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Background: Despite the recognized benefits of telemedicine use for pediatric emergency consultations, there are barriers to the widespread uptake of this technology. Quality improvement methods can be used to rapidly test implementation strategies. Our objective was to test telemedicine implementation strategies in real-world application using quality improvement methods. Our quality improvement aim was to achieve high rates of telemedicine use for pediatric transfer consultations. Methods: A multidisciplinary multisite improvement team identified that key drivers of increasing telemedicine use included telemedicine resource awareness, streamlined telemedicine workflow, provider buy-in, and data transparency. Interventions focused on telemedicine trainings, disseminating telemedicine uptake data, telemedicine reminders, telemedicine test calls, and preparing for telemedicine use for every transfer consultation. The outcome measure was percentage of pediatric emergency transfer consultations that used telemedicine. The balancing measure was time (minutes) from the initial transfer center call to completion of the consultation. Results: Multiple plan-do-study-act cycles were associated with special cause variation, with an upward shift in mean percentage of telemedicine use from 5% to 22%. Time from initial call to consultation completion remained unchanged. Conclusion: Our study supports the use of quality improvement methods to test telemedicine implementation strategies for pediatric telemedicine emergency consultations.
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Melhoria de Qualidade , Telemedicina , Criança , Emergências , Serviço Hospitalar de Emergência , Humanos , Estudos RetrospectivosRESUMO
We recently proposed that mitotic asynchrony in repairing tissue may underlie chronic inflammation and fibrosis, where immune cell infiltration is secondary to proinflammatory cross-talk among asynchronously repairing adjacent tissues. Building on our previous finding that mitotic asynchrony is associated with proinflammatory/fibrotic cytokine secretion (e.g., transforming growth factor [TGF]-ß1), here we provide evidence supporting cause-and-effect. Under normal conditions, primary airway epithelial basal cell populations undergo mitosis synchronously and do not secrete proinflammatory or profibrotic cytokines. However, when pairs of nonasthmatic cultures were mitotically synchronized at 12 hours off-set and then combined, the mixed cell populations secreted elevated levels of TGF-ß1. This shows that mitotic asynchrony is not only associated with but is also causative of TGF-ß1 secretion. The secreted cytokines and other mediators from asthmatic cells were not the cause of asynchronous regeneration; synchronously mitotic nonasthmatic epithelia exposed to conditioned media from asthmatic cells did not show changes in mitotic synchrony. We also tested if resynchronization of regenerating asthmatic airway epithelia reduces TGF-ß1 secretion and found that pulse-dosed dexamethasone, simvastatin, and aphidicolin were all effective. We therefore propose a new model for chronic inflammatory and fibrotic conditions where an underlying factor is mitotic asynchrony.
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Asma/metabolismo , Células Epiteliais/metabolismo , Mitose , Fator de Crescimento Transformador beta1/metabolismo , Afidicolina/administração & dosagem , Brônquios/metabolismo , Brônquios/patologia , Células Cultivadas , Meios de Cultivo Condicionados/química , Dexametasona/administração & dosagem , Epitélio/metabolismo , Fibrose , Humanos , Inflamação , Mucosa Respiratória/metabolismo , Sinvastatina/administração & dosagem , Fatores de TempoRESUMO
Asthma is a chronic inflammatory condition of the lower respiratory tract associated with airway hyperreactivity and mucus obstruction in which a majority of cases are due to an allergic response to environmental allergens. Glucocorticoids such as prednisone have been standard treatment for many inflammatory diseases for the past 60 years. However, despite their effectiveness, long-term treatment is often limited by adverse side effects believed to be caused by glucocorticoid receptor-mediated gene transcription. This has led to the pursuit of compounds that retain the anti-inflammatory properties yet lack the adverse side effects associated with traditional glucocorticoids. We have developed a novel series of steroidal analogues (VBP compounds) that have been previously shown to maintain anti-inflammatory properties such as NFκB-inhibition without inducing glucocorticoid receptor-mediated gene transcription. This study was undertaken to determine the effectiveness of the lead compound, VBP15, in a mouse model of allergic lung inflammation. We show that VBP15 is as effective as the traditional glucocorticoid, prednisolone, at reducing three major hallmarks of lung inflammation--NFκB activity, leukocyte degranulation, and pro-inflammatory cytokine release from human bronchial epithelial cells obtained from patients with asthma. Moreover, we found that VBP15 is capable of reducing inflammation of the lung in vivo to an extent similar to that of prednisone. We found that prednisolone--but not VBP15 shortens the tibia in mice upon a 5 week treatment regimen suggesting effective dissociation of side effects from efficacy. These findings suggest that VBP15 may represent a potent and safer alternative to traditional glucocorticoids in the treatment of asthma and other inflammatory diseases.
