exposure exacerbates asthma, and how these mechanisms compare with exacerbations induced by respiratory viruses, are poorly understood. We aimed to investigate the associations between regional air pollutant concentrations, respiratory illnesses, lung function, and upper airway transcriptional signatures in children with asthma, with particular focus on asthma exacerbations occurring in the absence of respiratory virus. METHODS: We performed a retrospective analysis of data from the MUPPITS1 cohort and validated our findings in the ICATA cohort. The MUPPITS1 cohort recruited 208 children aged 6-17 years living in urban areas across nine US cities with exacerbation-prone asthma between Oct 7, 2015, and Oct 18, 2016, and monitored them during reported respiratory illnesses. The last MUPPITS1 study visit occurred on Jan 6, 2017. The ICATA cohort recruited 419 participants aged 6-20 years with persistent allergic asthma living in urban sites across eight US cities between Oct 23, 2006, and March 25, 2008, and the last study visit occurred on Dec 30, 2009. We included participants from the MUPPITS1 cohort who reported a respiratory illness at some point during the follow-up and participants from the ICATA cohort who had nasal samples collected during respiratory illness or at a scheduled visit. We used air quality index values and air pollutant concentrations for PM2·5, PM10, O3, NO2, SO2, CO, and Pb from the US Environmental Protection Agency spanning the years of both cohorts, and matched values and concentrations to each illness for each participant. We investigated the associations between regional air pollutant concentrations and respiratory illnesses and asthma exacerbations, pulmonary function, and upper airway transcriptional signatures by use of a combination of generalised additive models, case crossover analyses, and generalised linear mixed-effects models. FINDINGS: Of the 208 participants from the MUPPITS1 cohort and 419 participants from the ICATA cohort, 168 participants in the MUPPITS1 cohort (98 male participants and 70 female participants) and 189 participants in the ICATA cohort (115 male participants and 74 female participants) were included in our analysis. We identified that increased air quality index values, driven predominantly by increased PM2·5 and O3 concentrations, were significantly associated with asthma exacerbations and decreases in pulmonary function that occurred in the absence of a provoking viral infection. Moreover, individual pollutants were significantly associated with altered gene expression in coordinated inflammatory pathways, including PM2·5 with increased epithelial induction of tissue kallikreins, mucus hypersecretion, and barrier functions and O3 with increased type-2 inflammation. INTERPRETATION: Our findings suggest that air pollution is an important independent risk factor for asthma exacerbations in children living in urban areas and is potentially linked to exacerbations through specific inflammatory pathways in the airway. Further investigation of these potential mechanistic pathways could inform asthma prevention and management approaches. FUNDING: National Institutes of Health, National Institute of Allergy and Infectious Diseases.


Subject(s)
Air Pollutants , Air Pollution , Asthma , Humans , Male , Child , Female , Adolescent , United States/epidemiology , Air Pollutants/analysis , Retrospective Studies , Air Pollution/adverse effects , Air Pollution/analysis , Asthma/epidemiology , Particulate Matter/analysis
6.
Front Sports Act Living ; 4: 1067190, 2022.
Article in English | MEDLINE | ID: mdl-36589782

ABSTRACT

Recruiting companies recommend elite female soccer players be ≥165 cm (5'5″) in stature. This study investigated if stature limits match-playing time and performance in elite World Cup soccer among players, positions, and countries. We hypothesized stature would not affect match-playing time or performance. Descriptive data were collected on 552 players from 2019 FIFA Women's World Cup. Odds ratios determined likelihood of starting for players <165 cm and ≥165 cm. ANOVAs compared playing time between stature groups, among positions, and between countries. Performance factors including assists, goals, attempts, corners, shots blocked, and defending blocks were reported. Independent t-tests compared differences between players (≥165 cm, < 165 cm). Data are reported, mean difference [95% confidence interval] [MD (95%CI)] and effect sizes (ES). On average, 32.3% of players were <165 cm. Of total players, no differences existed in total minutes (F = 0.98, p = 0.32), matches (F = 0.27 p = 0.59), or average minutes per match (F = 0.48, p = 0.49) between stature groups, regardless of position. No differences existed in playing time between players <165 cm and ≥165 cm among any positions (p > 0.05), or between countries (p > 0.05). Taller mid-fielders exhibited greater performance in goals, assists, attempts, shots blocked, and defending blocks (MD [95%CI] ES; assists, -0.44[-0.76,-0.11]0.59, p = 0.009; goals, -0.35[-0.69,-0.01]0.44, p = 0.047); attempts, 3.14[1.38, 4.90]0.80, p = 0.001; corners, 2.04[0.12, 3.95]0.48, p = 0.037; shots blocked, 0.96[0.40, 1.51]0.75, p = 0.001; defending blocks, 0.43[0.32,0.82]0.48, p = 0.035), however, actual differences were minimal. Our findings indicate stature does not inhibit playing and performing elite women's soccer, as nearly one-third of players were <165 cm.

