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BACKGROUND: In children suspected of asthma, diagnosis is confirmed via variable expiratory airflow limitation. However, there is no single gold standard test for diagnosing asthma. OBJECTIVE: This study aimed to evaluate the pulmonary function characteristics in children suspected of asthma without bronchodilator response (BDR) and bronchial hyperresponsiveness (BHR). METHODS: We utilized two separate real-world retrospective observational cohorts of children who underwent both spirometry and bronchial provocation testing for asthma. Spirometry parameters were collected and compared between definite asthma, probable asthma, and non-asthma groups. The original cohort comprised 1199 children who visited the Severance Hospital (Seoul, Korea) between January 2017 and December 2019. The external cohort included 105 children who visited the Gangnam Severance Hospital between January 2019 and December 2019. RESULTS: Probable asthma accounted for 16.8% and 32.4% of the original and external cohorts, respectively. This group showed a significantly higher FeNO level and prevalence of allergic sensitization. Baseline forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity (FVC), forced expiratory flow at 25-75% of FVC (FEF25-75), and FEF75 showed stepwise decrements from non-asthma, probable asthma, to definite asthma patients (P < 0.001). The probable asthma group showed significantly higher odds of abnormal FEV1/FVC (OR, 2.24 [95%CI, 1.43-3.52])and FEF25-75 (2.05 [1.13-3.73]) than the non-asthma group and lower odds of abnormal FEV1(0.05 [0.01-0.19]),FEV1 /FVC (0.27 [0.18-0.41]), FEF25-75 (0.17 [0.11-0.28]), and FEF75 (0.14 [0.08-0.24]) compared to the definite asthma group. The external cohort was consistent with the original cohort. CONCLUSION: We show evidence of airway dysfunction in children for whom a high clinical suspicion of asthma exists without evidence of BDR and BHR. Repeated pulmonary function tests that closely monitor for subtle lung function impairments and active utilization of additional tests, such as allergic screening and FeNO, should be considered to close the gap in diagnosing asthma.
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Japanese encephalitis (JE), caused by the Japanese encephalitis virus (JEV), is a highly threatening disease with no specific treatment. Fortunately, the development of vaccines has enabled effective defense against JE. However, re-emerging genotype V (GV) JEV poses a challenge as current vaccines are genotype III (GIII)-based and provide suboptimal protection. Given the isolation of GV JEVs from Malaysia, China, and the Republic of Korea, there is a concern about the potential for a broader outbreak. Under the hypothesis that a GV-based vaccine is necessary for effective defense against GV JEV, we developed a pentameric recombinant antigen using cholera toxin B as a scaffold and mucosal adjuvant, which was conjugated with the E protein domain III of GV by genetic fusion. This GV-based vaccine antigen induced a more effective immune response in mice against GV JEV isolates compared to GIII-based antigen and efficiently protected animals from lethal challenges. Furthermore, a bivalent vaccine approach, inoculating simultaneously with GIII- and GV-based antigens, showed protective efficacy against both GIII and GV JEVs. This strategy presents a promising avenue for comprehensive protection in regions facing the threat of diverse JEV genotypes, including both prevalent GIII and GI as well as emerging GV strains.
