RESUMO
BACKGROUND: Identifying metabolomic profiles of children with asthma has the potential to increase understanding of asthma pathophysiology. OBJECTIVE: To identify differences in plasma metabolites between children with and without current asthma at mid-childhood. METHODS: We used untargeted mass spectrometry to measure plasma metabolites in 237 children (46 current asthma cases and 191 controls) in Project Viva, a birth cohort from eastern Massachusetts, USA. Current asthma was assessed at mid-childhood (mean age 8.0 years). The ability of a broad spectrum metabolic profile to distinguish between cases and controls was assessed using partial least squares discriminant analysis. We used logistic regression models to identify individual metabolites that were differentially abundant by case-control status. We tested significant metabolites for replication in 411 children from the VDAART clinical trial. RESULTS: There was no evidence of a systematic difference in the metabolome of children reporting current asthma vs. healthy controls according to partial least squares discriminant analysis. However, several metabolites were associated with odds of current asthma at a nominally significant threshold (P < .05), including a metabolite of nicotinamide (N1-Methyl-2-pyridone-5-carboxamide (Odds Ratio (OR) = 2.8 (95% CI 1.1-8.0)), a pyrimidine metabolite (5,6-dihydrothymine (OR = 0.4 (95% CI 0.2-0.9)), bile constituents (biliverdin (OR = 0.4 (95%CI 0.1-0.9), taurocholate (OR = 2.0 (95% CI 1.2-3.4)), two peptides likely derived from fibrinopeptide A (ORs from 1.6 to 1.7), and a gut microbiome metabolite (p-cresol sulphate OR = 0.5 (95% CI 0.2-0.9)). The associations for N1-Methyl-2-pyridone-5-carboxamide and p-cresol sulphate replicated in the independent VDAART population (one-sided P values = .03-.04). CONCLUSIONS AND CLINICAL RELEVANCE: Current asthma is nominally associated with altered levels of several metabolites, including metabolites in the nicotinamide pathway, and a bacterial metabolite derived from the gut microbiome.
Assuntos
Asma/sangue , Biomarcadores/sangue , Metaboloma , Metabolômica , Asma/diagnóstico , Asma/imunologia , Estudos de Casos e Controles , Criança , Cromatografia Líquida , Feminino , Humanos , Masculino , Espectrometria de Massas , Metabolômica/métodos , Razão de ChancesRESUMO
Heterogeneous therapeutic responses to leukotriene modifiers (LTMs) are likely due to variation in patient genetics. Although prior candidate gene studies implicated multiple pharmacogenetic loci, to date, no genome-wide association study (GWAS) of LTM response was reported. In this study, DNA and phenotypic information from two placebo-controlled trials (total N=526) of zileuton response were interrogated. Using a gene-environment (G × E) GWAS model, we evaluated 12-week change in forced expiratory volume in 1 second (ΔFEV1) following LTM treatment. The top 50 single-nucleotide polymorphism associations were replicated in an independent zileuton treatment cohort, and two additional cohorts of montelukast response. In a combined analysis (discovery+replication), rs12436663 in MRPP3 achieved genome-wide significance (P=6.28 × 10(-08)); homozygous rs12436663 carriers showed a significant reduction in mean ΔFEV1 following zileuton treatment. In addition, rs517020 in GLT1D1 was associated with worsening responses to both montelukast and zileuton (combined P=1.25 × 10(-07)). These findings implicate previously unreported loci in determining therapeutic responsiveness to LTMs.
Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Loci Gênicos , Leucotrienos/metabolismo , Acetatos/uso terapêutico , Asma/genética , Asma/metabolismo , Estudos de Coortes , Ciclopropanos , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hidroxiureia/análogos & derivados , Hidroxiureia/uso terapêutico , Fenótipo , Polimorfismo de Nucleotídeo Único , Quinolinas/uso terapêutico , SulfetosRESUMO
Vitamin D has known effects on lung development and the immune system that may be important in the development, severity, and course of allergic diseases (asthma, eczema, and food allergy). Vitamin D deficiency is prevalent worldwide and may partly explain the increases in asthma and allergic diseases that have occurred over the last 50-60 years. In this review, we explore past and current knowledge on the effect of vitamin D on lung development and immunomodulation and present the evidence of its role in allergic conditions. While there is growing observational and experimental evidence for the role of vitamin D, well-designed and well-powered clinical trials are needed to determine whether supplementation of vitamin D should be recommended in these disorders.
