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BACKGROUND: High levels of neutrophil extracellular trap (NET) formation or NETosis and autoantibodies are related to poor prognosis and disease severity of COVID-19 patients. Human angiotensin-converting enzyme 2 (ACE2) cross-reactive anti-severe acute respiratory syndrome coronavirus 2 spike protein receptor-binding domain (SARS-CoV-2 RBD) antibodies (CR Abs) have been reported as one of the sources of anti-ACE2 autoantibodies. However, the pathological implications of CR Abs in NET formation remain unknown. METHODS: In this study, we first assessed the presence of CR Abs in the sera of COVID-19 patients with different severity by serological analysis. Sera and purified IgG from CR Abs positive COVID-19 patients as well as a mouse monoclonal Ab (mAb 127) that can recognize both ACE2 and the RBD were tested for their influence on NETosis and the possible mechanisms involved were studied. RESULTS: An association between CR Abs levels and the severity of COVID-19 in 120 patients was found. The CR Abs-positive sera and IgG from severe COVID-19 patients and mAb 127 significantly activated human leukocytes and triggered NETosis, in the presence of RBD. This NETosis, triggered by the coexistence of CR Abs and RBD, activated thrombus-related cells but was abolished when the interaction between CR Abs and ACE2 or Fc receptors was disrupted. We also revealed that CR Abs-induced NETosis was suppressed in the presence of recombinant ACE2 or the Src family kinase inhibitor, dasatinib. Furthermore, we found that COVID-19 vaccination not only reduced COVID-19 severity but also prevented the production of CR Abs after SARS-CoV-2 infection. CONCLUSIONS: Our findings provide possible pathogenic effects of CR Abs in exacerbating COVID-19 by enhancing NETosis, highlighting ACE2 and dasatinib as potential treatments, and supporting the benefit of vaccination in reducing disease severity and CR Abs production in COVID-19 patients.
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COVID-19 , Humanos , Animales , Ratones , SARS-CoV-2 , Enzima Convertidora de Angiotensina 2 , Vacunas contra la COVID-19 , Dasatinib , Inmunoglobulina G/metabolismo , Autoanticuerpos/metabolismo , Glicoproteína de la Espiga del Coronavirus , Unión ProteicaRESUMEN
BACKGROUND: Secondary pneumonia has a significant clinical impact on critically ill patients with COVID-19. AIM: Considering potential geographic variations, this study explores the clinical implications of secondary pneumonia within East Asian populations. METHODS: This multicenter, retrospective cohort study enrolled critical COVID-19 patients requiring intensive care units (ICUs) admission in Taiwan from December 31, 2020, to June 1, 2022. FINDINGS: Among the 187 critical COVID-19 patients, 80 (42.8%) developed secondary pneumonia. The primary causative pathogens were gram-negative bacilli (GNB) (76.8%). Gram-positive cocci and fungi were mainly observed during the initial two weeks of ICU stay. Notably, the incidence of pulmonary aspergillosis was 9.2% during the first week of ICU stay and all Staphylococcus aureus were susceptible to methicillin. Multi-drug resistant organisms (MDROs) were responsible for 28.3% of the cases, exhibiting significantly longer ICU stays compared to the non-MDRO group (median, 27 vs. 14 days, P < 0.001). In the multivariate analysis, Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores were associated with a significantly increased risk of secondary pneumonia. In-hospital mortality was significantly higher in patients with secondary pneumonia than in those without (37.7% vs. 16.7%, P = 0.02) and survival analysis demonstrated gram-negative bacilli-related secondary pneumonia contributed to a worse prognosis. CONCLUSIONS: Secondary pneumonia in critical COVID-19 patients significantly raised in-hospital mortality and extended hospital and ICU stays. Moreover, the presence of GNB notably predicted an unfavorable prognosis.