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Virus de la Encefalitis Japonesa (Especie) , Encefalitis Japonesa , Genotipo , Vacunas contra la Encefalitis Japonesa , Virus de la Encefalitis Japonesa (Especie)/genética , Virus de la Encefalitis Japonesa (Especie)/inmunología , Virus de la Encefalitis Japonesa (Especie)/clasificación , Animales , Encefalitis Japonesa/prevención & control , Encefalitis Japonesa/inmunología , Encefalitis Japonesa/virología , Vacunas contra la Encefalitis Japonesa/inmunología , Vacunas contra la Encefalitis Japonesa/administración & dosificación , Vacunas contra la Encefalitis Japonesa/genética , Ratones , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , Humanos , Ratones Endogámicos BALB C , Femenino , Antígenos Virales/inmunología , Antígenos Virales/genética , Eficacia de las Vacunas , Toxina del Cólera/genética , Toxina del Cólera/inmunologíaRESUMEN
BACKGROUND: The relationship between early life factors and childhood pulmonary function and structure in preterm infants remains unclear. PURPOSE: This study investigated the impact of bronchopulmonary dysplasia (BPD) and perinatal factors on childhood pulmonary function and structure. METHODS: This longitudinal cohort study included preterm participants aged ≥5 years born between 2005 and 2015. The children were grouped by BPD severity according to National Institutes of Health criteria. Pulmonary function tests (PFTs) were performed using spirometry. Chest computed tomography (CT) scans were obtained and scored for hyperaeration or parenchymal lesions. PFT results and chest CT scores were analyzed with perinatal factors. RESULTS: A total 150 children (66 females) aged 7.7 years (6.4-9.9 years) were categorized into non/mild BPD (n=68), moderate BPD (n=39), and severe BPD (n=43) groups. The median z score for forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and forced midexpiratory flow (FEF25%-75%) were significantly lower in the severe versus non/mild BPD group (-1.24 vs. -0.18, -0.22 vs. 0.41, -1.80 vs. -1.12, and -1.88 vs. -1.00, respectively; all P<0.05). The median z scores of FEV1, FEV1/ FVC, and FEF25%-75% among asymptomatic patients were also significantly lower in the severe versus non/mild BPD group (-0.82 vs. 0.09, -1.68 vs. -0.87, -1.59 vs. -0.61, respectively; all P<0.05). The severe BPD group had a higher median (range) CT score than the non/mild BPD group (6 [0-12] vs. 1 [0-10], P<0.001). Prenatal oligohydramnios was strongly associated with both low pulmonary function (FEV1/FVC
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PURPOSE: The respiratory syncytial virus (RSV) is a common respiratory virus that causes acute lower respiratory tract infectious diseases, particularly in young children and older individuals. Activated leukocyte cell adhesion molecule (ALCAM) is a membrane glycoprotein expressed in various cell types, including epithelial cells, and is associated with inflammatory responses and various cancers. However, the precise role of ALCAM in RSV-induced airway inflammation remains unclear, and our study aimed to explore this gap in the literature. METHODS: C57BL/6 wild-type, ALCAM knockout mice and airway epithelial cells were infected with RSV and the expression of ALCAM and inflammatory cytokines were measured. We also conducted further experiments using Anti-ALCAM antibody and recombinant ALCAM in airway epithelial cells. RESULTS: The expression levels of ALCAM and inflammatory cytokines increased in both RSV-infected mice and airway epithelial cells. Interestingly, IL-33 expression was significantly reduced in ALCAM-knockdown cells compared to control cells following RSV infection. Anti-ALCAM antibody treatment also reduced IL-33 expression following RSV infection. Furthermore, the phosphorylation of ERK1/2, p38, and JNK was diminished in ALCAM-knockdown cells compared to control cells following RSV infection. Notably, in the control cells, inhibition of these pathways significantly decreased the expression of IL-33. In vivo study also confirmed a reduction in inflammation induced by RSV infection in ALCAM deficient mice compared to wild-type mice. CONCLUSION: These findings demonstrate that ALCAM contributes to RSV-induced airway inflammation at least partly by influencing IL-33 expression through mitogen-activated protein kinase signaling pathways. These results suggest that targeting ALCAM could be a potential therapeutic strategy for alleviating IL-33-associated lung diseases.
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Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Animales , Ratones , Molécula de Adhesión Celular del Leucocito Activado/metabolismo , Citocinas/metabolismo , Inflamación/metabolismo , Interleucina-33/genética , Interleucina-33/metabolismo , Pulmón/metabolismo , Sistema de Señalización de MAP Quinasas , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Infecciones por Virus Sincitial Respiratorio/metabolismo , Virus Sincitial Respiratorio Humano/metabolismo , Transducción de SeñalRESUMEN
PURPOSE: Despite the risk of anaphylaxis, oral food challenges (OFCs) are performed clinically for various indications, particularly to confirm tolerance development. This study aimed to assess OFCs by relevant indications and build an outcome prediction model to help determine when to perform OFCs in children who are likely to have developed immune tolerance. METHODS: In total, 432 pediatric OFCs were retrospectively analyzed according to indications. Clinical characteristics, serum total immunoglobulin (Ig) E, blood eosinophils, and specific IgE and IgG4 levels for food allergens were noted and compared. Machine learning was utilized to select the most important variables in determining the passage of the OFCs, and prediction models were constructed using the selected variables. RESULTS: OFCs were most commonly performed to confirm tolerance development (number, %; 267, 61.8%). The most common food allergens tested were egg (191, 44.2%) and milk (135, 31.3%). Children who passed the egg challenges for confirming tolerance acquisition had significantly lower egg white-specific IgE level (P = 0.008). Similarly, those who passed milk challenges had significantly lower cow's milk-specific IgE (P = 0.002) and casein-specific IgE levels (P = 0.005). We developed a nomogram to predict the outcome of OFCs to determine the tolerance acquisition with the selected variables; lower food-specific IgE, higher total IgE, and younger age indicated a higher probability of passage. The area under the curve (95% confidence interval) was 0.623 (0.503-0.743) for egg and 0.734 (0.628-0.840) for milk. CONCLUSIONS: Serum total IgE and food-specific IgE combined with age showed trends toward passing OFCs for confirming tolerance development. The constructed model may be used by clinicians as a practical guide for minimizing the risks of OFCs and a timely reintroduction for children with food allergies.