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Glucocorticoides/uso terapêutico , Hipersensibilidade/complicações , Hipersensibilidade/tratamento farmacológico , Pneumonia/complicações , Pneumonia/tratamento farmacológico , Pregnadienodiois/uso terapêutico , Animais , Asma/complicações , Asma/metabolismo , Asma/patologia , Degranulação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Glucocorticoides/química , Glucocorticoides/farmacologia , Humanos , Leucócitos/efeitos dos fármacos , Leucócitos/fisiologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Osteogênese/efeitos dos fármacos , Ovalbumina , Pregnadienodiois/química , Pregnadienodiois/farmacologia , Tíbia/efeitos dos fármacos , Tíbia/patologiaRESUMO
BACKGROUND AND OBJECTIVE: Low serum 25-hydroxyvitamin D (25[OH]D) levels have been associated with increased susceptibility to and severity of respiratory viral infections. Hypovitaminosis D may be a modifiable risk factor in the severity of viral respiratory illnesses. The hypothesis for this study was that children hospitalized for respiratory illnesses would have lower serum 25(OH)D levels than controls and that 25(OH)D levels would be associated with illness severity among cases. METHODS: A case-control study of a sample of patients aged 6 months through 12 years hospitalized from January to May 2010 at an urban pediatric referral hospital was performed. Cases were children hospitalized for acute respiratory illnesses, and controls were children hospitalized for nonrespiratory illnesses. Illness severity among cases was assessed according to hospital length of stay, ICU admission, peripheral oxygen saturation, and pediatric risk of admission II score. Associations between serum 25(OH)D levels and dependent variables were tested for by using binary logistic and multivariable linear regression while controlling for admission diagnosis, age, gender, and race/ethnicity. RESULTS: The majority of cases (n = 38) and controls (n = 83) were African American (65.8% and 59.0%, respectively). Of the entire cohort (N = 121), 64.8% had vitamin D insufficiency (25[OH]D level ≤30 ng/mL) and 31.1% had vitamin D deficiency (25[OH]D level ≤20 ng/mL). Mean ± SD 25(OH)D levels did not differ between cases and controls (26.8 ± 11.5 vs 26.1 ± 10.6 ng/mL, respectively; P = .73). CONCLUSIONS: Hypovitaminosis D was common among cases and controls, but it was not significantly associated with the presence or severity of respiratory illnesses.
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PURPOSE: End-organ apoptosis is well-described in progressive sepsis and Multiple Organ Dysfunction Syndrome (MODS), especially where platelets accumulate (e.g. spleen and lung). We previously reported an acute sepsis-induced cytotoxic platelet phenotype expressing serine protease granzyme B. We now aim to define the site(s) of and mechanism(s) by which platelet granzyme B induces end-organ apoptosis in sepsis. METHODS: End-organ apoptosis in murine sepsis (i.e. polymicrobial peritonitis) was analyzed by immunohistochemistry. Platelet cytotoxicity was measured by flow cytometry following 90 minute ex vivo co-incubation with healthy murine splenocytes. Sepsis progression was measured via validated preclinical murine sepsis score. MEASUREMENTS AND MAIN RESULTS: There was evident apoptosis in spleen, lung, and kidney sections from septic wild type mice. In contrast, there was a lack of TUNEL staining in spleens and lungs from septic granzyme B null mice and these mice survived longer following induction of sepsis than wild type mice. In co-incubation experiments, physical separation of septic platelets from splenocytes by a semi-permeable membrane reduced splenocyte apoptosis to a rate indistinguishable from negative controls. Chemical separation by the platelet GPIIb/IIIa receptor inhibitor eptifibatide decreased apoptosis by 66.6±10.6% (pâ=â0.008). Mice treated with eptifibatide in vivo survived longer following induction of sepsis than vehicle control mice. CONCLUSIONS: In sepsis, platelet granzyme B-mediated apoptosis occurs in spleen and lung, and absence of granzyme B slows sepsis progression. This process proceeds in a contact-dependent manner that is inhibited ex vivo and in vivo by the platelet GPIIb/IIIa receptor inhibitor eptifibatide. The GPIIb/IIIa inhibitors and other classes of anti-platelet drugs may be protective in sepsis.
