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1.
Pediatr Res ; 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38811718

RESUMO

BACKGROUND: Preterm infants are susceptible to oxidative stress and prone to respiratory diseases. Autophagy is an important defense mechanism against oxidative-stress-induced cell damage and involved in lung development and respiratory morbidity. We hypothesized that autophagy marker levels differ between preterm and term infants. METHODS: In the prospective Basel-Bern Infant Lung Development (BILD) birth cohort we compared cord blood levels of macroautophagy (Beclin-1, LC3B), selective autophagy (p62) and regulation of autophagy (SIRT1) in 64 preterm and 453 term infants. RESULTS: Beclin-1 and LC3B did not differ between preterm and term infants. However, p62 was higher (0.37, 95% confidence interval (CI) 0.05;0.69 in log2-transformed level, p = 0.025, padj = 0.050) and SIRT1 lower in preterm infants (-0.55, 95% CI -0.78;-0.31 in log2-transformed level, padj < 0.001). Furthermore, p62 decreased (padj-value for smoothing function was 0.018) and SIRT1 increased (0.10, 95% CI 0.07;0.13 in log2-transformed level, padj < 0.001) with increasing gestational age. CONCLUSION: Our findings suggest differential levels of key autophagy markers between preterm and term infants. This adds to the knowledge of the sparsely studied field of autophagy mechanisms in preterm infants and might be linked to impaired oxidative stress response, preterm birth, impaired lung development and higher susceptibility to respiratory morbidity in preterm infants. IMPACT: To the best of our knowledge, this is the first study to investigate autophagy marker levels between human preterm and term infants in a large population-based sample in cord blood plasma This study demonstrates differential levels of key autophagy markers in preterm compared to term infants and an association with gestational age This may be linked to impaired oxidative stress response or developmental aspects and provide bases for future studies investigating the association with respiratory morbidity.

2.
Am J Respir Crit Care Med ; 205(1): 99-107, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34587471

RESUMO

Rationale: Infants born prematurely have impaired capacity to deal with oxidative stress shortly after birth. Objectives: We hypothesize that the relative impact of exposure to air pollution on lung function is higher in preterm than in term infants. Methods: In the prospective BILD (Basel-Bern Infant Lung Development) birth cohort of 254 preterm and 517 term infants, we investigated associations of particulate matter ⩽10 µm in aerodynamic diameter (PM10) and nitrogen dioxide with lung function at 44 weeks' postconceptional age and exhaled markers of inflammation and oxidative stress response (fractional exhaled nitric oxide [FeNO]) in an explorative hypothesis-driven study design. Multilevel mixed-effects models were used and adjusted for known confounders. Measurements and Main Results: Significant associations of PM10 during the second trimester of pregnancy with lung function and FeNO were found in term and preterm infants. Importantly, we observed stronger positive associations in preterm infants (born 32-36 wk), with an increase of 184.9 (95% confidence interval [CI], 79.1-290.7) ml/min [Formula: see text]e per 10-µg/m3 increase in PM10, than in term infants (75.3; 95% CI, 19.7-130.8 ml/min) (pprematurity × PM10 interaction = 0.04, after multiple comparison adjustment padj = 0.09). Associations of PM10 and FeNO differed between moderate to late preterm (3.4; 95% CI, -0.1 to 6.8 ppb) and term (-0.3; 95% CI, -1.5 to 0.9 ppb) infants, and the interaction with prematurity was significant (pprematurity × PM10 interaction = 0.006, padj = 0.036). Conclusions: Preterm infants showed significantly higher susceptibility even to low to moderate prenatal air pollution exposure than term infants, leading to increased impairment of postnatal lung function. FeNO results further elucidate differences in inflammatory/oxidative stress response when comparing preterm infants with term infants.


Assuntos
Poluentes Atmosféricos/toxicidade , Poluição do Ar/efeitos adversos , Recém-Nascido Prematuro/fisiologia , Pulmão/fisiopatologia , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/etiologia , Poluição do Ar/análise , Poluição do Ar/estatística & dados numéricos , Estudos de Casos e Controles , Feminino , Humanos , Recém-Nascido , Modelos Lineares , Pulmão/efeitos dos fármacos , Masculino , Exposição Materna/estatística & dados numéricos , Dióxido de Nitrogênio/toxicidade , Estresse Oxidativo , Material Particulado/toxicidade , Gravidez , Estudos Prospectivos , Testes de Função Respiratória , Suíça
3.
Allergy ; 77(12): 3606-3616, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35302662