Assuntos
Hipersensibilidade/imunologia , Imunomodulação , Vitamina D/imunologia , Humanos , Hipersensibilidade/epidemiologia , Hipersensibilidade/etiologia , Prevalência , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/epidemiologia , Deficiência de Vitamina D/imunologiaRESUMO
Reversibility of airway obstruction in response to ß2-agonists is highly variable among asthmatics, which is partially attributed to genetic factors. In a genome-wide association study of acute bronchodilator response (BDR) to inhaled albuterol, 534 290 single-nucleotide polymorphisms (SNPs) were tested in 403 white trios from the Childhood Asthma Management Program using five statistical models to determine the most robust genetic associations. The primary replication phase included 1397 polymorphisms in three asthma trials (pooled n=764). The second replication phase tested 13 SNPs in three additional asthma populations (n=241, n=215 and n=592). An intergenic SNP on chromosome 10, rs11252394, proximal to several excellent biological candidates, significantly replicated (P=1.98 × 10(-7)) in the primary replication trials. An intronic SNP (rs6988229) in the collagen (COL22A1) locus also provided strong replication signals (P=8.51 × 10(-6)). This study applied a robust approach for testing the genetic basis of BDR and identified novel loci associated with this drug response in asthmatics.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Adolescente , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/genética , Broncodilatadores/administração & dosagem , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
A pro-asthmatic culture milieu and ß2-agonist (isoproterenol) were previously shown to regulate the expression of select transcription factors (TFs) within human airway epithelial and smooth muscle cells. This study tests 1116 single-nucleotide polymorphisms (SNPs) across 98 of these TF genes for association with bronchodilator response (BDR) in asthma patients. Genotyping was conducted using the Illumina HumanHap550v3 Beadchip in 403 non-Hispanic White asthmatic children and their parents. SNPs were evaluated for association with BDR using family and population-based analyses. Forty-two SNPs providing P-values <0.1 in both analyses were then genotyped in three adult asthma trials. One SNP 5' of the thyroid hormone receptor-ß gene was associated with BDR in the childhood population and two adult populations (P-value=0.0012). This investigation identified a novel locus for inter-individual variability in BDR and represents a translation of a cellular drug-response study to potential personalization of clinical asthma management.
Assuntos
Asma/genética , Células Epiteliais/metabolismo , Miócitos de Músculo Liso/metabolismo , Receptores beta dos Hormônios Tireóideos/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/tratamento farmacológico , Asma/patologia , Biomarcadores Farmacológicos/metabolismo , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Criança , Pré-Escolar , Células Epiteliais/patologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Estudos de Associação Genética , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Miócitos de Músculo Liso/patologia , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Two primary chitinases have been identified in humans--acid mammalian chitinase (AMCase) and chitotriosidase (CHIT1). Mammalian chitinases have been observed to affect the host's immune response. The aim of this study was to test for association between genetic variation in the chitinases and phenotypes related to chronic obstructive pulmonary disease (COPD). Polymorphisms in the chitinase genes were selected based on previous associations with respiratory diseases. Polymorphisms that were associated with lung function level or rate of decline in the Lung Health Study (LHS) cohort were analyzed for association with COPD affection status in four other COPD case-control populations. Chitinase activity and protein levels were also related to genotypes. In the caucasian LHS population, the baseline forced expiratory volume in one second (FEV(1)) was significantly different between the AA and GG genotypic groups of the AMCase rs3818822 polymorphism. Subjects with the GG genotype had higher AMCase protein and chitinase activity compared with AA homozygotes. For CHIT1 rs2494303, a significant association was observed between rate of decline in FEV(1) and the different genotypes. In the African American LHS population, CHIT1 rs2494303 and AMCase G339T genotypes were associated with rate of decline in FEV(1). Although a significant effect of chitinase gene alleles was found on lung function level and decline in the LHS, we were unable to replicate the associations with COPD affection status in the other COPD study groups.