7.
J Conserv Dent ; 25(6): 596-599, 2022.
Article in English | MEDLINE | ID: mdl-36591588

ABSTRACT

Context: Manufacturers have produced a wide variety of nickel-titanium (NiTi) alloys, but the available literature is limited on the accuracy of some integrated electronic apex locators (EAL) used with different NiTi heat treatments in working length (WL) determination. Aim: This study aims to evaluate ex vivo , the influence of different heat treatments of NiTi instruments, and the diameter of the apical preparation on the accuracy of an EAL used during root canal preparation using an integrated EAL and motor unit. Materials and Methods: Nineteen extracted human mandibular incisors were included in the study. The WL control was determined by the visual method. Instruments of Mtwo, Reciproc, Reciproc Blue, WaveOne Gold, Twisted File Adaptive, and Hyflex CM systems, with diameters from 0.25 mm to 0.50 mm, were used to measure WL during root canal preparation. The electrical resistivity of instruments with a diameter of 0.25 mm from each system was evaluated using an Inductance, Capacitance, and Resistance (LCR) meter. Statistical Analysis Used: Data were statistically analyzed using Fisher's exact test and Kruskal-Wallis test. Results: The different heat treatments and different diameters did not influence the precision of the EAL (P > 0.05). Conclusion: The heat treatment and the diameter of the apical preparation did not influence the accuracy of WL determination by an EAL integrated with the endodontic motor.

8.
J Educ Health Promot ; 11: 329, 2022.
Article in English | MEDLINE | ID: mdl-36568008

ABSTRACT

BACKGROUND: Cervical cancer is the leading cause of death worldwide, especially in developing countries. More than one-fifth of newly diagnosed cervical cancer cases are occurring in India. Cervical cancer is a highly preventable and curable cancer compared with other types of cancer, if detected at an early stage. The present study has been carried out to assess whether a community-based, multicomponent, nurse-led intervention program improves cervical cancer screening behavior of women. MATERIALS AND METHODS: An experimental randomized controlled trial was carried out by recruiting 419 women in the age group of 30-60 years (246 in the experimental group and 173 in the control group) residing in a selected rural community (selected tribal settlements) of Idukki district of Kerala, India, using multistage cluster sampling. The intervention comprising small group education followed by reinforcement session, telephonic reminders, navigation and guidance for Pap smear, and follow-up visit by the investigator was administered to the experimental group, and the control group did not receive any intervention. Knowledge, attitude, and screening behavior of women related to prevention of cervical cancer were assessed before and twice after the intervention. RESULTS: The experimental and control groups were homogenous in all baseline sociodemographic variables. The community-based intervention program was effective in improving knowledge (P < 0.001), attitude (P < 0.001), and screening behavior (P < 0.001) of women regarding the prevention of cervical cancer. A significant moderate positive correlation was found between knowledge and screening behavior (r = 0.408). Significant association was found between knowledge, attitude, and practice regarding prevention of cervical cancer with education, age at the time of marriage, and number of pregnancies. CONCLUSION: The community-based, multicomponent, nurse-led intervention program was effective in improving cervical cancer screening behavior among women. Repeated motivation and reinforcement are needed to bring behavioral change and to increase uptake of screening services among rural women.

9.
Radiol Case Rep ; 18(2): 719-726, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36569226

ABSTRACT

Biodegradable hydrogel-based matrices are becoming more widely utilized for a variety of medical applications, including SpaceOAR which is a hydrogel injected into the recto-prostatic space under ultrasound guidance to protect the rectum during prostate radiation therapy. Although a greater number of these procedures are being performed, there are no case reports on the potential complications which may result. In this report, we present the first case of retrograde embolization of SpaceOAR hydrogel into the right common iliac artery during routine office administration, as well as subsequent interventional angiography, inpatient and outpatient management, and clinical and imaging results at 1.5-month patient follow-up.