RESUMO

BACKGROUND: Pollen exposure is associated with respiratory symptoms in children and adults. However, the association of pollen exposure with respiratory symptoms during infancy, a particularly vulnerable period, remains unclear. We examined whether pollen exposure is associated with respiratory symptoms in infants and whether maternal atopy, infant's sex or air pollution modifies this association. METHODS: We investigated 14,874 observations from 401 healthy infants of a prospective birth cohort. The association between pollen exposure and respiratory symptoms, assessed in weekly telephone interviews, was evaluated using generalized additive mixed models (GAMMs). Effect modification by maternal atopy, infant's sex, and air pollution (NO2 , PM2.5 ) was assessed with interaction terms. RESULTS: Per infant, 37 ± 2 (mean ± SD) respiratory symptom scores were assessed during the analysis period (January through September). Pollen exposure was associated with increased respiratory symptoms during the daytime (RR [95% CI] per 10% pollen/m3 : combined 1.006 [1.002, 1.009]; tree 1.005 [1.002, 1.008]; grass 1.009 [1.000, 1.23]) and nighttime (combined 1.003 [0.999, 1.007]; tree 1.003 [0.999, 1.007]; grass 1.014 [1.004, 1.024]). While there was no effect modification by maternal atopy and infant's sex, a complex crossover interaction between combined pollen and PM2.5 was found (p-value 0.003). CONCLUSION: Even as early as during the first year of life, pollen exposure was associated with an increased risk of respiratory symptoms, independent of maternal atopy and infant's sex. Because infancy is a particularly vulnerable period for lung development, the identified adverse effect of pollen exposure may be relevant for the evolvement of chronic childhood asthma.


Assuntos
Poluição do Ar , Asma , Lactente , Criança , Adulto , Humanos , Estudos Prospectivos , Pólen/efeitos adversos , Poluição do Ar/efeitos adversos , Asma/epidemiologia , Asma/etiologia , Asma/diagnóstico , Material Particulado
4.
Am J Obstet Gynecol ; 226(2): 257.e1-257.e11, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34364843

RESUMO

BACKGROUND: Globally, the number of children born by cesarean delivery is constantly increasing. However, hormonal and physiological changes associated with labor and vaginal delivery are considered necessary for lung maturation. OBJECTIVE: We aimed to assess whether the mode of delivery is associated with changes in respiratory and atopic outcomes during infancy and at school age. STUDY DESIGN: We included 578 children, born at ≥37 weeks of gestation, from a prospective birth cohort study. We compared weekly respiratory symptoms throughout the first year of life and infant lung function (tidal breathing and multiple-breath washout) at 5 weeks of age between children born by cesarean delivery (N=114) and those born by vaginal delivery (N=464) after term pregnancy in healthy women. At a follow-up visit conducted at 6 years of age (N=371, of which 65 were delivered by cesarean delivery), we assessed respiratory, atopic, and lung function outcomes (spirometry, body plethysmography, and multiple-breath washout). We performed adjusted regression analyses to examine the association between cesarean delivery and respiratory and atopic outcomes. To account for multiple testing, we used the Bonferroni correction, which led to an adapted significance level of P<.002. RESULTS: During infancy, children born by cesarean delivery did not have more respiratory symptoms than those born by vaginal delivery (median, 4 weeks; interquartile range, 7 weeks vs median, 5 weeks; interquartile range, 7 weeks; adjusted incidence rate ratio, 0.8; 95% confidence interval, 0.6-1.0; P=.02). Infant lung function was similar between the groups. Children born by cesarean delivery did not have a higher incidence of "ever wheezing" (adjusted odds ratio, 0.9; 95% confidence interval, 0.5-1.8; P=.78) or current asthma (adjusted odds ratio, 0.4; 95% confidence interval, 0.0-3.5; P=.42) at school age than those born by vaginal delivery. There was no difference in the lung function parameters between the groups. CONCLUSION: Cesarean delivery was not associated with respiratory symptoms in the first year of life, nor with different respiratory or atopic outcomes at school age, when compared with vaginal delivery. Our results indicate that there are no long-term consequences on the respiratory health of the child associated with cesarean delivery.