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Dengue virus is an enveloped virus with an icosahedral assembly of envelope proteins (E). The E proteins are arranged as a head-to-tail homodimer, and domain III (EDIII) is placed at the edge of the dimer, converging to a pentamer interface. For a structure-based approach, cholera toxin B (CTB) was harnessed as a structural scaffold for the five-fold symmetry of EDIII. Pivoted by an RNA-mediated chaperone for the protein folding and assembly, CTB-EDIII of dengue serotype 1 (DV1) was successfully produced as soluble pentamers in an E. coli host with a high yield of about 28 mg/L. Immunization of mice with CTB-DV1EDIII elicited increased levels of neutralizing antibodies against infectious viruses compared to the control group immunized with DV1EDIII without CTB fusion. IgG isotype switching into a balanced Th1/Th2 response was also observed, probably triggered by the intrinsic adjuvant activity of CTB. Confirming the immune-enhancing potential of CTB in stabilizing the pentamer assembly of EDIII, this study introduces a low-cost bacterial production platform designed to augment the soluble production of subunit vaccine candidates, particularly those targeting flaviviruses.
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Japanese encephalitis virus (JEV) is an enveloped icosahedral capsid virus with a prime neutralizing epitope present in E protein domain III (EDIII). E dimers are rearranged into a five-fold symmetry of icosahedrons. Cholera toxin B (CTB) and heat-labile enterotoxin B (LTB) of AB5-type toxin was used as the structural scaffold for emulating the pentameric axis of EDIII. We produced homo-pentameric EDIII through the genetic fusion of LTB or CTB in E. coli without recourse to additional refolding steps. Harnessing an RNA-mediated chaperone further enhanced the soluble expression and pentameric assembly of the chimeric antigen. The pentameric assembly was validated by size exclusion chromatography (SEC), non-reduced gel analysis, and a GM1 binding assay. CTB/LTB-EDIII chimeric antigen triggered high neutralizing antibodies against the JEV Nakayama strain after immunization in mice. Altogether, our proof-of-principle study creating a JEV-protective antigen via fusion with an AB5-type toxin as both a pentameric scaffold and a built-in adjuvant posits the bacterially produced recombinant chimeric antigen as a cost-effective alternative to conventional inactivated vaccines against JEV.
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Virus de la Encefalitis Japonesa (Especie) , Animales , Ratones , Virus de la Encefalitis Japonesa (Especie)/genética , Anticuerpos Antivirales , Escherichia coli/genética , Anticuerpos Neutralizantes , Vacunas Sintéticas/genética , Toxina del Cólera/genética , Ratones Endogámicos BALB CRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal, fibrotic, interstitial lung disease of unknown cause. Despite extensive studies, the underlying mechanisms of IPF development remain unknown. Here, we found that p300 was upregulated in multiple epithelial cells in lung samples from patients with IPF and mouse models of lung fibrosis. Lung fibrosis was significantly diminished by the alveolar type II (ATII) cell-specific deletion of the p300 gene. Moreover, we found that ubiquitin C-terminal hydrolase L3 (UCHL3)-mediated deubiquitination of p300 led to the transcriptional activation of the chemokines Ccl2, Ccl7, and Ccl12 through the cooperative action of p300 and C/EBPß, which consequently promoted M2 macrophage polarization. Selective blockade of p300 activity in ATII cells resulted in the reprogramming of M2 macrophages into antifibrotic macrophages. These findings demonstrate a pivotal role for p300 in the development of lung fibrosis and suggest that p300 could serve as a promising target for IPF treatment.