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Management of invasive mould infections (IMIs) is challenging in Asia, as awareness among medical practitioners can be low and resources are limited. Timely diagnosis and appropriate treatment of IMIs can mitigate the impact on morbidity and mortality, but diagnostic methods, as well as access to preferred antifungal medications, may vary throughout the region. Knowledge of local epidemiology and accurate diagnosis and identification of causal pathogens would facilitate optimal treatment but data in Asia are lacking. To address these unmet needs in the management of IMIs, this paper is a call for urgent action in the following areas: improving awareness of the threat of IMIs; providing education to frontline clinicians across a broad range of specialties on 'red flags' for suspicion of IMIs; prioritizing cost-effective rapid diagnostic testing; improving access to preferred antifungal medications; and closing the gaps in local epidemiological data on IMIs to inform local treatment guidelines.
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Antifúngicos , Hongos , Antifúngicos/uso terapéutico , Asia/epidemiologíaRESUMEN
BACKGROUND: Driving pressure (∆P) is an important factor that predicts mortality in acute respiratory distress syndrome (ARDS). We test the hypothesis that serial changes in daily ΔP rather than Day 1 ΔP would better predict outcomes of patients with ARDS. METHODS: This retrospective cohort study enrolled patients admitted to five intensive care units (ICUs) at a medical center in Taiwan between March 2009 and January 2018 who met the criteria for ARDS and received the lung-protective ventilation strategy. ∆P was recorded daily for 3 consecutive days after the diagnosis of ARDS, and its correlation with 60-day survival was analyzed. RESULTS: A total of 224 patients were enrolled in the final analysis. The overall ICU and 60-day survival rates were 52.7% and 47.3%, respectively. ∆P on Days 1, 2, and 3 was significantly lower in the survival group than in the nonsurvival group (13.8 ± 3.4 vs. 14.8 ± 3.7, p = 0.0322, 14 ± 3.2 vs. 15 ± 3.5, p = 0.0194, 13.6 ± 3.2 vs. 15.1 ± 3.4, p = 0.0014, respectively). The patients were divided into four groups according to the daily changes in ∆P, namely, the low ∆P group (Day 1 ∆P < 14 cmH2O and Day 3 ∆P < 14 cmH2O), decrement group (Day 1 ∆P ≥ 14 cmH2O and Day 3 ∆P < 14 cmH2O), high ∆P group (Day 1 ∆P ≥ 14 cmH2O and Day 3 ∆P ≥ 14 cmH2O), and increment group (Day 1 ∆P < 14 cmH2O and Day 3 ∆P ≥ 14 cmH2O). The 60-day survival significantly differed among the four groups (log-rank test, p = 0.0271). Compared with the low ΔP group, patients in the decrement group did not have lower 60-day survival (adjusted hazard ratio 0.72; 95% confidence interval [CI] 0.31-1.68; p = 0.4448), while patients in the increment group had significantly lower 60-day survival (adjusted hazard ratio 1.96; 95% CI 1.11-3.44; p = 0.0198). CONCLUSIONS: Daily ∆P remains an important predicting factor for survival in patients with ARDS. Serial changes in daily ΔP might be more informative than a single Day 1 ΔP value in predicting survival of patients with ARDS.
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Respiración Artificial/métodos , Síndrome de Dificultad Respiratoria/terapia , Anciano , Femenino , Estudios de Seguimiento , Hospitalización/tendencias , Humanos , Masculino , Presión , Pronóstico , Síndrome de Dificultad Respiratoria/mortalidad , Síndrome de Dificultad Respiratoria/fisiopatología , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Taiwán/epidemiologíaRESUMEN
BACKGROUND: Candidemia caused by uncommon Candida species is increasing and misidentification may compromise optimal antifungal therapy. This multicenter study aimed to evaluate the accuracy of species-level identification of uncommon Candida. METHODS: Uncommon causative species of candidemia identified in routine laboratories using CHROMagar, API-32C and VITEK-2 Yeast ID system were collected from July 2011 to June 2014. These isolates were further identified using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) system and sequencing of the internal transcribed spacer and 28S rRNA gene. Susceptibility of the isolates was determined. RESULTS: Of 85 isolates evaluated, Candida guilliermondii (n = 36) was the most common, followed by Candid sake (n = 7) and Candida famata (n = 4). Using DNA-sequencing analysis as standard, none of C. sake and C. famata was correct, while VITEK MS correctly identified 10 of the 11 isolates. With the exclusion of one unspecified Candida by DNA-sequencing methods, the accuracy of conventional methods and VITEK MS was 64.3% and 86.9%, respectively (p = 0.001). Eight isolates were confirmed to be yeasts other than Candida. Compared with other Candida species, C. guilliermondii showed elevated minimal inhibitory concentration of echinocandins. CONCLUSION: Misidentification of uncommon Candida species was common using the conventional methods, especially for C. sake and C. famata. MALDI-TOF MS assisted by DNA-sequencing methods should be considered.