Assuntos
Asma/epidemiologia , Cesárea/efeitos adversos , Sons Respiratórios/fisiopatologia , Asma/etiologia , Parto Obstétrico , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Gravidez , Estudos Prospectivos , Testes de Função Respiratória , Fatores de Risco
5.
Environ Res ; 203: 111776, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34329637

RESUMO

STUDY OBJECTIVES: During infancy, adequate sleep is crucial for physical and neurocognitive development. In adults and children, night-time noise exposure is associated with sleep disturbances. However, whether and to what extent infants' sleep is affected, is unknown. Thus, this study investigated the relationship between nocturnal transportation noise and actimetry-derived habitual sleep behavior across the first year of life. METHODS: In 144 healthy infants (63 girls), nocturnal (23:00-7:00) transportation noise (i.e., road, railway, and aircraft) was modelled at the infants' individual places of residence. Using actimetry, we recorded movement patterns for 11 days in a longitudinal design at 3, 6, and 12 months of age and derived the recently proposed core sleep composites of night-time sleep duration, activity, and variability. Using linear mixed-effects models, we determined associations between noise exposure and sleep composites. Sex, gestational age, parents' highest educational level, infants' age, and the existence of siblings served as control variables. RESULTS: In models without interactions, night-time transportation noise was unrelated to sleep composites across the first year of life (p > .16). Exploratory analyses of an interaction between noise and the existence of siblings yielded an association between night-time transportation noise and sleep duration in infants without siblings only (p = .004). CONCLUSION: In our study, sleep in infants during the first year of life was relatively robust against external perturbation by night-time transportation noise. However, particularly in children without siblings increasing night-time transportation noise reduced sleep duration. This suggests that the habitual noise environment may modulate individual susceptibility to adverse effects of noise on sleep.


Assuntos
Ruído dos Transportes , Transtornos do Sono-Vigília , Adulto , Aeronaves , Criança , Exposição Ambiental , Feminino , Humanos , Lactente , Estudos Longitudinais , Ruído dos Transportes/efeitos adversos , Sono
6.
Thorax ; 76(10): 996-1001, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33632766

RESUMO

RATIONALE: Asthma in pregnancy is associated with respiratory diseases in the offspring. OBJECTIVE: To investigate if maternal asthma is associated with lung function in early life. METHODS: Data on lung function measured at 5-6 weeks of age were combined from two large birth cohorts: the Bern Infant Lung Development (BILD) and the Australian Breathing for Life Trial (BLT) birth cohorts conducted at three study sites (Bern, Switzerland; Newcastle and Sydney, Australia). The main outcome variable was time to reach peak tidal expiratory flow as a percentage of total expiratory time(tPTEF:tE%). Bayesian linear hierarchical regression analyses controlling for study site as random effect were performed to estimate the effect of maternal asthma on the main outcome, adjusting for sex, birth order, breast feeding, weight gain and gestational age. In separate adjusted Bayesian models an interaction between maternal asthma and sex was investigated by including an interaction term. MEASUREMENTS AND MAIN RESULTS: All 406 BLT infants were born to mothers with asthma in pregnancy, while 193 of the 213 (91%) BILD infants were born to mothers without asthma. A significant interaction between maternal asthma and male sex was negatively associated with tPTEF:tE% (intercept 37.5; estimate: -3.5; 95% credible interval -6.8 to -0.1). Comparing the model posterior probabilities provided decisive evidence in favour of an interaction between maternal asthma and male sex (Bayes factor 33.5). CONCLUSIONS: Maternal asthma is associated with lower lung function in male babies, which may have lifelong implications on their lung function trajectories and future risk of wheezing and asthma.


Assuntos
Asma , Coorte de Nascimento , Austrália/epidemiologia , Teorema de Bayes , Feminino , Humanos , Lactente , Pulmão , Masculino , Gravidez
7.
Anal Chem ; 93(47): 15579-15583, 2021 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-34780695

RESUMO

Breath analysis by secondary electrospray ionization-high resolution mass spectrometry (SESI-HRMS) offers the possibility to measure comprehensive metabolic profiles. The technology is currently being deployed in several clinical settings in Switzerland and China. However, patients are required to exhale directly into the device located in a dedicated room. Consequently, clinical implementation in patients incapable of performing necessary exhalation maneuvers (e.g., infants) or immobile (e.g., too weak, elderly, or in intensive care) remains a challenge. The aim of this study was to develop a method to extend such breath analysis capabilities to this subpopulation of patients by collecting breath samples remotely (offline) and promptly (within 10 min) transfer them to SESI-HRMS for chemical analysis. We initially assessed the method in adults by comparing breath mass spectra collected offline with Nalophan bags against spectra of breath samples collected in real time. In total, 13 adults provided 176 pairs of real-time and offline measurements. Lin's concordance correlation coefficient (CCC) was used to estimate the agreement between offline and real-time analyses. Here, 1249 mass spectral features (55% of total detected) exhibited Lin's CCC > 0.6. Subsequently, the method was successfully deployed to analyze breath samples from infants (n = 16), obtaining as a result SESI-HRMS breath profiles. To demonstrate the clinical feasibility of the method, we measured in parallel other clinical variables: (i) lung function, which characterizes the breathing patterns, and (ii) nitric oxide, which is a surrogate marker of airway inflammation. As a showcase, we focused our analysis on the exhaled oxidative stress marker 4-hydroxynonenal and its association with nitric oxide and minute ventilation.