10.
Chemphyschem ; : e202200724, 2022 Dec 14.
Article in English | MEDLINE | ID: mdl-36516050

ABSTRACT

As atomic layer deposition (ALD) emerges as a method to fabricate architectures with atomic precision, emphasis is placed on understanding surface reactions and nucleation mechanisms. ALD of titanium dioxide with TiCl4 and water has been used to investigate deposition processes in general, but the effect of surface termination on the initial TiO2 nucleation lacks needed mechanistic insights. This work examines the adsorption of TiCl4 on Cl-, H-, and HO- terminated Si(100) and Si(111) surfaces to elucidate the general role of different surface structures and defect types in manipulating surface reactivity of growth and non-growth substrates. The surface sites and their role in the initial stages of deposition are examined by X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM). Density functional theory (DFT) computations of the local functionalized silicon surfaces suggest oxygen-containing defects are primary drivers of selectivity loss on these surfaces.

12.
BMC Genomics ; 23(1): 819, 2022 Dec 10.
Article in English | MEDLINE | ID: mdl-36496393

ABSTRACT

BACKGROUND: As omics measurements profiled on different molecular layers are interconnected, integrative approaches that incorporate the regulatory effect from multi-level omics data are needed. When the multi-level omics data are from the same individuals, gene expression (GE) clusters can be identified using information from regulators like genetic variants and DNA methylation. When the multi-level omics data are from different individuals, the choice of integration approaches is limited. METHODS: We developed an approach to improve GE clustering from microarray data by integrating regulatory data from different but partially overlapping sets of individuals. We achieve this through (1) decomposing gene expression into the regulated component and the other component that is not regulated by measured factors, (2) optimizing the clustering goodness-of-fit objective function. We do not require the availability of different omics measurements on all individuals. A certain amount of individual overlap between GE data and the regulatory data is adequate for modeling the regulation, thus improving GE clustering. RESULTS: A simulation study shows that the performance of the proposed approach depends on the strength of the GE-regulator relationship, degree of missingness, data dimensionality, sample size, and the number of clusters. Across the various simulation settings, the proposed method shows competitive performance in terms of accuracy compared to the alternative K-means clustering method, especially when the clustering structure is due mostly to the regulated component, rather than the unregulated component. We further validate the approach with an application to 8,902 Framingham Heart Study participants with data on up to 17,873 genes and regulation information of DNA methylation and genotype from different but partially overlapping sets of participants. We identify clustering structures of genes associated with pulmonary function while incorporating the predicted regulation effect from the measured regulators. We further investigate the over-representation of these GE clusters in pathways of other diseases that may be related to lung function and respiratory health. CONCLUSION: We propose a novel approach for clustering GE with the assistance of regulatory data that allowed for different but partially overlapping sets of individuals to be included in different omics data.


Subject(s)
DNA Methylation , Genomics , Humans , Genomics/methods , Cluster Analysis , Sample Size , Gene Expression
13.
Ann Thorac Surg ; 2022 Dec 05.
Article in English | MEDLINE | ID: mdl-36481325

ABSTRACT

BACKGROUND: Early postoperative catheterizations (EPOCs) within 6 weeks after a congenital heart surgical procedure can treat residual lesions and provide important clinical information. However, EPOCs are often assumed to impose additional risk on a vulnerable patient population. This study aimed to describe the EPOC population, evaluate procedural safety, compare EPOC patients with procedure-matched non-EPOC patients, and determine risk factors for poor outcomes using data from the Congenital Cardiac Catheterization Project on Outcomes registry. METHODS: In a retrospective cohort, demographic, clinical, and procedural characteristics were analyzed for diagnostic and interventional catheterizations performed in 13 participating institutions from January 2014 to December 2017, excluding patients after heart transplant. The primary outcome was a high-severity adverse event (AE). Three distinct analyses included (1) describing the full cohort and EPOC patients, (2) comparing EPOC patients with and without a high-severity AE, and (3) comparing EPOC patients with controls matched on case type. RESULTS: This study included 17,776 catheterizations, with 1399 EPOCs. The high-severity AE rate was 6.4% overall, 8.9% in the EPOC cohort, and 8.4% in matched controls (P = .74). The association between EPOC status and high-severity AE was not significant in a multivariable model (P = .17). In EPOCs with a high-severity AE, median procedure duration was 30 minutes longer (P < .001), and median time from surgical procedure to catheterization was 3 days longer (P = .05). CONCLUSIONS: EPOC was not associated with additional risk. Individual patient characteristics of size and hemodynamic vulnerability may serve as informative predictors. Timely catheterization may preempt further clinical deterioration, and intraprocedure duration optimization may correlate with improved outcomes.