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Candida , Sepsis , Candida/genética , Humanos , Saccharomycetales , Análisis de Secuencia de ADN , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
Pulmonary artery hypertension (PAH) pathology involves extracellular matrix (ECM) remodeling in cardiac tissues, thus promoting cardiac fibrosis progression. miR-29a-3p reportedly inhibits lung progression and liver fibrosis by regulating ECM protein expression; however, its role in PAH-induced fibrosis remains unclear. In this study, we aimed to investigate the role of miR-29a-3p in cardiac fibrosis progression in PAH and its influence on ECM protein thrombospondin-2 (THBS2) expression. The diagnostic and prognostic values of miR-29a-3p and THBS2 in PAH were evaluated. The expressions and effects of miR-29a-3p and THBS2 were assessed in cell culture, monocrotaline-induced PAH mouse model, and patients with PAH. The levels of circulating miR-29a-3p and THBS2 in patients and mice with PAH decreased and increased, respectively. miR-29a-3p directly targets THBS2 and regulates THBS2 expression via a direct anti-fibrotic effect on PAH-induced cardiac fibrosis. The circulating levels of miR-29a-3p and THBS2 were correlated with PAH diagnostic parameters, suggesting their independent prognostic value. miR-29a-3p targeted THBS2 expression via a direct anti-fibrotic effect on PAH-induced cardiac fibrosis, indicating miR-29a-3p acts as a messenger with promising therapeutic effects.
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Regulación de la Expresión Génica , MicroARNs/genética , Miocardio/patología , Hipertensión Arterial Pulmonar/genética , Trombospondinas/genética , Adulto , Anciano , Anciano de 80 o más Años , Animales , Modelos Animales de Enfermedad , Femenino , Fibrosis , Humanos , Masculino , Ratones , MicroARNs/sangre , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Miocardio/metabolismo , Miocardio/ultraestructura , Proteómica/métodos , Hipertensión Arterial Pulmonar/metabolismo , Trombospondinas/metabolismo , Adulto JovenRESUMEN
High mobility group box 1 (HMGB1) has been demonstrated to promote the migration and invasion of non-small cell lung cancer (NSCLC). However, the mechanism of action of HMGB1 in regulating tumor mobility remains unclear. Therefore, we aimed to investigate whether HMGB1 affects mitochondria distribution and regulates dynamin-related protein 1 (DRP1)-mediated lamellipodia/filopodia formation to promote NSCLC migration. The regulation of mitochondrial membrane tension, dynamics, polarization, fission process, and cytoskeletal rearrangements in lung cancer cells by HMGB1 was analyzed using confocal microscopy. The HMGB1-mediated regulation of DRP1 phosphorylation and colocalization was determined using immunostaining and co-immunoprecipitation assays. The tumorigenic potential of HMGB1 was assessed in vivo and further confirmed using NSCLC patient samples. Our results showed that HMGB1 increased the polarity and mobility of cells (mainly by regulating the cytoskeletal system actin and microtubule dynamics and distribution), promoted the formation of lamellipodia/filopodia, and enhanced the expression and phosphorylation of DRP1 in both the nucleus and cytoplasm. In addition, HMGB1 and DRP1 expressions were positively correlated and exhibited poor prognosis and survival in patients with lung cancer. Collectively, HMGB1 plays a key role in the formation of lamellipodia and filopodia by regulating cytoskeleton dynamics and DRP1 expression to promote lung cancer migration.