Assuntos
Testes Respiratórios , Expiração , Adulto , Idoso , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Pulmão , Óxido Nítrico
8.
Eur Respir J ; 58(5)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33863747

RESUMO

BACKGROUND: Diagnosing asthma in children represents an important clinical challenge. There is no single gold-standard test to confirm the diagnosis. Consequently, over- and under-diagnosis of asthma is frequent in children. METHODS: A task force supported by the European Respiratory Society has developed these evidence-based clinical practice guidelines for the diagnosis of asthma in children aged 5-16 years using nine Population, Intervention, Comparator and Outcome (PICO) questions. The task force conducted systematic literature searches for all PICO questions and screened the outputs from these, including relevant full-text articles. All task force members approved the final decision for inclusion of research papers. The task force assessed the quality of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. RESULTS: The task force then developed a diagnostic algorithm based on the critical appraisal of the PICO questions, preferences expressed by lay members and test availability. Proposed cut-offs were determined based on the best available evidence. The task force formulated recommendations using the GRADE Evidence to Decision framework. CONCLUSION: Based on the critical appraisal of the evidence and the Evidence to Decision framework, the task force recommends spirometry, bronchodilator reversibility testing and exhaled nitric oxide fraction as first-line diagnostic tests in children under investigation for asthma. The task force recommends against diagnosing asthma in children based on clinical history alone or following a single abnormal objective test. Finally, this guideline also proposes a set of research priorities to improve asthma diagnosis in children in the future.


Assuntos
Asma , Asma/diagnóstico , Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Criança , Expiração , Humanos , Óxido Nítrico , Espirometria
9.
Environ Res ; 202: 111633, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34256075

RESUMO

BACKGROUND: Air pollution and greenness are associated with short- and long-term respiratory health in children but the underlying mechanisms are only scarcely investigated. The nasal microbiota during the first year of life has been shown to be associated with respiratory tract infections and asthma development. Thus, an interplay between greenness, air pollution and the early nasal microbiota may contribute to short- and long-term respiratory health. We aimed to examine associations between fine particulate matter (PM2.5), nitrogen dioxide (NO2) and greenness with the nasal microbiota of healthy infants during the first year of life in a European context with low-to-moderate air pollution levels. METHODS: Microbiota characterization was performed using 16 S rRNA pyrosequencing of 846 nasal swabs collected fortnightly from 47 healthy infants of the prospective Basel-Bern Infant Lung Development (BILD) cohort. We investigated the association of satellite-based greenness and an 8-day-average exposure to air pollution (PM2.5, NO2) with the nasal microbiota during the first year of life. Exposures were individually estimated with novel spatial-temporal models incorporating satellite data. Generalized additive mixed models adjusted for known confounders and considering the autoregressive correlation structure of the data were used for analysis. RESULTS: Mean (SD) PM2.5 level was 17.1 (3.8 µg/m3) and mean (SD) NO2 level was 19.7 (7.9 µg/m3). Increased PM2.5 and increased NO2 were associated with reduced within-subject Ruzicka dissimilarity (PM2.5: per 1 µg/m3 -0.004, 95% CI -0.008, -0.001; NO2: per 1 µg/m3 -0.004, 95% CI -0.007, -0.001). Whole microbial community comparison with nonmetric multidimensional scaling revealed distinct microbiota profiles for different PM2.5 exposure levels. Increased NO2 was additionally associated with reduced abundance of Corynebacteriaceae (per 1 µg/m3: -0.027, 95% CI -0.053, -0.001). No associations were found between greenness and the nasal microbiota. CONCLUSION: Air pollution was associated with Ruzicka dissimilarity and relative abundance of Corynebacteriaceae. This suggests that even low-to-moderate exposure to air pollution may impact the nasal microbiota during the first year of life. Our results will be useful for future studies assessing the clinical relevance of air-pollution-induced alterations of the nasal microbiota with subsequent respiratory disease development.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Microbiota , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/toxicidade , Poluição do Ar/análise , Poluição do Ar/estatística & dados numéricos , Criança , Exposição Ambiental/análise , Exposição Ambiental/estatística & dados numéricos , Humanos , Lactente , Estudos Longitudinais , Dióxido de Nitrogênio/análise , Material Particulado/análise , Material Particulado/toxicidade , Estudos Prospectivos
10.
Eur Respir J ; 55(4)2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31862765