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Células Epiteliales Alveolares , Fibrosis Pulmonar Idiopática , Ubiquitina Tiolesterasa , Animales , Ratones , Quimiocina CCL2/genética , Enzimas Desubicuitinizantes , Fibrosis Pulmonar Idiopática/genética , Pulmón , Humanos , Ubiquitina Tiolesterasa/metabolismo , Proteína p300 Asociada a E1ARESUMEN
Background: Spirometry is an unrivalled tool for determining asthma and asthma severity. The ratio of forced expiratory volume (FEV) in 1 second (FEV1) to forced vital capacity (FVC) and the forced expiratory flow between 25% and 75% of FVC (FEF25-75) are well-known markers of airway obstruction, but they are limited by low reproducibility, particularly in children. In this study, we defined terminal expiration volume (TEV) as FEV in 3 seconds forced expiratory volume in 3 seconds (FEV3) minus forced expiratory volume in 1 seconds (FEV1) and investigate whether TEV/FEV3 can function as a coherent marker to compensate for existing markers. Methods: This retrospective study comprised 980 children ages ≤ 18 years who underwent spirometry and the bronchial provocation testing. TEV/FEV3 was compared with regard to asthma presence and severity. The findings were verified with an external validation group (n = 105). Results: FEV3 was obtained in 837 children (85.4%). TEV/FEV3 was significantly higher in patients with asthma than in patients who did not have asthma (17.1 ± 5.5 versus 12.0 ± 4.4, p < 0.001). External validation with 73 patients showed similar results (18.0 ± 5.9 in asthma versus 10.2 ± 5.1 in non-asthma, p < 0.001). The discriminatory power of TEV/FEV3 for asthma was comparable with that of FEF25-75 (p = 0.804). TEV/FEV3 significantly increased with asthma severity (mild, 16.1 ± 5.4; moderate, 17.7 ± 5.4; severe, 22.0 ± 5.3; p < 0.001). For patients who could not achieve FEV3, FEF25-75 demonstrated no significant difference between mild and moderate asthma, and could not discriminate asthma or asthma severity. Conclusion: TEV/FEV3 is a new metric that may help diagnose and determine asthma severity by using conventional spirometry by assessing small airway dysfunction. TEV/FEV3 promotes a reassessment of the reliability of other spirometric parameters, particularly in young children. Caution is needed in interpreting the result of spirometry in children who cannot achieve FEV3.
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Asma , Niño , Humanos , Preescolar , Reproducibilidad de los Resultados , Estudios Retrospectivos , Asma/diagnóstico , Pruebas de Función Respiratoria , EspirometríaRESUMEN
Hyperoxia is frequently used for treating acute respiratory failure, but it can cause acute lung injury. Nucleotide-binding domain and leucine-rich-repeat-containing family member X1 (NLRX1) is localized in mitochondria and involved in production of reactive oxygen species, inflammation, and apoptosis, which are the features of hyperoxic acute lung injury (HALI). The contribution of NLRX1 to HALI has not previously been addressed. Thus, to investigate the role of NLRX1 in hyperoxia, we generated a murine model of HALI in wild-type (WT) and NLRX1-/- mice by exposure to > 95% oxygen for 72 h. As a result, NLRX1 expression was elevated in mice exposed to hyperoxia. In acute lung injury, levels of inflammatory cells, protein leakage, cell cytotoxicity, and pro-inflammatory cytokines were diminished in NLRX1-/- mice compared to WT mice. In a survival test, NLRX1-/- mice showed reduced mortality under hyperoxic conditions, and apoptotic cell death and caspase expression and activity were also lower in NLRX1-/- mice. Furthermore, levels of the MAPK signaling proteins ERK 1/2, JNK, and p38 were decreased in NLRX1-deficient mice than in WT mice exposed to hyperoxia. The study shows that a genetic deficit in NLRX1 can suppress hyperoxia-induced apoptosis, suggesting that NLRX1 acts as a pivotal regulator of HALI.