Assuntos
Quitinases/genética , Volume Expiratório Forçado , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Idoso , Líquido da Lavagem Broncoalveolar/química , Estudos de Casos e Controles , Quitinases/metabolismo , Feminino , Variação Genética , Genótipo , Humanos , Pulmão/metabolismo , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Doença Pulmonar Obstrutiva Crônica/enzimologia , Fenômenos Fisiológicos Respiratórios , FumarRESUMO
BACKGROUND: Increasing evidence links altered intestinal flora in infancy to eczema and asthma. No studies have investigated the influence of maternal intestinal flora on wheezing and eczema in early childhood. OBJECTIVE: To investigate the link between maternal intestinal flora during pregnancy and development of wheeze and eczema in infancy. METHODS: A total of 60 pregnant women from the Boston area gave stool samples during the third trimester of their pregnancy and answered questions during pregnancy about their own health, and about their children's health when the child was 2 and 6 months of age. Quantitative culture was performed on stool samples and measured in log(10)colony-forming units (CFU)/gram stool. Primary outcomes included infant wheeze and eczema in the first 6 months of life. Atopic wheeze, defined as wheeze and eczema, was analysed as a secondary outcome. RESULTS: In multivariate models adjusted for breastfeeding, day care attendance and maternal atopy, higher counts of maternal total aerobes (TA) and enterococci (E) were associated with increased risk of infant wheeze (TA: OR 2.32 for 1 log increase in CFU/g stool [95% CI 1.22, 4.42]; E: OR 1.57 [95% CI 1.06, 2.31]). No organisms were associated with either eczema or atopic wheeze. CONCLUSIONS AND CLINICAL RELEVANCE: In our cohort, higher maternal total aerobes and enterococci were related to increased risk of infant wheeze. Maternal intestinal flora may be an important environmental exposure in early immune system development.
Assuntos
Exposição Ambiental/efeitos adversos , Mucosa Intestinal/microbiologia , Sons Respiratórios/etiologia , Adulto , Aleitamento Materno , Eczema/etiologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez , Fatores de RiscoRESUMO
BACKGROUND: Experimental animal data on the gram-negative bacterial (GNB) biomarker endotoxin suggest that persistence, dose, and timing of exposure are likely to influence its effects on allergy and wheeze. In epidemiologic studies, endotoxin may be a sentinel marker for a microbial milieu, including gram-positive bacteria (GPB) as well as GNB, that may influence allergy and asthma through components (pathogen-associated molecular patterns) that signal through innate Toll-like receptor pathways. OBJECTIVE: To determine the influence of current GNB and GPB exposures on asthma and allergic sensitization in school-aged children. METHODS: We examined the relationship between bacterial biomarkers and current asthma and allergic sensitization in 377 school-aged children in a birth cohort study. We then evaluated the effects of school-aged endotoxin, after controlling for exposure in early life. RESULTS: Exposure to GNB was inversely associated with asthma and allergic sensitization at school age [for >median endotoxin: prevalence odds ratio (POR)=0.34, 95% CI=0.2-0.7, for current asthma and prevalence ratio=0.77, 95% CI=0.6-0.97, for allergic sensitization]. In contrast, elevated GPB in the bed was inversely associated with current asthma (POR=0.41, 95% CI=0.2-0.9) but not with allergic sensitization (POR=1.07, 95% CI=0.8-1.4). School-aged endotoxin exposure remained protective in models for allergic disease adjusted for early-life endotoxin. CONCLUSION: Both GNB and GPB exposures are associated with decreased asthma symptoms, but may act through different mechanisms to confer protection. Endotoxin exposure in later childhood is not simply a surrogate of early-life exposure; it has independent protective effects on allergic disease.