14.
JACC Adv ; : 100143, 2022 Nov 30.
Article in English | MEDLINE | ID: mdl-36471862

ABSTRACT

Background: The Coronavirus disease 2019 (COVID-19) pandemic has posed tremendous stress on the health care system. Its effects on pediatric/congenital catheterization program practice and performance have not been described. Objectives: To evaluate how case volumes, risk-profile, and outcomes of pediatric/congenital catheterization procedures changed in response to the first wave of COVID-19 and after that wave. Methods: A multicenter retrospective observational study was performed using Congenital Cardiac Catheterization Project on Outcomes Registry (C3PO) data to study changes in volume, case mix, and outcomes (high-severity adverse events [HSAEs]) during the first wave of COVID (March 1, 2020, to May 31, 2020) in comparison to the period prior to (January 1, 2019, to February 28, 2020) and after (June 1, 2020, to December 31, 2020) the first wave. Multivariable analyses adjusting for case type, hemodynamic vulnerability, and age group were performed. Hospital responses to the first wave were captured with an electronic study instrument. Results: During the study period, 12,557 cases were performed at 14 C3PO hospitals (with 8% performed during the first wave of COVID and 32% in the postperiod). Center case volumes decreased from a median 32.1 cases/mo (interquartile range: 20.7-49.0) before COVID to 22 cases/mo (interquartile range: 13-31) during the first wave (P = 0.001). The proportion of cases with risk factors for HSAE increased during the first wave, specifically proportions of infants and neonates (P < 0.001) and subjects with renal insufficiency (P = 0.02), recent cardiac surgery (P < 0.001), and a higher hemodynamic vulnerability score (P = 0.02). The observed HSAE risk did not change significantly (P = 0.13). In multivariable analyses, odds of HSAE during the first wave of COVID (odds ratio: 0.75) appeared to be lower than that before COVID, but the difference was not significant (P = 0.09). Conclusion: Despite increased case-mix complexity, C3PO programs maintained, if not improved, their performance in terms of HSAE. Exploratory analyses of practice changes may inform future harm-reduction efforts.

15.
Allergy ; 2022 Nov 30.
Article in English | MEDLINE | ID: mdl-36448508

ABSTRACT

BACKGROUND: Intestinal microenvironmental perturbations may increase food allergy risk. We hypothesize that children with clinical food allergy, those with food sensitization, and healthy children can be differentiated by intestinal metabolites in the first years of life. METHODS: In this ancillary analysis of the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we performed untargeted metabolomic profiling in 824 stool samples collected at ages 3-6 months, 1 year and 3 years. Subjects included 23 with clinical food allergy at age 3 and/or 6 years, 151 with food sensitization but no clinical food allergy, and 220 controls. We identified modules of correlated, functionally related metabolites and sought associations of metabolite modules and individual metabolites with food allergy/sensitization using regression models. RESULTS: Several modules of functionally related intestinal metabolites were reduced among subjects with food allergy, including bile acids at ages 3-6 months and 1 year, amino acids at age 3-6 months, steroid hormones at 1 year, and sphingolipids at age 3 years. One module primarily containing diacylglycerols was increased in those with food allergy at age 3-6 months. Fecal caffeine metabolites at age 3-6 months, likely derived from breast milk, were increased in those with food allergy and/or sensitization (beta = 5.9, 95% CI 1.0-10.8, p = .02) and were inversely correlated with fecal bile acids and bilirubin metabolites, though maternal plasma caffeine levels were not associated with food allergy and/or sensitization. CONCLUSIONS: Several classes of bioactive fecal metabolites are associated with food allergy and/or sensitization including bile acids, steroid hormones, sphingolipids, and caffeine metabolites.