RESUMO

BACKGROUND: The multiple breath nitrogen washout (N2MBW) technique is increasingly used to assess the degree of ventilation inhomogeneity in school-aged children with lung disease. However, reference values for healthy children are currently not available. The aim of this study was to generate reference values for N2MBW outcomes in a cohort of healthy Caucasian school-aged children. METHODS: N2MBW data from healthy Caucasian school-age children between 6 and 18 years old were collected from four experienced centres. Measurements were performed using an ultrasonic flowmeter (Exhalyzer D, Eco Medics AG, Duernten, Switzerland) and were analysed with commercial software (Spiroware version 3.2.1, Eco Medics AG). Normative values and upper limits of normal (ULN) were generated for lung clearance index (LCI) at 2.5% (LCI2.5%) and at 5% (LCI5%) of the initial nitrogen concentration and for moment ratios (M1/M0 and M2/M0). A prediction equation was generated for functional residual capacity (FRC). RESULTS: Analysis used 485 trials from 180 healthy Caucasian children aged from 6 to 18 years old. While LCI increased with age, this increase was negligible (0.04 units·year-1 for LCI2.5%) and therefore fixed ULN were defined for this age group. These limits were 7.91 for LCI2.5%, 5.73 for LCI5%, 1.75 for M1/M0 and 6.15 for M2/M0, respectively. Height and weight were found to be independent predictors of FRC. CONCLUSION: We report reference values for N2MBW outcomes measured on a commercially available ultrasonic flowmeter device (Exhalyzer D, Eco Medics AG) in healthy school-aged children to allow accurate interpretation of ventilation distribution outcomes and FRC in children with lung disease.


Assuntos
Pulmão , Instituições Acadêmicas , Adolescente , Testes Respiratórios , Criança , Capacidade Residual Funcional , Humanos , Testes de Função Respiratória , Suíça
11.
Am J Respir Crit Care Med ; 199(8): 987-995, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30321487

RESUMO

RATIONALE: The prognostic value of cardiopulmonary exercise testing (CPET) for survival in cystic fibrosis (CF) in the context of current clinical management, when controlling for other known prognostic factors, is unclear. OBJECTIVES: To determine the prognostic value of CPET-derived measures beyond peak oxygen uptake ( V. o2peak) following rigorous adjustment for other predictors. METHODS: Data from 10 CF centers in Australia, Europe, and North America were collected retrospectively. A total of 510 patients completed a cycle CPET between January 2000 and December 2007, of which 433 fulfilled the criteria for a maximal effort. Time to death/lung transplantation was analyzed using Cox proportional hazards regression. In addition, phenotyping using hierarchical Ward clustering was performed to characterize high-risk subgroups. MEASUREMENTS AND MAIN RESULTS: Cox regression showed, even after adjustment for sex, FEV1% predicted, body mass index (z-score), age at CPET, Pseudomonas aeruginosa status, and CF-related diabetes as covariates in the model, that V. o2peak in % predicted (hazard ratio [HR], 0.964; 95% confidence interval [CI], 0.944-0.986), peak work rate (% predicted; HR, 0.969; 95% CI, 0.951-0.988), ventilatory equivalent for oxygen (HR, 1.085; 95% CI, 1.041-1.132), and carbon dioxide (HR, 1.060; 95% CI, 1.007-1.115) (all P < 0.05) were significant predictors of death or lung transplantation at 10-year follow-up. Phenotyping revealed that CPET-derived measures were important for clustering. We identified a high-risk cluster characterized by poor lung function, nutritional status, and exercise capacity. CONCLUSIONS: CPET provides additional prognostic information to established predictors of death/lung transplantation in CF. High-risk patients may especially benefit from regular monitoring of exercise capacity and exercise counseling.