Assuntos
Asma , Endotoxinas/imunologia , Exposição Ambiental , Habitação , Hipersensibilidade , Alérgenos/imunologia , Asma/epidemiologia , Asma/imunologia , Asma/prevenção & controle , Criança , Pré-Escolar , Estudos de Coortes , Poeira/imunologia , Feminino , Bactérias Gram-Negativas/imunologia , Bactérias Gram-Positivas/imunologia , Humanos , Hipersensibilidade/epidemiologia , Hipersensibilidade/imunologia , Hipersensibilidade/prevenção & controle , Masculino , Ácidos Murâmicos/imunologiaRESUMO
Superoxide dismutase-3 (SOD3) is a major extracellular antioxidant enzyme, and previous studies have indicated a possible role of this gene in chronic obstructive pulmonary disease (COPD). We hypothesized that polymorphisms in the SOD3 gene would be associated with COPD and COPD-related phenotypes. We genotyped three SOD3 polymorphisms (rs8192287 (E1), rs8192288 (I1), and rs1799895 (R213G)) in a case-control cohort, with severe COPD cases from the National Emphysema Treatment Trial (NETT, n = 389) and smoking controls from the Normative Aging Study (NAS, n = 472). We examined whether the single nucleotide polymorphisms (SNPs) were associated with COPD status, lung function variables, and quantitative computed tomography (CT) measurements of emphysema and airway wall thickness. Furthermore, we tried to replicate our initial findings in two family-based studies, the International COPD Genetics Network (ICGN, n = 3061) and the Boston Early-Onset COPD Study (EOCOPD, n = 949). In NETT COPD cases, the minor alleles of SNPs E1 and I1 were associated with a higher percentage of emphysema (%LAA950) on chest CT scan (p = .029 and p = .0058). The association with E1 was replicated in the ICGN family study, where the minor allele was associated with more emphysema (p = .048). Airway wall thickness was positively associated with the E1 SNP in ICGN; however, this finding was not confirmed in NETT. Quantitative CT data were not available in EOCOPD. The SNPs were not associated with lung function variables or COPD status in any of the populations. In conclusion, polymorphisms in the SOD3 gene were associated with CT emphysema but not COPD susceptibility, highlighting the importance of phenotype definition in COPD genetics studies.
Assuntos
Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/genética , Enfisema Pulmonar/genética , Superóxido Dismutase/genética , Idoso , Feminino , Frequência do Gene , Genótipo , Humanos , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Fenótipo , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Enfisema Pulmonar/complicações , Fumar/genética , Tomografia Computadorizada por Raios XRESUMO
Although alveolar wall thinning has been attributed to apoptosis of interstitial lung lipofibroblasts (LFs), the underlying molecular mechanism(s) remains unknown. Although the physiological vitamin D steroid hormone 1alpha,25(OH)(2)D(3) (1,25D) has been suggested as a local paracrine/autocrine effector of fetal lung maturation and is known to affect fibroblast apoptosis, its effects on LF apoptosis are unknown. We determined the role of 1,25D and its metabolite, C-3-epimer (3-epi-1,25D), on LF and alveolar type II (ATII) cell differentiation, proliferation, and apoptosis. Embryonic day 19 Sprague-Dawley fetal rat lung LFs and ATII cells were treated with 1,25D or 3-epi-1,25D (1 x 10(-10) to 1 x 10(-8) M) for 24 h, and cell proliferation, apoptosis, and differentiation were assessed. Both 1,25D and 3-epi-1,25D exhibited dose-dependent increases in expression of the key homeostatic epithelial-mesenchymal differentiation markers, increased LF and ATII cell proliferation, and decreased apoptosis. Furthermore, rat pups administered 1,25D from postnatal days 0 to 14 showed increased expressions of key LF and ATII cell differentiation markers, increased Bcl-2-to-Bax ratio as an index of decreased spontaneous alveolar LF and ATII cell apoptosis, increased alveolar count, and a paradoxical increase in septal thickness. We conclude that spatial- and temporal-specific actions of vitamin D play a critical role in perinatal lung maturation by stimulating key alveolar epithelial-mesenchymal interactions and by modulating LF proliferation/apoptosis. These data not only provide the biological rationale for the presence of an alveolar vitamin D paracrine system, but also provide the first integrated molecular mechanism for increased surfactant synthesis and alveolar septal thinning during perinatal lung maturation.