16.
Pathogens ; 11(11)2022 Nov 15.
Article in English | MEDLINE | ID: mdl-36422608

ABSTRACT

Lettuce is the most commonly cultivated leafy vegetable in Greece, available in the market throughout the year. In this study, an emerging foliar disease observed in commercial farms has been associated to the pathogen Fusarium equiseti, a member of the Fusarium incarnatum-equiseti species complex (FIESC). Thirty F. equiseti isolates obtained from symptomatic lettuce plants were identified on the basis of morphology and evaluated for their pathogenicity. The isolates were further characterized using amplification and sequence analysis of the internal transcribed region (ITS-rDNA), and of the translation elongation factor 1-alpha (TEF1-a), calmodulin (CAM), beta-tubulin (Bt), and small subunit (SSU) genes. Moreover, a novel RT-qPCR assay was developed, designing a primer pair and a probe based on the TEF1-a sequences. This assay showed high specificity, amplifying F. equiseti DNA samples, while no amplification product was observed from samples of other common soilborne fungi. The generated RT-qPCR assay could be a useful tool for the detection and quantification of F. equiseti in soil samples deriving from fields cultivated with lettuce and other leafy vegetables, hosts of this specific pathogen.

17.
J Biomed Mater Res B Appl Biomater ; 2022 Nov 20.
Article in English | MEDLINE | ID: mdl-36404401

ABSTRACT

Numerous biomaterials have been developed for application in blood-contacting medical devices to prevent thrombosis; however, few materials have been applied to full-scale devices and evaluated for hemocompatibility under clinical blood flow conditions. We applied a dual-action slippery liquid-infused (LI) nitric oxide (NO)-releasing material modification (LINO) to full-scale blood circulation tubing for extracorporeal lung support and evaluated the tubing ex vivo using swine whole blood circulated for 6 h at a clinically relevant flow. LINO tubing was compared to unmodified tubing (CTRL) and isolated LI and NO-releasing modifications (n = 9/group). The primary objective was to evaluate safety and blood compatibility of this approach, prior to progression to in vivo testing of efficacy in animal models. The secondary objective was to evaluate coagulation outcomes relevant to hemocompatibility. No untoward effects of the coating, such as elevated methemoglobin fraction, were observed. Additionally, LINO delayed platelet loss until 6 h versus the reduction in platelet count in CTRL at 3 h. At 6 h, LINO significantly reduced the concentration of platelets in an activated P-selectin expressing state versus CTRL (32 ± 1% decrease, p = .02). Blood clot deposition was significantly reduced on LINO blood pumps (p = .007) and numerically reduced on tubing versus CTRL. Following blood exposure, LINO tubing continued to produce a measurable NO-flux (0.20 ± 0.06 × 10-10  mol cm-2  min-1 ). LINO is a potential solution to reduce circuit-related bleeding and clotting during extracorporeal organ support, pending future extended testing in vivo using full-scale extracorporeal lung support devices.

18.
J Allergy Clin Immunol ; 2022 Nov 15.
Article in English | MEDLINE | ID: mdl-36400177

ABSTRACT

BACKGROUND: Prior studies suggest that vitamin D may modify the effects of environmental exposures, however, none have investigated gestational vitamin D and cumulative tobacco smoke exposure (TSE) throughout pregnancy and early life. OBJECTIVE: We investigated the effects of early life TSE on child lung function and the modulatory effects of gestational vitamin D on this association. METHODS: The Vitamin D Antenatal Asthma Reduction Trial recruited nonsmoking pregnant women and followed the mother-child pairs to age 6 years. TSE was assessed with questionnaires and plasma cotinine measurements in the mothers (10-18 and 32-38 gestational weeks) and children (1, 3, and 6 years). Cumulative TSE was calculated from the repeated cotinine measurements. 25-hydroxyvitamin D (25[OH]D) levels were measured at 10-18 and 32-38 gestational weeks. Lung function was assessed at 6 years with spirometry and impulse oscillometry. RESULTS: Of the 476 mother-child pairs, 205 (43%) had increased cotinine levels at ≥1 time point. Cumulative TSE was associated with decreased FEV1 (ß -0.043 L, P=0.018) and increased respiratory resistance (R5; ß 0.060 kPa/L/s, P=0.002). This association persisted in subjects with insufficient (<30 ng/ml) 25(OH)D levels throughout pregnancy (ß 0.077 kPa/L/s, P=0.016 for R5) but not among those with sufficient levels throughout pregnancy. CONCLUSION: Cumulative TSE from pregnancy to childhood is associated with dose- and duration-dependent decreases in child lung function at 6 years even in the absence of reported maternal smoking. Gestational vitamin D may modulate this effect and have therapeutic potential for minimizing the adverse effect of TSE on lung throughout early life.