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Dinaminas/metabolismo , Proteína HMGB1/metabolismo , Neoplasias Pulmonares/metabolismo , Células A549 , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Dinaminas/fisiología , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Proteínas HMGB/metabolismo , Proteína HMGB1/fisiología , Humanos , Neoplasias Pulmonares/genética , Masculino , Ratones , Ratones SCID , Microscopía Confocal/métodos , Mitocondrias/genética , Dinámicas Mitocondriales , Proteínas Mitocondriales/metabolismo , Fosforilación , Seudópodos/metabolismoRESUMEN
In a multicenter study, we determined a prevalence rate of 4% for azole-resistant Aspergillus fumigatus in Taiwan. Resistance emerged mainly from the environment (TR34/L98H, TR34/L98H/S297T/F495I, and TR46/Y121F/T289A mutations) but occasionally during azole treatment. A high mortality rate observed for azole-resistant aspergillosis necessitates diagnostic stewardship in healthcare and antifungal stewardship in the environment.
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Aspergillus fumigatus , Azoles , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Aspergillus fumigatus/genética , Azoles/farmacología , Farmacorresistencia Fúngica , Proteínas Fúngicas/genética , Pruebas de Sensibilidad Microbiana , Taiwán/epidemiologíaRESUMEN
OBJECTIVES: Recent metabolomic studies of sepsis showed that increased circulatory acylcarnitines were associated with worse survival. However, it is unknown whether plasma carnitine and acylcarnitines can reflect the severity of sepsis, and the role of specific acylcarnitines in prognostic assessment need further confirmation. This study aimed to clarify these questions. DESIGN: Prospective multicenter cohort studies with derivation and validation cohort design. SETTING: ICUs at two medical centers and three regional hospitals in Taiwan. PATIENTS: Patients with sepsis and acute organ dysfunction were enrolled. Recruitment of the derivation (n = 90) and validation cohorts (n = 120) occurred from October 2010 through March 2012 and January 2013 through November 2014, respectively. INTERVENTIONS: Plasma samples were collected immediately after admission, and the levels of carnitine and acylcarnitines were measured by ultra-high performance liquid chromatography-mass spectrometry. MEASUREMENTS AND MAIN RESULTS: In the derivation cohort, increased plasma levels of short- and medium-chain acylcarnitines were significantly associated with hepatobiliary dysfunction, renal dysfunction, thrombocytopenia, and hyperlactatemia. However, acetylcarnitine is the only acylcarnitine significantly correlating with various plasma cytokine concentrations and also associated with blood culture positivity and 28-day mortality risk. The association between plasma acetylcarnitine and multiple organ dysfunction severity, blood culture positivity, and 28-day mortality, was confirmed in the validation cohort. Patients with high plasma acetylcarnitine (≥ 6,000 ng/mL) had significantly increased 28-day mortality compared with those with plasma acetylcarnitine less than 6,000 ng/mL (52.6% vs 13.9%; hazard ratio, 5.293; 95% CI, 2.340-11.975; p < 0.001 by Cox proportional hazard model). CONCLUSIONS: We confirm that plasma acetylcarnitine can reflect the severity of organ dysfunction, inflammation, and infection in sepsis and can serve as a prognostic biomarker for mortality prediction.
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Acetilcarnitina/sangre , Insuficiencia Multiorgánica/sangre , Sepsis/sangre , Anciano , Biomarcadores/sangre , Carnitina/sangre , Femenino , Humanos , Masculino , Insuficiencia Multiorgánica/etiología , Insuficiencia Multiorgánica/mortalidad , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Sepsis/complicaciones , Sepsis/mortalidad , Taiwán/epidemiologíaRESUMEN
A restricted-access material-hybrid monolithic column was prepared based on single-component organosiloxane and dynamic grafting of δ-gluconolactone for on-line solid phase extraction of tetracycline antibiotic residues from milk. The hybrid monolithic column was prepared in a stainless-steel chromatographic column using methyltrimethoxysilane as the single precursor. δ-Gluconolactone was covalently coupled to aminopropyl derivatized hybrid monolithic column, which formed hydrophilic structures on the surface of the pore of the restricted-access material-hybrid monolithic column. The columns were characterized by scanning electron microscopy, thermogravimetric analysis, Fourier transform infrared spectroscopy, nitrogen adsorption, contact angle analysis, dynamic adsorption, and chromatographic performance evaluation. The restricted-access material-hybrid monolithic column was applied to the on-line extraction of tetracycline residues from milk. An enrichment factor of 15.8 and a good sample clean-up effect were obtained under the optimized conditions. The recoveries of the three spiked milk samples were between 81.7 and 102.5% with relative standard deviations (n = 3) in the range of 2-5%. The limits of detection (S/N = 3) for target compounds were in the range of 3.80-9.03 µg/kg. The results show that the on-line extraction using the restricted-access material-hybrid monolithic column was powerful for food sample pretreatment with high selectivity and good clean-up effect.