Assuntos
Apoptose/efeitos dos fármacos , Calcitriol/farmacologia , Comunicação Celular/efeitos dos fármacos , Células Epiteliais/citologia , Fibroblastos/citologia , Mesoderma/citologia , Alvéolos Pulmonares/citologia , Animais , Biomarcadores/metabolismo , Calcitriol/administração & dosagem , Calcitriol/química , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Feminino , Fibroblastos/efeitos dos fármacos , Mesoderma/efeitos dos fármacos , Modelos Biológicos , Comunicação Parácrina/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , EstereoisomerismoRESUMO
BACKGROUND: Interleukin-6 (IL6) is a pleiotropic pro-inflammatory and immunomodulatory cytokine which probably plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). There is a functional single nucleotide polymorphism (SNP), -174G/C, in the promoter region of IL6. It was hypothesised that IL6 SNPs influence susceptibility for impaired lung function and COPD in smokers. METHODS: Seven and five SNPs in IL6 were genotyped in two nested case-control samples derived from the Lung Health Study (LHS) based on phenotypes of rate of decline of forced expiratory volume in 1 s (FEV(1)) over 5 years and baseline FEV(1) at the beginning of the LHS. Serum IL6 concentrations were measured for all subjects. A partially overlapping panel of nine IL6 SNPs was genotyped in 389 cases of COPD from the National Emphysema Treatment Trial (NETT) and 420 controls from the Normative Aging Study (NAS). RESULTS: In the LHS, three IL6 SNPs were associated with decline in FEV(1) (0.023< or =p< or =0.041 in additive models). Among them, the IL6_-174C allele was associated with a rapid decline in lung function. The association was more significant in a genotype-based analysis (p = 0.006). In the NETT-NAS study, IL6_-174G/C and four other IL6 SNPs, all of which are in linkage disequilibrium with IL6_-174G/C, were associated with susceptibility to COPD (0.01< or =p< or =0.04 in additive genetic models). CONCLUSION: The results suggest that the IL6_-174G/C SNP is associated with a rapid decline in FEV(1) and susceptibility to COPD in smokers.
Assuntos
Interleucina-6/genética , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/genética , Estudos de Casos e Controles , Feminino , Volume Expiratório Forçado , Haplótipos , Humanos , Interleucina-6/sangue , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Fenótipo , Doença Pulmonar Obstrutiva Crônica/fisiopatologiaRESUMO
BACKGROUND: Ozone (O3) exposure is known to cause oxidative stress. This study investigated the acute effects of O(3) on lung function in the elderly, a suspected risk group. It then investigated whether genetic polymorphisms of antioxidant genes (heme oxygenase-1 (HMOX1) and glutathione S-transferase pi (GSTP1)) modified these associations. METHODS: 1100 elderly men from the Normative Aging Study were examined whose lung function (forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1)) was measured every 3 years from 1995 to 2005. The study genotyped the GSTP1 Ile105Val and Ala114Val polymorphisms and the (GT)n repeat polymorphism in the HMOX1 promoter, classifying repeats as short (n<25) or long (n> or =25). Ambient O(3) was measured continuously at locations in the Greater Boston area. Mixed linear models were used, adjusting for known confounders. RESULTS: A 15 ppb increase in O(3) during the previous 48 h was associated with a 1.25% decrease in FEV(1) (95% CI: -1.96% to -0.54%). This estimated effect was worsened with either the presence of a long (GT)n repeat in HMOX1 (-1.38%, 95% CI: -2.11% to -0.65%) or the presence of an allele coding for Val105 in GSTP1 (-1.69%, 95% CI: -2.63% to -0.75%). A stronger estimated effect of O(3) on FEV(1) was found in subjects carrying both the GSTP1 105Val variant and the HMOX1 long (GT)n repeat (-1.94%, 95% CI: -2.89% to -0.98%). Similar associations were also found between FVC and O(3) exposure. CONCLUSIONS: Our results suggest that O(3) has an acute effect on lung function in the elderly, and the effects may be modified by the presence of specific polymorphisms in antioxidant genes.