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Apoptose/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Peptídeos/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Sepse/sangue , Sepse/patologia , Animais , Caspases/metabolismo , Progressão da Doença , Eptifibatida , Granzimas/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Linfócitos/efeitos dos fármacos , Masculino , Camundongos , Peptídeos/uso terapêutico , Perforina/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Sepse/tratamento farmacológico , Sepse/metabolismo , Baço/efeitos dos fármacos , Baço/imunologiaRESUMO
OBJECTIVE: Leukocyte persistence during chronic (quiescent) phases of asthma is a major hallmark of the disease. The mechanisms regulating these persistent leukocyte populations are not clearly understood. An alternative family of chemoattracting proteins, cyclophilins (Cyps), has recently been shown to contribute to leukocyte recruitment in animal models of allergic asthma. The goals of this study were to determine whether Cyps are present in asthma patients during the chronic phase of the disease and to investigate whether levels of Cyps associate with clinical parameters of disease severity. METHODS: Nasal wash samples from an urban cohort of 137 patients of age 6-20 years with physician-diagnosed asthma were examined for the presence of cyclophilin A (CypA), cyclophilin B (CypB), as well as several other classical chemokines. Linear, logistic, or ordinal regressions were performed to identify associations between Cyps, chemokines, and clinical parameters of asthma. The asthma cohort was further divided into previously established phenotypic clusters (cluster 1: n = 55; cluster 2: n = 31; and cluster 3: n = 51) and examined for associations. RESULTS: Levels of CypB in the asthma group were highly elevated compared to nonasthmatic controls, while a slight increase in Monocyte Chemotactic Protein-1 (MCP-1) was also observed. CypA and MCP-1 were associated with levels of eosinophil cationic protein (ECP; a marker of eosinophil activation). Cluster-specific associations were found for CypA and CypB and clinical asthma parameters [e.g. forced expiratory volume in 1 second (FEV(1)) and ECP]. CONCLUSIONS: Cyps are present in nasal wash samples of asthma patients and may be a novel biomarker for clinical parameters of asthma severity.
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Asma/metabolismo , Ciclofilinas/análise , Fenótipo , Adolescente , Asma/fisiopatologia , Biomarcadores/análise , Quimiocina CCL2/análise , Quimiocinas/análise , Criança , Proteína Catiônica de Eosinófilo/análise , Espaço Extracelular/química , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Líquido da Lavagem Nasal/química , Adulto JovemRESUMO
INTRODUCTION: Low vitamin D levels have been associated with asthma severity in children. Young, urban African Americans (AAs) have high rates of hypovitaminosis D and asthma. Our objective was to determine associations between variants in vitamin D metabolism genes and asthma characteristics in a pilot study of young urban AAs. MATERIALS AND METHODS: Two urban AA cohorts of subjects aged 6 to 20 years (139 subjects with asthma and 74 subjects without asthma) were genotyped for 12 single nucleotide polymorphisms (SNPs) in 3 vitamin D metabolism genes: VDR (vitamin D receptor), CYP24A1 (cytochrome P450 vitamin D 24-hydroxylase), and CYP2R1 (cytochrome P450 vitamin D 25-hydroxylase). In a case-control analysis, SNPs were studied for associations with an asthma diagnosis. Within the asthmatic cohort, SNPs were analyzed for associations with quantitative asthma characteristics. All analyses were adjusted for age, sex, and body mass index percentile. RESULTS: Only the CYP2R1 SNP rs10766197 homozygous minor genotype was associated with asthma (P = 0.044). CYP24A1 SNP rs2248137 was associated with lower vitamin D levels (P = 0.006). Within the asthma cohort, multiple significant associations between SNPs and asthma characteristics were identified; VDR SNP rs2228570 was associated with the higher nighttime asthma morbidity scores (P = 0.04), lower baseline spirometric measures (P < 0.05), 1 or more positive aeroallergen skin test (P = 0.003), and increased immunoglobulin E levels (P < 0.001). DISCUSSION: This pilot study demonstrates that variants in vitamin D metabolism genes are associated with quantitative asthma characteristics in young, urban AAs. The collection of these associations provides evidence for the need for a large population-based study of vitamin D-relevant SNPs in this cohort.