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Lesión Pulmonar Aguda , Hiperoxia , Animales , Ratones , Apoptosis , Muerte Celular , Transducción de Señal , Proteínas MitocondrialesRESUMEN
Hypoxemia and multiple organ dysfunction are significant contributors to mortality in patients with pediatric acute respiratory distress syndrome (PARDS). P50, the oxygen tension at which hemoglobin is 50% saturated, is a measure of hemoglobin-oxygen affinity, and its alteration might have implications for tissue hypoxia and organ dysfunction. The purpose of this single-center, retrospective study was to evaluate P50 levels in PARDS and to determine the association between P50 and clinical outcomes. The study included 212 children diagnosed with PARDS according to the Pediatric Acute Lung Injury Consensus Conference definition who required invasive mechanical ventilation and had arterial blood gas results of hemoglobin oxygen saturation < 97% at the time of diagnosis. P50 levels were calculated using Doyle's method, and organ dysfunction was assessed using the Pediatric Logistic Organ Dysfunction-2 score. Most patients exhibited more than one dysfunctional extrapulmonary organ at PARDS onset. P50 increased with increasing PARDS severity (mild (26.6 [24.9-29.6]), moderate (26.8 [25.0-29.5]), and severe PARDS (29.1 [26.1-32.4] mmHg; P = 0.025). Moreover, P50 demonstrated a significant positive association with extrapulmonary organ dysfunction score (ß = 0.158, P = 0.007) and risk of mortality (adjusted hazard ratio, 1.056; 95% confidence interval, 1.015-1.098; P = 0.007), irrespective of initial PARDS severity. The relationship between P50 and mortality was largely mediated by extrapulmonary organ dysfunction. A high P50 value at the time of PARDS diagnosis may be associated with mortality via dysfunctional extrapulmonary organs. Future studies should consider P50 as a potential candidate index for risk stratification of PARDS patients.
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Insuficiencia Multiorgánica , Síndrome de Dificultad Respiratoria , Niño , Humanos , Hipoxia , Insuficiencia Multiorgánica/etiología , Oxígeno , Respiración Artificial/métodos , Síndrome de Dificultad Respiratoria/terapia , Estudios RetrospectivosRESUMEN
PURPOSE: The prevalence of food allergy, triggered by T-helper type 2 (Th2) cell-mediated inflammation, is increasing worldwide. Interleukin (IL)-18 plays an important role in inflammatory diseases by binding with the IL-18 receptor. IL-18/IL-18 receptor α (IL-18Rα) is a cofactor for immunoglobulin E (IgE) production and Th2 cell development. Studies have not investigated the association between the IL-18/IL-18Rα signaling pathway and food allergy. Here, we investigated the role of IL-18Rα in food allergy induction and development. METHODS: Wild-type (WT) and IL-18Rα-null mutant (IL-18Rα-/-) C57BL/6 mice were sensitized and challenged using ovalbumin (OVA) for food allergy induction. Food allergy symptoms, T cell-mediated immune responses, and signal transducer and activator of transcription (STAT)/suppressors of cytokine signaling (SOCS) pathways were analyzed in mice. RESULTS: IL-18Rα expression was increased in WT mouse intestines after OVA treatment. Food allergy-induced IL-18Rα-/- mice showed attenuated systemic food allergic reactions, OVA-specific IgE and mouse mast cell protease-1 production, inflammatory cell infiltration, and T cell activation. Ex vivo experiments showed that cell proliferation and Th2 cytokine production were lower in IL-18Rα-/- mouse splenocytes than in WT mouse splenocytes. IL-18Rα blockade in WT splenocytes attenuated cell proliferation and Th2 cytokine production. Moreover, STAT3 phosphorylation was reduced in IL-18Rα-/- mice, and SOCS3 and SOCS1 activation were diminished in IL-18Rα-/- intestinal T cells. CONCLUSIONS: IL-18Rα regulates allergic reactions and immune responses by regulating T cell responses in food allergies. Moreover, IL-18Rα is involved in the STAT/SOCS signaling pathways. Targeting IL-18Rα signaling might be a novel therapeutic strategy for food allergy.