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Antibacterianos/análisis , Residuos de Medicamentos/análisis , Gluconatos/química , Lactonas/química , Leche/química , Extracción en Fase Sólida , Tetraciclina/análisis , Animales , Gluconatos/síntesis química , Lactonas/síntesis química , Dióxido de Silicio/químicaRESUMEN
Emerging azole resistance in Aspergillus fumigatus poses a serious threat to human health. This nationwide surveillance study investigated the prevalence and molecular characteristics of azole-resistant A. fumigatus environmental isolates in Taiwan, an island country with increasing use of azole fungicides. Of the 2760 air and soil samples screened from 2014 to 2016, 451 A. fumigatus isolates were recovered from 266 samples and 34 isolates from 29 samples displayed resistance to medical azoles (itraconazole, voriconazole or posaconazole). The resistance prevalence was 10.9% and 7.5% in A. fumigatus-positive samples and isolates respectively. Most (29, 85.3%) azole-resistant isolates harboured TR34 /L98H mutations, which were widely distributed, clustered genetically with clinical isolates, and had growth rates that were similar to those of the wild-type isolates. Microsatellite genotyping revealed both the global spread of the TR34 /L98H isolates and the occurrence of TR34 /L98H/S297T/F495I isolates belonging to local microsatellite genotypes. AfuMDR3 and atrF, two efflux transporter genes, were constitutively upregulated in two individual resistant isolates without cyp51A mutations, highlighting their potential roles in azole resistance. These results emphasize the need for periodic environmental surveillance at the molecular level in regions in which azole fungicides are applied, and agricultural fungicide management strategies that generate less selective pressure should be investigated.
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Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Aspergilosis/epidemiología , Aspergillus fumigatus/efectos de los fármacos , Aspergillus fumigatus/genética , Azoles/uso terapéutico , Farmacorresistencia Fúngica/genética , Microbiología del Aire , Aspergilosis/microbiología , Aspergillus fumigatus/aislamiento & purificación , Sistema Enzimático del Citocromo P-450/genética , Proteínas Fúngicas/genética , Genotipo , Humanos , Itraconazol/uso terapéutico , Pruebas de Sensibilidad Microbiana , Repeticiones de Microsatélite/genética , Mutación/genética , Prevalencia , Microbiología del Suelo , Taiwán/epidemiología , Triazoles/uso terapéutico , Voriconazol/uso terapéuticoAsunto(s)
Oxígeno/sangre , Síndrome de Dificultad Respiratoria/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Reproducibilidad de los Resultados , Síndrome de Dificultad Respiratoria/sangre , Síndrome de Dificultad Respiratoria/mortalidad , Síndrome de Dificultad Respiratoria/terapia , Estudios RetrospectivosRESUMEN
Candida auris is a recently identified multi-resistant Candida species, first reported in Japan in 2009, and poses a serious global health threat. Lack of awareness of this new Candida species and difficulties with laboratory identification have impacted significantly on outbreak detection and management, and compromised patient outcome. Accordingly, there is an urgent need to raise awareness of healthcare personnel to this emerging pathogen and determine its prevalence, impact, and challenges to the Taiwan healthcare system. Enhanced laboratory testing strategies are needed to differentiate C. auris from other Candida species to provide accurate diagnosis and implement control measures early enough to prevent hospital outbreaks. In this report, we review the key epidemiological, microbiological and clinical characteristics of C. auris and provide the results of a multicenter surveillance study of C. auris in Taiwan. We also conducted a web-based survey to determine awareness of the medical community to C. auris and the capability of Taiwanese hospital laboratories to identify this microorganism. C. auris has not yet been isolated from humans in Taiwan, but the unique features of this microorganism and its ability to reach across international boundaries justify the importance of these initiatives in Taiwan.