Assuntos
Fibrose Cística/diagnóstico , Teste de Esforço , Adolescente , Adulto , Criança , Fibrose Cística/mortalidade , Fibrose Cística/fisiopatologia , Fibrose Cística/cirurgia , Feminino , Humanos , Transplante de Pulmão/estatística & dados numéricos , Masculino , Consumo de Oxigênio , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Adulto Jovem
12.
J Pediatr ; 205: 61-69.e1, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30416016

RESUMO

OBJECTIVE: To test whether low variability of tidal volume (VT) and capnographic indices are predictive of subsequent respiratory morbidity in preterm infants. STUDY DESIGN: In a birth cohort of 133 preterm infants, lung function was performed at 44 weeks postmenstrual age. Associations between the coefficient of variation (CV) of VT (CVVT) and of expired CO2 volume per breath (CVVE,CO2) with rehospitalization, wheeze, and inhalation therapy during infancy were assessed using logistic regression. Area under the curve (AUC) analysis was used to assess whether outcome prediction using bronchopulmonary dysplasia (BPD) classification was enhanced by CVVT or CVVE,CO2. RESULTS: For each IQR decrease in CVVT (range, 4%-35%) and CVVE,CO2 (range, 5%-40%), the OR for rehospitalization increased by 2.25 (95% CI, 1.21-4.20) and 2.31 (95% CI, 1.20-4.45), respectively. The predictive value of BPD for rehospitalization was improved when CVVT or CVVE,CO2 was added to the model, with the AUC increasing from 0.56 to 0.66 in both models. No association was found for the other outcomes. CONCLUSIONS: Compared with BPD classification alone, including near-term variability of tidal breathing parameters improves the prediction of rehospitalization in infancy. These findings may inform parent counseling and monitoring strategies in preterm infants.


Assuntos
Displasia Broncopulmonar/fisiopatologia , Pulmão/fisiopatologia , Volume de Ventilação Pulmonar/fisiologia , Capnografia/métodos , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Modelos Logísticos , Masculino , Readmissão do Paciente , Estudos Prospectivos , Curva ROC , Respiração Artificial/métodos , Respiração Artificial/estatística & dados numéricos , Testes de Função Respiratória/métodos , Taxa Respiratória , Fatores de Risco , Índice de Gravidade de Doença
13.
Anal Bioanal Chem ; 411(19): 4883-4898, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30989265

RESUMO

Despite the attractiveness of breath analysis as a non-invasive means to retrieve relevant metabolic information, its introduction into routine clinical practice remains a challenge. Among all the different analytical techniques available to interrogate exhaled breath, secondary electrospray ionization high-resolution mass spectrometry (SESI-HRMS) offers a number of advantages (e.g., real-time, yet wide, metabolome coverage) that makes it ideal for untargeted and targeted studies. However, so far, SESI-HRMS has relied mostly on lab-built prototypes, making it difficult to standardize breath sampling and subsequent analysis, hence preventing further developments such as multi-center clinical studies. To address this issue, we present here a number of new developments. In particular, we have characterized a new SESI interface featuring real-time readout of critical exhalation parameters such as CO2, exhalation flow rate, and exhaled volume. Four healthy subjects provided breath specimens over a period of 1 month to characterize the stability of the SESI-HRMS system. A first assessment of the repeatability of the system using a gas standard revealed a coefficient of variation (CV) of 2.9%. Three classes of aldehydes, namely 4-hydroxy-2-alkenals, 2-alkenals and 4-hydroxy-2,6-alkedienals-hypothesized to be markers of oxidative stress-were chosen as representative metabolites of interest to evaluate the repeatability and reproducibility of this breath analysis analytical platform. Median and interquartile ranges (IQRs) of CVs for CO2, exhalation flow rate, and exhaled volume were 3.2% (1.5%), 3.1% (1.9%), and 5.0% (4.6%), respectively. Despite the high repeatability observed for these parameters, we observed a systematic decay in the signal during repeated measurements for the shorter fatty aldehydes, which eventually reached a steady state after three/four repeated exhalations. In contrast, longer fatty aldehydes showed a steady behavior, independent of the number of repeated exhalation maneuvers. We hypothesize that this highly molecule-specific and individual-independent behavior may be explained by the fact that shorter aldehydes (with higher estimated blood-to-air partition coefficients; approaching 100) mainly get exchanged in the airways of the respiratory system, whereas the longer aldehydes (with smaller estimated blood-to-air partition coefficients; approaching 10) are thought to exchange mostly in the alveoli. Exclusion of the first three exhalations from the analysis led to a median CV (IQR) of 6.7 % (5.5 %) for the said classes of aldehydes. We found that such intra-subject variability is in general much lower than inter-subject variability (median relative differences between subjects 48.2%), suggesting that the system is suitable to capture such differences. No batch effect due to sampling date was observed, overall suggesting that the intra-subject variability measured for these series of aldehydes was biological rather than technical. High correlations found among the series of aldehydes support this notion. Finally, recommendations for breath sampling and analysis for SESI-HRMS users are provided with the aim of harmonizing procedures and improving future inter-laboratory comparisons. Graphical abstract.