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Asma/genética , Variação Genética , Vitamina D/metabolismo , Adolescente , Negro ou Afro-Americano , Asma/etnologia , Asma/patologia , Estudos de Casos e Controles , Criança , Estudos de Coortes , Feminino , Genótipo , Haplótipos , Humanos , Imunoglobulina E/imunologia , Masculino , Projetos Piloto , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol/genética , Espirometria/métodos , Esteroide Hidroxilases/genética , População Urbana , Deficiência de Vitamina D/genética , Vitamina D3 24-HidroxilaseRESUMO
Asthma is an inflammatory condition for which anti-inflammatory glucocorticoids are the standard of care. However, similar efficacy has not been shown for agents targeting inflammatory cells and pathways. This suggests a noninflammatory cell contributor (e.g., epithelium) to asthmatic inflammation. Herein, we sought to define the intrinsic and glucocorticoid-affected properties of asthmatic airway epithelium compared with normal epithelium. Human primary differentiated normal and asthmatic airway epithelia were cultured in glucocorticoid-free medium beginning at -48 hours. They were pulsed with dexamethasone (20 nM) or vehicle for 2 hours at -26, -2, +22, and +46 hours. Cultures were mechanically scrape-wounded at 0 hours and exposed continuously to bromodeoxyuridine (BrdU). Cytokine secretions were analyzed using cytometric bead assays. Wound regeneration/mitosis was analyzed by microscopy and flow cytometry. Quiescent normal (n = 3) and asthmatic (n = 6) epithelia showed similar minimal inflammatory cytokine secretion and mitotic indices. After wounding, asthmatic epithelia secreted more basolateral TGF-ß1, IL-10, IL-13, and IL-1ß (P < 0.05) and regenerated less efficiently than normal epithelia (+48 h wound area reduction = [mean ± SEM] 50.2 ± 7.5% versus 78.6 ± 7.7%; P = 0.02). Asthmatic epithelia showed 40% fewer BrdU(+) cells at +48 hours (0.32 ± 0.05% versus 0.56 ± 0.07% of total cells; P = 0.03), and those cells were more dyssynchronously distributed along the cell cycle (52 ± 10, 25 ± 4, 23 ± 7% for G1/G0, S, and G2/M, respectively) than normal epithelia (71 ± 1, 12 ± 2, and 17 ± 2% for G1/G0, S, and G2/M, respectively). Dexamethasone pulses improved asthmatic epithelial inflammation and regeneration/mitosis. In summary, we show that inflammatory/fibrogenic cytokine secretions are correlated with dyssynchronous mitosis upon injury. Intermittent glucocorticoids simultaneously decreased epithelial cytokine secretions and resynchronized mitosis. These data, generated in an airway model lacking inflammatory cells, support the concept that epithelium contributes to asthmatic inflammation.