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Antifúngicos/farmacología , Candida/patogenicidad , Candidiasis/epidemiología , Control de Infecciones/métodos , Candida/efectos de los fármacos , Candidiasis/prevención & control , Infección Hospitalaria/prevención & control , Farmacorresistencia Fúngica Múltiple , Humanos , Estudios Multicéntricos como Asunto , Taiwán/epidemiologíaRESUMEN
Metastasis is common in lung cancer and is associated with poor clinical outcomes and increased mortality. Curcumin is a natural anti-cancer agent that inhibits the metastasis of various cancers by modulating the expression of micro (mi) RNAs such as miR-98, which acts as a tumor suppressor. This study investigated the effect of curcumin on miR-98 expression and in vitro cell line growth and invasiveness in lung cancer. Curcumin treatment enhanced the expression of miR-98 and reduced that of the miR-98 target gene LIN28A as well as matrix metalloproteinase (MMP) 2 and MMP9 in vitro and in vivo. MiR-98 overexpression suppressed lung cancer cell migration and invasion by inhibiting LIN28A-induced MMP2 and MMP9 expression. Meanwhile, LIN28A level was downregulated by overexpression of miR-98 mimic. Induction of miR-98 by curcumin treatment suppressed MMP2 and MMP9 by targeting LIN28A. These findings provide insight into the mechanisms by which curcumin suppresses lung cancer cell line growth in vitro and in vivo and invasiveness in vitro.
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Antineoplásicos/farmacología , Curcumina/farmacología , Neoplasias Pulmonares/genética , MicroARNs/genética , Proteínas de Unión al ARN/genética , Activación Transcripcional/efectos de los fármacos , Regiones no Traducidas 3' , Animales , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Interferencia de ARN , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
INTRODUCTION: Patients with end-stage renal disease (ESRD(Pos)) usually have multiple comorbidities and are predisposed to acute organ failure and in-hospital mortality. We assessed the effect of ESRD on the poorly understood long-term mortality risk after a first-ever mechanical ventilation (1-MV) for acute respiratory failure. METHODS: The data source was Taiwan's National Health Insurance (NHI) Research Database. All patients given a 1-MV between 1999 and 2008 from one million randomly selected NHI beneficiaries were identified (n = 38,659). Patients with or without ESRD (ESRD(Neg)) after a 1-MV between 1999 and 2008 were retrospectively compared and followed from the index admission date to death or the end of 2011. ESRD(Pos) patients (n = 1185; mean age: 65.9 years; men: 51.5 %) were individually matched to ESRD(Neg) patients (ratio: 1:8) using a propensity score method. The primary outcome was death after a 1-MV. The effect of ESRD on the risk of death after MV was assessed. A Cox proportional hazard regression model was used to assess how ESRD affected the mortality risk after a 1-MV. RESULTS: The baseline characteristics of the two cohorts were balanced, but the incidence of mortality was higher in ESRD(Pos) patients than in ESRD(Neg) patients (342.30 versus 179.67 per 1000 person-years; P <0.001; covariate-adjusted hazard ratio: 1.43; 95 % confidence interval: 1.31-1.51). For patients who survived until discharge, ESRD was not associated with long-term (>4 years) mortality. CONCLUSIONS: ESRD increased the mortality risk after a 1-MV, but long-term survival seemed similar.