Assuntos
Envelhecimento/fisiologia , Antioxidantes/fisiologia , Volume Expiratório Forçado/efeitos dos fármacos , Ozônio/farmacologia , Capacidade Vital/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/farmacologia , Monitoramento Ambiental/métodos , Volume Expiratório Forçado/genética , Genótipo , Glutationa Transferase/genética , Heme Oxigenase-1/genética , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/genética , Ozônio/análise , Capacidade Vital/genética , Adulto JovemRESUMO
PURPOSE OF REVIEW: Asthma exhibits significant heterogeneity in occurrence and severity over the lifespan. Our goal is to discuss recent evidence regarding determinants of the natural history of asthma during childhood, and review the rationale behind and status of major efforts to alter its course. RECENT FINDINGS: Variations in microbial exposures are associated with risk of allergic disease, and the use of bacterial lysates may be a promising preventive strategy. Exposure to air pollution appears to be particularly damaging in prenatal and early life, and interventions to reduce pollution are feasible and result in clinical benefit. E-cigarette use may have a role in harm reduction for conventional cigarette smokers with asthma, but has undefined short-term and long-term effects that must be clarified. Vitamin D insufficiency over the first several years of life is associated with risk of asthma, and vitamin D supplementation reduces the risk of severe exacerbations. SUMMARY: The identification of risk factors for asthma occurrence, persistence and severity will continue to guide efforts to alter the natural history of the disease. We have reviewed several promising strategies that are currently under investigation. Vitamin D supplementation and air pollution reduction have been shown to be effective strategies and warrant increased investigation and implementation.
Assuntos
Asma/epidemiologia , Infecções Bacterianas/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Poluição do Ar/efeitos adversos , Animais , Asma/prevenção & controle , Criança , Sistemas Eletrônicos de Liberação de Nicotina , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Exposição Materna/efeitos adversos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Risco , Fumar/efeitos adversos , Vitamina DRESUMO
OBJECTIVE: Vitamin D deficiency is associated with asthma and reactive airway disease in childhood but its potential contribution to bronchopulmonary dysplasia (BPD) in preterm infants is unknown. Preterm infants have lower levels of 25-hydroxyvitamin D (25(OH)D) at birth and are at risk for nutritional deficiencies after birth. The objective of the study was to evaluate the association of 25(OH)D concentrations at birth and at 36 weeks' corrected gestational age with BPD in preterm infants born before 29 completed weeks of gestation. STUDY DESIGN: We collected umbilical cord blood samples from 44 preterm infants (gestational age <29 weeks) delivered at Brigham and Women's Hospital in Boston. In addition, with parental consent we collected venous samples at 36 weeks' corrected age from 20 preterm infants born before 29 weeks' gestation (including 6 infants with previously collected cord blood). Samples were frozen at -80 °C until subsequent measurement of 25(OH)D levels by chemiluminescence. We used multivariable logistic models to adjust for gestational age and considered other confounding variables, including maternal race, age, mode of delivery and infant sex. RESULTS: Among 44 infants, 41 (93.2%) survived and 3 (6.8%) died before 36 weeks' corrected age. Median 25(OH)D levels at birth were 30.4 ng ml(-1) in preterm infants who subsequently died or developed BPD and 33.8 ng ml(-1) in infants who survived without BPD (P=0.6). Median 25(OH)D levels at corrected age of 36 weeks were 59.0 ng ml(-1) among survivors without BPD and 64.2 ng ml(-1) among survivors with BPD (P=0.9). Neither cord blood nor 36 weeks' corrected 25(OH)D levels were associated with odds of death or BPD (adjusted odds ratio (OR) 1.00, 95% confidence interval (CI): 0.73 to 1.37; and OR 0.93, 95% CI: 0.61 to 1.43, respectively). CONCLUSIONS: Among this population of extremely preterm infants neither cord blood nor the 36 weeks' corrected age 25(OH)D levels were associated with development of BPD. Notably, at the current level of supplementation, all extremely preterm infants in our cohort had achieved 25(OH)D levels >30 ng ml(-1) by 36 weeks' corrected age, which is thought to represent sufficiency in adult and pediatric populations.