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Bronchopulmonary dysplasia (BPD) can cause respiratory morbidity beyond the neonatal period. We aimed to analyze the association of BPD on childhood lower respiratory illness (LRI) and asthma among patients diagnosed with respiratory distress syndrome (RDS). This case-control study analyzed data between 2002 and 2015 from a nationwide database. We included 55,066 children with RDS. Two-year LRI and asthma at ages 3 and 5 were assessed. Readmission for LRIs within 2 years of birth occurred in 53.9% and 37.9% of the BPD (n = 9470) and non-BPD (n = 45,596) cases, respectively. In the BPD group, the median number of hospitalizations, mechanical ventilation and oxygen use rates were significantly higher, while the hospitalization duration was significantly longer (P < 0.001 for all). The relative risk of BPD was 1.42 (1.39-1.45) on total readmission and 6.53 (5.96-7.15) on intensive care unit readmission. Asthma prevalence was significantly higher in BPD group (57.6% vs. 48.9% at age 3 and 44.3% vs. 38.2% at age 5, P < 0.001). In children with RDS, BPD could affect repetitive and worse LRI as an independent risk factor for respiratory morbidity during the first 2 years of life. BPD may also be a crucial risk factor for asthma in preschoolers.
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Asma , Displasia Broncopulmonar , Síndrome de Dificultad Respiratoria del Recién Nacido , Adolescente , Adulto , Asma/complicaciones , Asma/epidemiología , Displasia Broncopulmonar/complicaciones , Displasia Broncopulmonar/epidemiología , Estudios de Casos y Controles , Niño , Preescolar , Humanos , Recién Nacido , Morbilidad , Síndrome de Dificultad Respiratoria del Recién Nacido/complicaciones , Síndrome de Dificultad Respiratoria del Recién Nacido/epidemiología , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: We aimed to examine the delay in antiviral initiation in rapid antigen test (RAT) false-negative children with influenza virus infection and to explore the clinical outcomes. We additionally conducted a medical cost-benefit analysis. METHODS: This single-center, retrospective study included children (aged < 10 years) with influenza-like illness (ILI), hospitalized after presenting to the emergency department during three influenza seasons (2016-2019). RAT-false-negativity was defined as RAT-negative and polymerase chain reaction-positive cases. The turnaround time to antiviral treatment (TAT) was from the time when RAT was prescribed to the time when the antiviral was administered. The medical cost analysis by scenarios was also performed. RESULTS: A total of 1,430 patients were included, 7.5% were RAT-positive (n = 107) and 2.4% were RAT-false-negative (n = 20). The median TAT of RAT-false-negative patients was 52.8 hours, significantly longer than that of 4 hours in RAT-positive patients (19.2-100.1, P < 0.001). In the multivariable analysis, TAT of ≥ 24 hours was associated with a risk of severe influenza infection and the need for mechanical ventilation (odds ratio [OR], 6.8, P = 0.009 and OR, 16.2, P = 0.033, respectively). The medical cost varied from $11.7-187.3/ILI patient. CONCLUSION: Antiviral initiation was delayed in RAT-false-negative patients. Our findings support the guideline that children with influenza, suspected of having severe or progressive infection, should be treated immediately.
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Antivirales/uso terapéutico , Gripe Humana/diagnóstico , Gripe Humana/tratamiento farmacológico , Tiempo de Tratamiento , Antígenos Virales/sangre , Niño , Preescolar , Análisis Costo-Beneficio , Reacciones Falso Negativas , Femenino , Humanos , Lactante , Gripe Humana/sangre , Gripe Humana/economía , Masculino , Orthomyxoviridae/inmunología , República de Corea , Estudios RetrospectivosRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by fibroproliferative matrix molecule accumulation, collagen deposition, and apoptosis. Activated leukocyte cell-adhesion molecule (ALCAM; CD166) is a cell-adhesion molecule that has been implicated in adhesive and migratory attribution, including leukocyte homing and trafficking and cancer metastasis. We investigated the role of ALCAM on pulmonary fibrosis development in murine models. Thus, a bleomycin-induced pulmonary fibrosis model was established with wild-type and ALCAM-/- mice. Pulmonary fibrosis was also induced in transforming growth factor-ß1 (TGF-ß1)-transgenic mice that conditionally overexpress TGF-ß1 upon doxycycline administration. In both models, observed reduced ALCAM levels in lung tissue and BAL fluid in pulmonary fibrosis-induced wild-type mice compared with control mice. We also observed reduced ALCAM expression in the lung tissue of patients with pulmonary fibrosis compared with normal lung tissue. ALCAM-/- mice showed an exacerbated lung fibrosis response compared with wild-type mice, and this was accompanied by increased cell death. Further investigation for identification of the signaling pathway revealed that PI3K and ERK signaling pathways are involved in bleomycin-induced fibrosis. Collectively, these results highlight that ALCAM plays a protective role in the pathogenesis of pulmonary fibrosis that inhibits epithelial cell apoptosis through the PI3K-Akt signaling pathway. Our findings demonstrate the potential of ALCAM as a therapeutic target for IPF and may aid the development of new strategies for the management and treatment of patients with IPF.