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Mortalidad Hospitalaria/tendencias , Fallo Renal Crónico/mortalidad , Diálisis Renal/efectos adversos , Respiración Artificial/mortalidad , Sobrevivientes/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Comorbilidad , Femenino , Humanos , Fallo Renal Crónico/epidemiología , Masculino , Persona de Mediana Edad , Diálisis Renal/mortalidad , Respiración Artificial/efectos adversos , Respiración Artificial/estadística & datos numéricos , Estudios Retrospectivos , Factores de Riesgo , Taiwán/epidemiologíaRESUMEN
Acute lung injury (ALI) is associated with an inflammation-mediated process, and the transcription factor, Krüppel-like factor 5 (KLF5), might play a crucial role in inflammatory lung disease. In this study, we evaluated KLF5, reactive oxygen species (ROS), and inflammatory responses in a lipopolysaccharide- (LPS-) induced ALI model to elucidate the role of KLF5 in ALI. Our data indicated that LPS upregulates proinflammatory cytokine expression in human bronchial epithelial cells in a dose-dependent manner. We observed upregulated KLF5 protein expression in human bronchial epithelial cells exposed to LPS, with peak expression 1 h after LPS treatment, and subsequent upregulation of p65 protein expression and p65 phosphorylation at Ser276. These results indicate that KLF5 mediates proinflammatory cytokine expression by upregulating nuclear factor-kappaB (NF-κB) phosphorylation at p65 in response to LPS. LPS treatment also increased ROS production and simultaneously upregulated KLF5 expression and NF-κB translocation. N-acetylcysteine significantly reduced ROS levels and KLF5 and NF-κB translocation in nuclear extracts. Therefore, N-acetylcysteine pretreatment before LPS exposure reduces ROS, downregulates KLF5 expression, and subsequently reduces inflammatory responses by scavenging ROS. Overall, our study results indicate that KLF5 mediates proinflammatory cytokine expression through upregulation of NF-κB phosphorylation at p65 in LPS-induced ALI.
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Lesión Pulmonar Aguda/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Lipopolisacáridos/toxicidad , FN-kappa B/metabolismo , Lesión Pulmonar Aguda/inducido químicamente , Animales , Línea Celular , Humanos , Ratones , Ratones Endogámicos BALB C , Fosforilación , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Three-dimensional (3D)-printed models are cost-effective and can be customized by trainers. This study designed a 3D-printed airway suction simulator for use by respiratory therapy (RT) students. The objective was to demonstrate the cost-effectiveness and application of 3D-printed models in respiratory care training, aiming to enhance the educational experience for RT students. METHODS: This study developed a 3D-printed airway suction simulator that was cost-effective. A randomized controlled trial was conducted involving RT students to compare effectiveness in a 3D-model group and a control group. Skill assessments and written examinations were used to evaluate the participants' knowledge and skills. RESULTS: A total of 38 second-year RT students were randomly assigned to either the 3D-model group (n = 19) or the control group (n = 19). One participant in the 3D-model group was lost to follow-up during the planned direct observation of procedural skills (DOPS) assessment and satisfaction questionnaire completion. The posttest written examination scores were significantly higher in the 3D-model group than in the control group (100% vs 80%, P = .02). The scores from the DOPS and satisfaction questionnaire were comparable in the 2 groups. CONCLUSIONS: This study demonstrated that 3D printing can be used to create a safe and cost-effective airway suction simulator for use by RT students, with potential to enhance training methods. Further research is necessary.
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The inhibitor of DNA-binding 2 (ID2) plays a major role in tumor dedifferentiation in non-small cell lung cancer (NSCLC). Studies have indicated an inverse correlation between ID2 expression and NSCLC cell invasiveness. However, the mechanisms through which ID2 activation is regulated are currently unclear. We overexpressed ID2 in H1299 cells and extensively characterized their cellular behaviors. By employing a serial deletion approach combined with a reporter assay, we pinpointed the basal promoter region of ID2. We also examined the DNA methylation status of the ID2 promoter to elucidate the epigenetic mechanisms driving ID2 regulation. Our results revealed that ID2 overexpression effectively inhibited the migration, invasion, proliferation, and colony formation abilities of H1299 cells. The region from -243 to +202 played a major role in driving the transcriptional activity of ID2. Sequence analysis results indicated that the transcription factor Yin Yang 1 (YY1) might be crucial in the regulation of ID2 expression. The ectopically expressed YY1 activated both the expression levels of ID2 and the transcriptional activity of the ID2 promoter, potentially contributing to its repressive activity on cancer cell growth. Furthermore, site-directed mutagenesis and chromatin immunoprecipitation assays revealed that YY1 may target the -120 and -76 sites of the ID2 promoter, thereby activating its transcriptional activity. The ID2 promoter regions were also fully methylated in CL1-5 cells, and the methylation level was correlated with the expression levels of the ID2 promoter. Moreover, the YY1-induced suppression of colony formation was counteracted by ID2 knockdown, which suggests that YY1 represses cell colony growth through the regulation of ID2. Our results indicate that YY1 plays a role in transactivating ID2 expression and might also contribute to the repression of colony growth through the regulation of ID2.