Assuntos
Displasia Broncopulmonar/etiologia , Recém-Nascido Prematuro/sangue , Deficiência de Vitamina D/complicações , Vitamina D/análogos & derivados , Displasia Broncopulmonar/mortalidade , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido de muito Baixo Peso/sangue , Modelos Logísticos , Masculino , Estudos Prospectivos , Vitamina D/sangueRESUMO
BACKGROUND: We investigated associations between ambient pollution levels and cardiovascular function in a repeated measures study including 163 observations on twenty-one 53- to 87-year-old active Boston residents observed up to 12 times from June to September 1997. Particles with aerodynamic diameter =2.5 microm (PM(2.5)) were measured continuously using a tapered element oscillating microbalance. METHODS AND RESULTS: The protocol involved 25 minutes per week of continuous Holter ECG monitoring, including 5 minutes of rest, 5 minutes of standing, 5 minutes of exercise outdoors, 5 minutes of recovery, and 20 cycles of slow breathing. Heart rate variability (HRV) was assessed through time domain variables: the standard deviation of normal RR intervals (SDNN) and the square root of the mean of the squared differences between adjacent normal RR intervals (r-MSSD). Mean 4-hour PM(2.5) levels ranged from 3 to 49 microg/m(3); 1-hour ozone levels ranged from 1 to 77 ppb. In multivariate analyses, significantly less HRV (SDNN and r-MSSD) was associated with elevated PM(2.5). During slow breathing, a reduction in r-MSSD of 6.1 ms was associated with an interquartile (14.3 microg/m(3)) increase in PM(2.5) during the hour of and the 3 hours previous to the Holter session (P=0.006). During slow breathing, a multiple pollution model was associated with a reduction in r-MSSD of 5.4 ms (P=0.02) and 5.5 ms (P=0.03) for interquartile changes in PM(2.5) and ozone, respectively, resulting in a combined effect equivalent to a 33% reduction in the mean r-MSSD. CONCLUSIONS: Particle and ozone exposure may decrease vagal tone, resulting in reduced HRV.
Assuntos
Poluição do Ar , Frequência Cardíaca/fisiologia , Idoso , Idoso de 80 Anos ou mais , Eletrocardiografia Ambulatorial , Exercício Físico/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Ozônio/análise , Tamanho da Partícula , Valores de Referência , Respiração , Fatores de TempoRESUMO
OBJECTIVE: To examine the relationship between day care attendance and illnesses of the upper and lower respiratory tract in the first year of life. STUDY DESIGN: Prospective birth cohort study. METHODS: Children (N = 498) who had at least 1 parent with a history of allergy or asthma were enrolled at birth and followed prospectively for the first year of life. A home visit at 2 to 3 months of age and bimonthly telephone questionnaires were used to obtain information on day care arrangements, home characteristics, respiratory symptoms, and physician-diagnosed illnesses of the upper and lower respiratory tract. RESULTS: Day care attendance in the first year of life was associated with two or more doctor-diagnosed ear infections (OR: 2.4; 95% CI: 1.7-3.6), three or more parental reports of runny or stuffed nose (OR: 3.2; 95% CI: 1.9-5.5), a doctor's diagnosis of sinusitis (OR: 2.2; 95% CI: 1.1-4.2), and doctor-diagnosed lower respiratory illnesses (croup, bronchitis, bronchiolitis, and pneumonia; OR: 1.6; 95% CI: 1.0-2.4). For children attending day care, exposure to pets in day care, the presence of a rug or carpet in the area where the child slept in day care, and a nonresidential setting for day care all were independent predictors of two or more doctor-diagnosed ear infections. CONCLUSIONS: The results suggest that day care increases the risk of illnesses of the upper and lower respiratory tract in the first year of life for children with a familial history of atopy. Specific environmental exposures within day care, such as the presence of pets or having a rug or carpet in the area where children sleep, may increase the risk of recurrent ear infections in the first year of life among children with familial history of atopy who attend day care.