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Molécula de Adhesión Celular del Leucocito Activado , Antígenos CD/metabolismo , Moléculas de Adhesión Celular Neuronal/metabolismo , Proteínas Fetales/metabolismo , Fibrosis Pulmonar Idiopática , Molécula de Adhesión Celular del Leucocito Activado/metabolismo , Animales , Bleomicina , Humanos , Fibrosis Pulmonar Idiopática/metabolismo , Leucocitos/patología , Pulmón/patología , Ratones , Ratones Endogámicos C57BL , Fosfatidilinositol 3-Quinasas/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Viral respiratory infection causes inflammatory lung disease. Chitinase 3-like 1 (CHI3L1) contributes to airway inflammation, but its role in human airway epithelial cells following viral infection is unclear. Thus, we investigated whether CHI3L1 regulates inflammatory responses caused by viral infections in airway epithelial cells. Human bronchial epithelial cells, BEAS-2B, were stimulated with a synthetic analog of viral double-stranded RNA, polyinosinic:polycytidylic acid (poly(I:C)). To confirm the specific role of CHI3L1, CHI3L1 was knocked down in BEAS-2B cells using shRNA lentivirus. The expression of CHI3L1 and proinflammatory cytokines such as IL-8 and phosphorylation of mitogen-activated protein kinase (MAPK) pathways were analyzed. In addition to poly(I:C), BEAS-2B cells were infected with the human respiratory syncytial virus (RSV) A2 strain, and CHI3L1 and IL-8 expression was analyzed. Stimulating the cells with poly(I:C) increased CHI3L1 and IL-8 expression, whereas IL-8 expression was abrogated in CHI3L1 knockdown BEAS-2B cells. Poly(I:C) stimulation of BEAS-2B cells resulted in phosphorylation of MAPK pathways, and inhibition of MAPK pathways significantly abolished IL-8 secretion. Phosphorylation of MAPK pathways was diminished in CHI3L1 knockdown BEAS-2B cells. Infection with RSV increased CHI3L1 and IL-8 expression. IL-8 expression induced by RSV infection was abrogated in CHI3L1 knockdown cells. In conclusion, CHI3L1 may be involved in IL-8 secretion by regulating MAPK pathways during respiratory viral infections in airway epithelial cells.
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Proteína 1 Similar a Quitinasa-3/metabolismo , Células Epiteliales/metabolismo , Interleucina-8/metabolismo , Pulmón/citología , ARN Bicatenario/metabolismo , Línea Celular , Citocinas/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/virología , Humanos , Mediadores de Inflamación/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fosforilación/efectos de los fármacos , Poli I-C/farmacología , Infecciones por Virus Sincitial Respiratorio/patología , Infecciones por Virus Sincitial Respiratorio/virología , Virus Sincitial Respiratorio Humano/efectos de los fármacos , Virus Sincitial Respiratorio Humano/fisiologíaRESUMEN
BACKGROUND: The pathophysiology of childhood food allergy (FA) and its natural history are poorly understood. Clarification of the underlying mechanism may help identify novel biomarkers and strategies for clinical intervention in children with FA. OBJECTIVE: This study aimed to identify metabolites associated with the development and resolution of FA. METHODS: The metabolomic profiles of 20 children with FA and 20 healthy controls were assessed by liquid chromatography-tandem mass spectrometry. Comparative analysis was performed to identify metabolites associated with FA and FA resolution. For subjects with FA, serum samples were collected at the time of diagnosis and after resolution to identify the changes in metabolite levels. The selected metabolites were then quantified in a quantification cohort to validate the results. Finally, genome-wide association analysis of the metabolite levels was performed. RESULTS: The study demonstrated a significantly higher level of sphingolipid metabolites and a lower level of acylcarnitine metabolites in children with FA than those in healthy controls. At diagnosis, subjects with resolving FA had a significantly high level of omega-3 metabolites and a low level of platelet-activating factors compared to persistent FA. However, the level of omega-3 metabolites decreased in children with resolving FA but increased in children with persistent FA during the same time. The quantification data of omega-3-derived resolvins, platelet-activating factor, and platelet-activating factor acetylhydrolase activity further supported these results. CONCLUSION: The lipid metabolite profile is closely related to childhood FA and FA resolution. This study suggests potential predictive biomarkers and provides insight into the mechanisms underlying childhood FA.