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Asma/metabolismo , Células Epiteliais/citologia , Inflamação , Mitose , Adolescente , Adulto , Asma/fisiopatologia , Brônquios/metabolismo , Criança , Citocinas/metabolismo , Feminino , Citometria de Fluxo/métodos , Glucocorticoides/metabolismo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Allergic asthma is characterized by airway inflammation associated with recruitment and activation of eosinophils. In mice, allergen exposure induces platelet migration to the airways that is necessary for eosinophil recruitment and activation. We therefore hypothesized that in the airways of human subjects with asthma, platelet activation would be positively associated with eosinophil activation and platelet and eosinophil activation would both be associated with clinical asthma characteristics. METHODS: Nasal wash levels of P-selectin (a measure of platelet activation) and eosinophil cationic protein (ECP) (a measure of eosinophil activation) were compared with each other and with clinical asthma characteristics in a cross-sectional study of urban children and adolescents (age range, 6-20 years) with asthma. RESULTS: Regression analysis revealed a significantly positive association between log10 P-selectin levels and log10 ECP levels (ß = 0.50 ng/mL [95% confidence interval, 0.05-0.94 ng/mL]; P = 0.029). Additionally, ECP was significantly and negatively associated with 2 asthma-related quality of life measurements, and P-selectin was associated with one of these. CONCLUSIONS: Our study shows the first significant association between platelet and eosinophil activation in airways of human subjects with asthma. These data provide a first step toward delineating what seems to be an important role for platelets in airway eosinophilia.
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Asma/imunologia , Inflamação/imunologia , Ativação Plaquetária/imunologia , Eosinofilia Pulmonar/imunologia , Adolescente , Asma/fisiopatologia , Criança , Estudos Transversais , Proteína Catiônica de Eosinófilo/análise , Proteína Catiônica de Eosinófilo/metabolismo , Feminino , Humanos , Inflamação/fisiopatologia , Masculino , Líquido da Lavagem Nasal/química , Selectina-P/análise , Selectina-P/metabolismo , Eosinofilia Pulmonar/fisiopatologia , Qualidade de Vida , Saúde da População Urbana , Adulto JovemRESUMO
BACKGROUND: Several mechanisms of glucocorticoid resistance in asthma have been proposed. P-glycoprotein (P-gp), a ubiquitous efflux transport protein, is associated with variability in the disposition of many drugs and interindividual variability in drug treatment response. This study was undertaken to determine the effect of P-gp expression on glucocorticoid efflux from airway epithelial cells. HYPOTHESIS: Decreasing respiratory epithelial P-gp expression in dexamethasone-exposed airway epithelial cells in vitro will increase intracellular dexamethasone concentration. METHODS: A549 lung epithelial cells, transfected with small interfering RNA (siRNA) targeted at messenger RNA for the gene encoding P-gp, were exposed to 100-nM dexamethasone for 15 minutes. Transfection efficiency of siRNA, P-gp expression, and intracellular dexamethasone were measured with flow cytometry. RESULTS: Cells transfected with both negative siRNA and siRNA targeted at P-gp exhibited a positive correlation of P-gp expression with intracellular dexamethasone. The mean ± SEM correlation coefficients were 0.78 ± 0.07 for cells transfected with negative siRNA and 0.79 ± 0.08 for cells transfected with siRNA targeted at P-gp. DISCUSSION: Contrary to our hypothesis, the positive correlation between P-gp expression and intracellular dexamethasone suggests that P-gp is not a primary transporter of glucocorticoids from airway epithelial cells. Increased P-gp expression is unlikely to be an important mechanism of glucocorticoid resistance in asthma.