Assuntos
Testes Respiratórios/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Adulto , Bactérias/isolamento & purificação , Biomarcadores/metabolismo , Expiração , Feminino , Filtração/instrumentação , Humanos , Masculino , Metabolômica , Estresse Oxidativo , Reprodutibilidade dos Testes , Vírus/isolamento & purificação
16.
J Perinat Med ; 45(5): 627-633, 2017 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-28195553

RESUMO

AIM: To evaluate risk factors for pulmonary hemorrhage (PH) in extremely low birth weight infants (ELBW) taking into consideration coagulation screens, platelet counts, transfusion of fresh frozen plasma (FFP), and platelet concentrates prior to PH. PATIENTS AND METHODS: A retrospective case-control study consisting of 20 ELBW infants with PH and 40 matched controls. Coagulation screens, platelet counts at birth and at onset of PH, and transfusion frequencies prior to PH were compared to case-controls at birth and 24-96 h after birth. RESULTS: While the initial platelet counts, fibrinogen concentrations, and international normalized ratios were similar in PH infants and controls, the activated partial prothrombin time was prolonged (P=0.05). Compared to 28% of case controls (P<0.05), 55% of infants with later PH received FFP prior to PH. Platelet counts were significantly lower at onset of PH (median 81/nL; range: 37-236/nL) compared to controls (166/nL; 27-460/nL; P<0.005). Multivariate analysis indicated a lack of antenatal steroids, supplemental oxygen, and transfusion of FFP as independent risk factors for PH. CONCLUSION: Prolonged activated partial thromboplastin time (aPTT) might be associated with PH. PH does not primarily depend upon severe thrombocytopenia. A developmental mismatch in hemostasis by transfusion of adult donor plasma should be considered a risk factor for PH.


Assuntos
Hemorragia/epidemiologia , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Pneumopatias/epidemiologia , Reação Transfusional/complicações , Alemanha/epidemiologia , Hemorragia/sangue , Hemorragia/etiologia , Humanos , Recém-Nascido , Pneumopatias/sangue , Pneumopatias/etiologia , Plasma , Estudos Retrospectivos , Fatores de Risco
17.
Am J Med Genet A ; 170A(5): 1274-7, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26762561

RESUMO

Weaver syndrome is an overgrowth syndrome characterized by pre- and postnatal overgrowth with distinctive craniofacial appearance. Mutations in the enhancer of zeste homolog 2 (EZH2) gene were found to cause Weaver syndrome, and have been associated with hematologic malignancies, including acute myeloid leukemia (AML). We present the first report of a patient with Weaver syndrome, who developed AML and harbored an EZH2 mutation. The clinical course of the 16-year-old female adolescent patient was complicated by a secondary hemophagocytic lymphohistiocytosis. Genomic DNA was isolated from bone marrow cells at AML diagnosis. Polymerase chain reactions were performed with primers covering all exons of the EZH2 gene. We found a novel heterozygous EZH2 mutation within exon 5 that caused an amino acid change from proline to leucine at position 132 (p.Pro132Leu) within the catalytic D1 domain. Analysis of a remission sample also showed this mutation, indicating a germline mutation. It remains to be elucidated whether EZH2 mutations contribute to disease severity in specific AML cases.


Assuntos
Anormalidades Múltiplas/genética , Hipotireoidismo Congênito/genética , Anormalidades Craniofaciais/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Deformidades Congênitas da Mão/genética , Leucemia Mieloide Aguda/genética , Linfo-Histiocitose Hemofagocítica/genética , Anormalidades Múltiplas/fisiopatologia , Adolescente , Substituição de Aminoácidos/genética , Hipotireoidismo Congênito/complicações , Hipotireoidismo Congênito/fisiopatologia , Anormalidades Craniofaciais/complicações , Anormalidades Craniofaciais/fisiopatologia , Feminino , Deformidades Congênitas da Mão/complicações , Deformidades Congênitas da Mão/fisiopatologia , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/fisiopatologia , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/fisiopatologia
19.
BMC Pulm Med ; 16(1): 81, 2016 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-27193312