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Hipersensibilidad a los Alimentos , Estudio de Asociación del Genoma Completo , Metabolismo de los Lípidos , Biomarcadores , Niño , Humanos , Metabolómica/métodos , EsfingolípidosRESUMEN
BACKGROUND: Genome-wide association studies (GWASs) of asthma have identified several risk alleles and loci, but most have been conducted in individuals with European-ancestry. Studies in Asians, especially children, are still lacking. We aimed to identify susceptibility loci by performing the first GWAS of asthma in Korean children with persistent asthma. METHODS: We used a discovery set of 741 children with persistent asthma as cases and 589 healthy children and 551 healthy adults as controls to perform a GWAS. We validated our GWAS findings using UK Biobank data. We then used the Genotype-Tissue Expression database to identify expression quantitative trait loci of candidate variants. Finally, we quantified proteins of genes associated with asthma. RESULTS: Variants at the 17q12-21 locus and SNPs in CYBRD1 and TNFSF15 genes were associated with persistent childhood asthma at genome-wide thresholds of significance. Four SNPs in the TNFSF15 gene were also associated with childhood-onset asthma in British white participants in the UK Biobank data. The asthma-associated rs7856856-C allele, the lead SNP, was associated with decreased TNFSF15 expression in whole blood and in arteries. Korean children with asthma had lower serum TNFSF15 levels than controls, and those with the asthma risk rs7856856-CC genotype exhibited the lowest serum TNFSF15 levels overall, especially asthmatic children. CONCLUSIONS: Our GWAS of persistent childhood asthma with allergic sensitization identified a new susceptibility gene, TNFSF15, and replicated associations at the 17q12-21 childhood-onset asthma locus. This novel association may be mediated by reduced expression of serum TNFSF15 and loss of suppression of angiogenesis.
Asunto(s)
Asma , Estudio de Asociación del Genoma Completo , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral , Adulto , Asma/genética , Estudios de Casos y Controles , Niño , Predisposición Genética a la Enfermedad , Humanos , Polimorfismo de Nucleótido Simple , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genéticaRESUMEN
OBJECTIVE: Evaluation of airway inflammation and dysfunction is important in management of allergic rhinitis (AR) since AR is a risk factor for developing asthma. Theoretical nonlinear modeling of exhaled nitric oxide (NO) has revealed extended flow-independent NO parameters that could explain where or how NO metabolism was altered. We aimed to evaluate the association between extended NO parameters and bronchial hyperresponsiveness (BHR) in children with AR. METHODS: Exhaled NO was measured in 74 children with AR on the same day they underwent the provocholine challenge test (PCT). Extended NO was measured in three different exhaled flow rates (30, 100, 200 mL/s) and calculated using the Högman-Meriläinen model. We compared the extended NO parameters including bronchial NO (JawNO), airway tissue NO (CawNO), alveolar tissue NO (CaNO), and diffusing capacity of NO (DawNO) between AR with and without BHR groups, and analyzed the correlation between extended NO parameters and the response-dose ratio (RDR) of the PCT. We additionally evaluated 49 respiratory healthy controls. RESULTS: Among the 74 children with AR, nine showed BHR. JawNO increased more in children with AR than the control group. In children with AR, JawNO was higher in the AR with BHR than without BHR group, and was correlated positively with log RDR (r = 0.373, p = .001). CONCLUSIONS: Extended NO analysis including JawNO can be a useful tool for assessing BHR in AR.