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Epigenetic regulation and mitochondrial dysfunction are essential to the progression of idiopathic pulmonary fibrosis (IPF). Curcumin (CCM) in inhibits the progression of pulmonary fibrosis by regulating the expression of specific miRNAs and pulmonary fibroblast mitochondrial function; however, the underlying mechanism is unclear. C57BL/6 mice were intratracheally injected with bleomycin (5â¯mg/kg) and treated with CCM (25â¯mg/kg body weight/3 times per week, intraperitoneal injection) for 28 days. Verhoeff-Van Gieson, Picro sirius red, and Masson's trichrome staining were used to examine the expression and distribution of collagen and elastic fibers in the lung tissue. Pulmonary fibrosis was determined using micro-computed tomography and transmission electron microscopy. Human pulmonary fibroblasts were transfected with miR-29a-3p, and RT-qPCR, immunostaining, and western blotting were performed to determine the expression of DNMT3A and extracellular matrix collagen-1 (COL1A1) and fibronectin-1 (FN1) levels. The expression of mitochondrial electron transport chain complex (MRC) and mitochondrial function were detected using western blotting and Seahorse XFp Technology. CCM in increased the expression of miR-29a-3p in the lung tissue and inhibited the DNMT3A to reduce the COL1A1 and FN1 levels leading to pulmonary extracellular matrix remodeling. In addition, CCM inhibited pulmonary fibroblasts MRC and mitochondrial function via the miR-29a-3p/DNMT3A pathway. CCM attenuates pulmonary fibrosis via the miR-29a-3p/DNMT3A axis to regulate extracellular matrix remodeling and mitochondrial function and may provide a new therapeutic intervention for preventing pulmonary fibrosis.
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Curcumina , ADN Metiltransferasa 3A , Matriz Extracelular , Fibroblastos , Ratones Endogámicos C57BL , MicroARNs , Mitocondrias , Animales , MicroARNs/genética , MicroARNs/metabolismo , Curcumina/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , ADN Metiltransferasa 3A/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/efectos de los fármacos , Humanos , Ratones , Masculino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Bleomicina , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/tratamiento farmacológico , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismo , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN (Citosina-5-)-Metiltransferasas/genética , Fibrosis Pulmonar Idiopática/patología , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/metabolismo , Modelos Animales de EnfermedadRESUMEN
Type 2 alveolar epithelial (AT2) cells of the lung are fundamental in regulating alveolar inflammation in response to injury. Impaired mitochondrial long-chain fatty acid ß-oxidation (mtLCFAO) in AT2 cells is assumed to aggravate alveolar inflammation in acute lung injury (ALI), yet the importance of mtLCFAO to AT2 cell function needs to be defined. Here we show that expression of carnitine palmitoyltransferase 1a (CPT1a), a mtLCFAO rate limiting enzyme, in AT2 cells is significantly decreased in acute respiratory distress syndrome (ARDS). In mice, Cpt1a deletion in AT2 cells impairs mtLCFAO without reducing ATP production and alters surfactant phospholipid abundance in the alveoli. Impairing mtLCFAO in AT2 cells via deleting either Cpt1a or Acadl (acyl-CoA dehydrogenase long chain) restricts alveolar inflammation in ALI by hindering the production of the neutrophilic chemokine CXCL2 from AT2 cells. This study thus highlights mtLCFAO as immunometabolism to injury in AT2 cells and suggests impaired mtLCFAO in AT2 cells as an anti-inflammatory response in ARDS.