RESUMO

BACKGROUND: Single nucleotide polymorphisms (SNPs) in chitinase 3-like 1 (CHI3L1), the gene encoding YKL-40, and increased serum YKL-40 levels are associated with severe forms of asthma. It has never been addressed whether SNPs in CHI3L1 and cord blood YKL-40 levels could already serve as potential biomarkers for milder forms of asthma. We assessed in an unselected population whether SNPs in CHI3L1 and cord blood YKL-40 levels at birth are associated with respiratory symptoms, lung function changes, asthma, and atopy. METHODS: In a prospective birth cohort of healthy term-born neonates (n = 260), we studied CHI3L1 polymorphisms, and measured cord blood YKL-40 levels by ELISA in (n = 170) infants. Lung function was performed at 5 weeks and 6 years. Respiratory health during the first year of life was assessed weekly by telephone interviews. Diagnosis of asthma and allergic sensitisation was assessed at 6 years (n = 142). RESULTS: The SNP rs10399805 was significantly associated with asthma at 6 years. The odds ratio for asthma was 4.5 (95 % CI 1.59-12.94) per T-allele. This finding was unchanged when adjusting for cord blood YKL-40 levels. There was no significant association for cord blood YKL-40 levels and asthma. SNPs in CHI3L1 and cord blood YKL-40 were not associated with lung function measurements at 5 weeks and 6 years, respiratory symptoms in the first year, and allergic sensitisation at 6 years. CONCLUSION: Genetic variation in CHI3L1 might be related to the development of milder forms of asthma. Larger studies are warranted to establish the role of YKL-40 in that pathway.


Assuntos
Asma/sangue , Asma/genética , Proteína 1 Semelhante à Quitinase-3/sangue , Biomarcadores/sangue , Criança , Proteína 1 Semelhante à Quitinase-3/genética , Feminino , Sangue Fetal/metabolismo , Predisposição Genética para Doença , Humanos , Hipersensibilidade Imediata , Recém-Nascido , Modelos Lineares , Masculino , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Estudos Prospectivos , Testes de Função Respiratória , Fatores de Risco , Suíça
20.
J Biol Chem ; 289(6): 3262-75, 2014 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-24347165

RESUMO

Glucocorticoids represent the mainstay therapy for many lung diseases, providing outstanding management of asthma but performing surprisingly poorly in patients with acute respiratory distress syndrome, chronic obstructive pulmonary disease, lung fibrosis, and blunted lung development associated with bronchopulmonary dysplasia in preterm infants. TGF-ß is a pathogenic mediator of all four of these diseases, prompting us to explore glucocorticoid/TGF-ß signaling cross-talk. Glucocorticoids, including dexamethasone, methylprednisolone, budesonide, and fluticasone, potentiated TGF-ß signaling by the Acvrl1/Smad1/5/8 signaling axis and blunted signaling by the Tgfbr1/Smad2/3 axis in NIH/3T3 cells, as well as primary lung fibroblasts, smooth muscle cells, and endothelial cells. Dexamethasone drove expression of the accessory type III TGF-ß receptor Tgfbr3, also called betaglycan. Tgfbr3 was demonstrated to be a "switch" that blunted Tgfbr1/Smad2/3 and potentiated Acvrl1/Smad1 signaling in lung fibroblasts. The Acvrl1/Smad1 axis, which was stimulated by dexamethasone, was active in lung fibroblasts and antagonized Tgfbr1/Smad2/3 signaling. Dexamethasone acted synergistically with TGF-ß to drive differentiation of primary lung fibroblasts to myofibroblasts, revealed by acquisition of smooth muscle actin and smooth muscle myosin, which are exclusively Smad1-dependent processes in fibroblasts. Administration of dexamethasone to live mice recapitulated these observations and revealed a lung-specific impact of dexamethasone on lung Tgfbr3 expression and phospho-Smad1 levels in vivo. These data point to an interesting and hitherto unknown impact of glucocorticoids on TGF-ß signaling in lung fibroblasts and other constituent cell types of the lung that may be relevant to lung physiology, as well as lung pathophysiology, in terms of drug/disease interactions.


Assuntos
Receptores de Ativinas Tipo I/metabolismo , Fibroblastos/metabolismo , Glucocorticoides/farmacologia , Pulmão/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteoglicanas/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Smad1/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Receptores de Ativinas Tipo I/genética , Animais , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Feminino , Fibroblastos/citologia , Humanos , Pulmão/citologia , Camundongos , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Células NIH 3T3 , Proteínas Serina-Treonina Quinases/genética , Proteoglicanas/genética , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/genética , Transdução de Sinais/fisiologia , Proteína Smad1/genética , Proteína Smad2/genética , Proteína Smad3/genética , Fator de Crescimento Transformador beta/genética
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