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Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Dexametasona/farmacologia , Glucocorticoides/farmacologia , Mucosa Respiratória/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/genética , Citometria de Fluxo , Humanos , Neoplasias Pulmonares , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Mucosa Respiratória/efeitos dos fármacos , TransfecçãoRESUMO
OBJECTIVE: Asthma in children and adolescents is a heterogeneous syndrome comprised of multiple subgroups with variable disease expression and response to environmental exposures. The goal of this study was to define homogeneous phenotypic clusters within a cohort of children and adolescents with asthma and to determine overall and within-cluster associations between environmental tobacco smoke (ETS) exposure and asthma characteristics. METHODS: A combined hierarchical/k-means cluster analysis of principal component variables was used to define phenotypic clusters within a cohort of 6- to 20-year-old urban and largely minority subjects. RESULTS: Among the 154 subjects, phenotypic cluster analysis defined three independent clusters (Cluster 1 [n = 57]; Cluster 2 [n = 33]; Cluster 3 [n = 58]). A small fourth cluster (n = 6) was excluded. Patients in Cluster 1 were predominantly males, with a relative abundance of neutrophils in their nasal washes. Patients in Cluster 2 were predominantly females with high body mass index percentiles and later-onset asthma. Patients in Cluster 3 had higher eosinophil counts in their nasal washes and lower Asthma Control Test (ACT) scores. Within-cluster regression analysis revealed several significant associations between ETS exposure and phenotypic characteristics that were not present in the overall cohort. ETS exposure was associated with a significant increase in nasal wash neutrophils (beta coefficient = 0.73 [95% confidence interval, CI: 0.11 to 1.35]; p = .023) and a significant decrease in ACT score (-5.17 [-8.42 to -1.93]; p = .003) within Cluster 1 and a significant reduction in the bronchodilator-induced % change in forced expiratory volume in one second (FEV(1)) (-36.32 [-62.18 to -10.46]; p = .009) within Cluster 3. CONCLUSIONS: Clustering techniques defined more homogeneous subgroups, allowing for the detection of otherwise undetectable associations between environmental tobacco smoke exposure and asthma characteristics.
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Asma/etiologia , Negro ou Afro-Americano , Poluição por Fumaça de Tabaco/efeitos adversos , Adolescente , Adulto , Asma/etnologia , Criança , Análise por Conglomerados , Estudos de Coortes , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Fenótipo , Análise de Componente PrincipalRESUMO
BACKGROUND: Asthma, a major cause of chronic lung disease worldwide, has increased in prevalence in all age and ethnic groups, particularly in urban areas where cigarette smoking is common. Cigarette smoke (CS) significantly impacts the development of asthma and is strongly associated with increased asthma-related morbidity. PURPOSE: To evaluate bioinformatic analyses predicting that CS would alter expression of tissue inhibitor of metalloproteinase (TIMP) 1 and matrix metalloproteinase (MMP) 9 in asthmatic epithelium. METHODS: Primary differentiated normal (n = 4) and asthmatic (n = 4) human respiratory epithelia on collagen-coated Transwells at air-liquid interface were exposed for 1 hour to CS condensate (CSC) or hydrogen peroxide (H2O2). Tissue inhibitor of metalloproteinase 1 and MMP-9 protein levels were measured at 24 hours by enzyme-linked immunosorbent assay in cell lysates and in apical and basolateral secretions. RESULTS: Tissue inhibitor of metalloproteinase 1 and MMP-9 levels in the apical secretions of normal and asthmatic epithelia were unchanged after exposure to CSC and H2O2. However, CSC increased TIMP-1 levels in the basolateral secretions of both normal and asthmatic epithelia, but decreased MMP-9 levels only in asthmatic basolateral secretions, resulting in a 2.5-fold lower MMP-9/TIMP-1 ratio that corresponded to decreased MMP-9 activity in CS-exposed asthmatic basolateral secretions. CONCLUSIONS: These data validate our prior bioinformatic analyses predicting that TIMP-1 plays a role in the stress response to CS and indicate that asthmatics exposed to CS may be more susceptible to MMP-9-mediated airway remodeling. This is in agreement with the current paradigm that a reduction in the MMP-9/TIMP-1 ratio is a milieu that favors subepithelial airway remodeling in chronic asthma.