Assuntos
Creches , Hipersensibilidade Imediata/genética , Infecções Respiratórias/epidemiologia , Asma/epidemiologia , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Otite Média/epidemiologia , Estudos Prospectivos , Sons Respiratórios , Fatores de RiscoAssuntos
Asma/sangue , Asma/genética , Imunoglobulina E/sangue , Receptores Acoplados a Proteínas G/genética , Adolescente , Adulto , Alelos , Animais , Especificidade de Anticorpos , Antígenos de Dermatophagoides/efeitos adversos , Asma/epidemiologia , Estudos de Casos e Controles , Colômbia , Feminino , Haplótipos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Receptores Acoplados a Proteínas G/metabolismoRESUMO
The efficacy and safety of intracavernosal alprostadil was evaluated for the treatment of erectile dysfunction in men with type I or type II diabetes mellitus. This was an open-label, flexible dose-escalating study involving 336 men (77% of whom were Asian/Oriental) enrolled by 15 centres in Australia, Canada and seven countries in Asia. The effective alprostadil dose, ie the dose producing penile rigidity adequate for intercourse and lasting up to 60 min, was established by titration at the clinic prior to entry into the 6 month self-treatment home phase. All men were fully trained in the self-injection technique before entry into the home phase. Efficacy and safety were assessed using patient and partner diaries and by interview at clinic visits during the titration phase and after 1, 3 and 6 months of treatment. An effective home dose was established by titration for 94% of the 336 men (median dose 20 microg, range 2.5-60 microg). Of 278 (83%) men who entered the home phase, 277 men (247 with type II diabetes and 30 with type I diabetes) had evaluable data for alprostadil dosage and clinical response. During the home phase, a satisfactory erectile response was achieved after 99% of injections, and the median alprostadil dose remained unchanged. The initial home dose and clinical response were similar in type I and type II diabetic men. Treatment was generally well tolerated with a low incidence of penile pain (24%) In conclusion, intracavernosal alprostadil was effective and well tolerated in type I and type II diabetic men with erectile dysfunction of mixed aetiology.
Assuntos
Alprostadil/uso terapêutico , Complicações do Diabetes , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/etiologia , Adulto , Idoso , Alprostadil/administração & dosagem , Alprostadil/efeitos adversos , Relação Dose-Resposta a Droga , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Grupos Raciais , Autoadministração , Vasodilatadores/administração & dosagem , Vasodilatadores/efeitos adversos , Vasodilatadores/uso terapêuticoRESUMO
Asthma prevalence in the United States has been reported to be higher in minority groups such as Blacks and Hispanics. Because a disproportionate number of individuals from such minority groups are of low socioeconomic status (SES), it is unclear how much of the racial/ethnic differences in asthma prevalence is related to low SES. We investigated the effect of SES on the relationship between race/ethnicity and asthma prevalence in a cohort of families with a history of asthma or allergies from the Boston, Massachusetts area. From 499 families, a cohort of 998 parents and 307 children was identified. We used total yearly family income (<$50,000 vs. > or = $50, 000), highest level of education (< or = high school vs. > or = college), and residence in high-poverty areas vs. low-poverty areas as measures of SES. Yearly family income <$50,000, < or = high school education, and residence in high poverty areas were all associated with increased risks for asthma in both cohorts. In the parental cohort, Blacks and Hispanics (OR = 2.1, 95% CI = 1.5, 2.8; and OR = 2.2, 95% CI = 1.5, 3.2, respectively) were at greater risk for asthma than Whites. In the cohort of children, Black and Hispanic children (OR = 2.9, 95% CI = 1.0, 8.0; and OR = 5.3, 95% CI = 1.6, 17.5, respectively) were also at increased risk for asthma. When the three measures of SES were included in the multivariable models, the risks associated with Blacks and Hispanics decreased in both cohorts: OR = 1.4, 95% CI = 0.9, 2.0; and OR = 1.6, 95% CI = 1.0, 2. 6, respectively, for the parents; and OR = 0.8, 95% CI = 0.2, 3.0; and 2.5, 95% CI = 0.5, 11.7, respectively, for the children. We conclude that a large proportion of the racial/ethnic differences in asthma prevalence in our study is explained by factors related to income, area of residence, and level of education.