19.
Chron Respir Dis ; 19: 14799731221139294, 2022.
Article in English | MEDLINE | ID: mdl-36351077

ABSTRACT

BACKGROUND: Low body mass index (BMI) is associated with COPD, but temporal relationships between airflow obstruction (AO) development and emphysematous change are unclear. We investigated longitudinal changes in BMI, AO, and lung density throughout adulthood using data from the Framingham Offspring Cohort (FOC). METHODS: BMI trajectories were modelled throughout adulthood in 4587 FOC participants from Exam 2 (mean age = 44), through Exam 9 (mean age = 71), in AO participants and non-AO participants (AO n = 1036), determined by spirometry, using fractional polynomial growth curves. This process was repeated for low lung density (LLD) and non LLD participants (LLD n = 225) determined by Computed Tomography. Spirometry decline was compared separately between tertiles of BMI in those aged <40 years and associations between fat and lean mass (measured using Dual Energy X-ray Absorptiometry, DEXA) and development of AO and LLD were also assessed. Additional analyses were performed with adjustment for smoking volume. RESULTS: The BMI trajectory from 30 years of age was visually lower in the AO group than both non-AO smokers (non-<AO-S) and non-AO non-smokers (non-AO-N). Similarly, BMI trajectories were visually lower in participants with LLD throughout adulthood compared to normal lung density smokers and non-smokers. Differences remained after adjustment for smoking volume. The lowest BMI tertile in ages <40 years was associated with the steepest subsequent decline in FEV1/FVC ratio in both sexes. CONCLUSION: Mean BMI is lower throughout adulthood in AO and LLD participants. Lower BMI is associated with a steeper decline in the ratio of FEV1/FVC. These findings suggest body mass may precede and potentially have a role in the development of COPD lung pathophysiology.


Subject(s)
Emphysema , Lung Diseases , Pulmonary Disease, Chronic Obstructive , Pulmonary Emphysema , Male , Female , Humans , Adult , Aged , Body Mass Index , Forced Expiratory Volume/physiology , Vital Capacity/physiology , Pulmonary Emphysema/diagnostic imaging , Lung/diagnostic imaging , Spirometry , Pulmonary Disease, Chronic Obstructive/epidemiology
20.
J Struct Biol ; 214(4): 107918, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36343842

ABSTRACT

C/EBPß is a key regulator of numerous cellular processes, but it can also contribute to tumorigenesis and viral diseases. It binds to specific DNA sequences (C/EBP sites) and interacts with other transcription factors to control expression of multiple eukaryotic genes in a tissue and cell-type dependent manner. A body of evidence has established that cell-type-specific regulatory information is contained in the local DNA sequence of the binding motif. In human epithelial cells, C/EBPß is an essential cofactor for TGFß signaling in the case of Smad2/3/4 and FoxO-dependent induction of the cell cycle inhibitor, p15INK4b. In the TGFß-responsive region 2 of the p15INK4b promoter, the Smad binding site is flanked by a C/EBP site, CTTAA•GAAAG, which differs from the canonical, palindromic ATTGC•GCAAT motif. The X-ray crystal structure of C/EBPß bound to the p15INK4b promoter fragment shows how GCGC-to-AAGA substitution generates changes in the intermolecular interactions in the protein-DNA interface that enhances C/EBPß binding specificity, limits possible epigenetic regulation of the promoter, and generates a DNA element with a unique pattern of methyl groups in the major groove. Significantly, CT/GA dinucleotides located at the 5'ends of the double stranded element maintain local narrowing of the DNA minor groove width that is necessary for DNA recognition. Our results suggest that C/EBPß would accept all forms of modified cytosine in the context of the CpT site. This contrasts with the effect on the consensus motif, where C/EBPß binding is modestly increased by cytosine methylation, but substantially decreased by hydroxymethylation.

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