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Asma/enzimologia , Metaloproteinase 9 da Matriz/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Fumar/efeitos adversos , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Adulto , Asma/patologia , Brônquios , Células Cultivadas , Criança , Pré-Escolar , Biologia Computacional , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fisiologia , Mucosa Respiratória/enzimologia , Mucosa Respiratória/patologia , Adulto JovemRESUMO
OBJECTIVE: The goal of this study was to examine the prevalence of vitamin D insufficiency and deficiency among urban African-American (AA) youth with asthma compared with control subjects without asthma. STUDY DESIGN: A cross-sectional case-control study was conducted at an urban pediatric medical center. Total 25-hydroxyvitamin D insufficiency (<30 ng/mL) and deficiency (<20 ng/mL) were assessed in urban self-reported AA patients, aged 6 to 20 years, with (n = 92) and without (n = 21) physician-diagnosed asthma. RESULTS: Blood samples were available for 85 (92%) cases. The prevalence of vitamin D insufficiency and deficiency were significantly greater among cases than control subjects (73/85 [86%] vs 4/21 [19%], adjusted odds ratio = 42 [95% confidence interval: 4.4 to 399] for insufficiency and 46/85 [54%] vs 1/21 [5%], adjusted odds ratio = 20 [95% confidence interval: 1.4 to 272] for deficiency). CONCLUSIONS: Most of this sample of urban AA youth with persistent asthma were vitamin D deficient or insufficient. Given the emerging associations between low vitamin D levels and asthma, strong consideration should be given to routine vitamin D testing in urban AA youth, particularly those with asthma.
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Asma/epidemiologia , Negro ou Afro-Americano/estatística & dados numéricos , Deficiência de Vitamina D/epidemiologia , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Estudos Transversais , District of Columbia/epidemiologia , Feminino , Humanos , Masculino , Estações do Ano , População Urbana , Adulto JovemRESUMO
Cigarette smoke exposure induces a respiratory epithelial response that is mediated in part by oxidative stress. The contribution of oxidative stress to cigarette smoke-induced responses in asthmatic respiratory epithelium is not well understood. We sought to increase this understanding by employing data integration and systems biology approaches to publicly available microarray data deposited over the last several years. In this study, we analyzed 14 publicly available asthma- or tobacco-relevant data series and found 4 (2 mice and 2 human) that fulfilled adequate signal/noise thresholds using unsupervised clustering and F test statistics. Using significance filters and a 4-way Venn diagram approach, we identified 26 overlapping genes in the epithelial transcriptional stress response to cigarette smoke and asthma. This test set corresponded to a 26-member gene/protein network containing 18 members that were highly regulated in a fifth data series of direct lung oxidative stress. Of those network members, 2 stood out (ie, tissue inhibitor of metalloproteinase 1 and thrombospondin 1) owing to central location within the network and marked up-regulation sustained at later times in response to oxidative stress. These analyses identified key relationships and primary hypothetical targets for future studies of cigarette smoke-induced oxidative stress in asthma.
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Asma/genética , Asma/metabolismo , Redes Reguladoras de Genes , Pulmão/metabolismo , Estresse Oxidativo/genética , Animais , Asma/etiologia , Linhagem Celular , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Pulmão/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Análise de Sequência com Séries de Oligonucleotídeos , Estresse Oxidativo/efeitos dos fármacos , Fosgênio/toxicidade , Fumar/efeitos adversos , Fumar/genética , Fumar/metabolismo , Biologia de Sistemas , Trombospondinas/genética , Inibidor Tecidual de Metaloproteinase-1/genéticaRESUMO
RATIONALE: Sepsis-related mortality results in part from immunodeficiency secondary to profound lymphoid apoptosis. The biological mechanisms responsible are not understood. OBJECTIVES: Because recent evidence shows that platelets are involved in microvascular inflammation and that they accumulate in lymphoid microvasculature in sepsis, we hypothesized a direct role for platelets in sepsis-related lymphoid apoptosis. METHODS: We studied megakaryocytes and platelets from a murine-induced sepsis model, with validation in septic children, which showed induction of the cytotoxic serine protease granzyme B. MEASUREMENTS AND MAIN RESULTS: Platelets from septic mice induced marked apoptosis of healthy splenocytes ex vivo. Platelets from septic granzyme B null (-/-) mice showed no lymphotoxicity. CONCLUSIONS: Our findings establish a conceptual advance in sepsis: Septic megakaryocytes produce platelets with acutely altered mRNA profiles, and these platelets mediate lymphotoxicity via granzyme B. Given the contribution of lymphoid apoptosis to sepsis-related mortality, modulation of platelet granzyme B becomes an important new target for investigation and therapy.