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1.
Respir Physiol Neurobiol ; 272: 103330, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31639457

RESUMO

IL-1ß, HMGB1, HO-1, and LDH in the pleural effusions (PE) of patients with transudative, infectious, and malignant etiologies were determined using ELISA and enzymatic assays. IL-1ß, HMGB1, HO-1, and LDH showed significant differences between the three etiologies. Post-hoc analysis revealed higher levels of HO-1 and HMGB1 in infectious versus transudative effusion. Higher levels of IL-1ß were found in infectious versus transudative or malignant effusion. The comparison of LDH levels showed significant differences. Positive correlations were found between IL-1ß, HMGB1, and LDH in infectious effusions. The samples were then divided into cancerous and non-cancerous groups, and logistic regression revealed that increasing IL-1ß levels were significantly associated with a decrease in cancer risk after adjusting for HMGB1, HO-1, and LDH. Our findings suggest that IL-1ß, HMGB1, HO-1, and LDH are expressed differently, with positive correlations between HMGB1, IL-1ß, and LDH in infectious effusions, and low IL-1ß expression in malignant effusions.

2.
J Clin Med ; 8(12)2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31835897

RESUMO

BACKGROUND: Transient receptor potential ankyrin 1 (TRPA1), a redox-sensing Ca2+-influx channel, serves as a gatekeeper for inflammation. However, the role of TRPA1 in kidney injury remains elusive. METHODS: The retrospective cohort study recruited 46 adult patients with acute kidney injury (AKI) and biopsy-proven acute tubular necrosis (ATN) and followed them up for more than three months. The subjects were divided into high- and low-renal-tubular-TRPA1-expression groups for the comparison of the total recovery of renal function and mortality within three months. The significance of TRPA1 in patient prognosis was evaluated using Kaplan-Meier curves and logistic regression analysis. RESULTS: Of the 46 adult AKI patients with ATN, 12 totally recovered renal function. The expression level of tubular TRPA1 was detected by quantitative analysis of the immunohistochemistry of biopsy specimens from ATN patients. The AKI patients with high tubular TRPA1 expression showed a high incidence of nontotal renal function recovery than those with low tubular TRPA1 expression (OR = 7.14; 95%CI 1.35-37.75; p = 0.02). High TRPA1 expression was independently associated with nontotal recovery of renal function (adjusted OR = 6.86; 95%CI 1.26-37.27; p = 0.03). CONCLUSION: High tubular TRPA1 expression was associated with the nontotal recovery of renal function. Further mechanistic studies are warranted.

3.
Biomolecules ; 9(12)2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31771225

RESUMO

A natural compound from Wasabia japonica, 6-(methylsulfinyl) hexyl isothiocyanate (6-MITC) was investigated for its anti-leukemia activity and mechanism of action. It was found that 6-MITC inhibited the viability of human chronic myelogenous leukemia K562 cells along with extensive mitotic arrest, spindle multipolarity, and cytoplasmic vacuole accumulation. The evidence of autophagy included the validation of autophagosomes with double-layered membranes under transmission electron microscopy, LC3I/II conversion, and the induction of G2/M phase arrest observed with acridine orange staining of treated cells, as well as the elevation of phosphorylated-histone H3 expression at the M phase. With regard to the expression of proteins related to mitosis, the downregulation of p-CHK1, p-CHK2, p-cdc25c, and p-cdc2, as well as the upregulation of cyclin B1, p-cdc20, cdc23, BubR1, Mad2, and p-plk-1 was observed. The knockdown of cdc20 was unable to block the effect of 6-MITC. The differentiation of k562 cells into monocytes, granulocytes, and megakaryocytes was not affected by 6-MITC. The 6-MITC-induced unique mode of cell death through the concurrent induction of mitosis and autophagy may have therapeutic potential. Further studies are required to elucidate the pathways associated with the counteracting occurrence of mitosis and autophagy.

4.
Br J Clin Pharmacol ; 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31633826

RESUMO

It remains uncertain whether statin use is associated with the risks of tuberculosis (TB) and herpes zoster in patients with type 2 diabetes. This study aims to assess the effects of statins vs nonstatin lipid-lowering agents on the risk of these infectious diseases in patients with diabetes. METHODS: Participants in the Taiwan National Health Insurance Research Database diagnosed with type 2 diabetes in 2001-2013 were classified as statin users, nonstatin users and lipid-lowering drug-free groups. Participants were observed for incident TB and herpes zoster from diabetes diagnosis until treatment crossover or December 2013. Statin user and nonstatin user were the time-dependent variables in Cox regression analysis. RESULTS: Over 240 782 person-years of observation, statin users (n = 17 696) were associated with a lower TB risk than nonstatin users (n = 5327) and the drug-free group (n = 22 316) (adjusted hazard ratio [aHR]: 0.66; 95% confidence interval [CI]: 0.44-0.99 and aHR: 0.57; 95% CI: 0.44-0.73). Compared with nonstatin users, statin users showed a dose-dependent association with TB risk (low-potency statin users, aHR: 0.692; 95% CI: 0.455-1.053; high-potency users, aHR: 0.491; 95% CI: 0.241-0.999). Statin users presented with a higher risk of herpes zoster than nonstatin users and the drug-free group (aHR: 1.23; 95% CI: 1.01-1.50 and aHR: 1.20; 95% CI: 1.09-1.33). The risks of TB and herpes zoster were not statistically different between nonstatin users and the drug-free group. CONCLUSION: Compared with nonstatin drugs, statin use was specifically associated with a decreased risk of TB but a moderately increased risk of herpes zoster in this cohort study.

6.
Free Radic Biol Med ; 143: 354-365, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31437479

RESUMO

BACKGROUND: Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor and has been proposed to be an independent risk factor for cardiovascular diseases. However, little is known about its role in the regulation of lipid metabolism. In this study, we investigated the effect of ADMA on cholesterol metabolism and its underlying molecular mechanism. METHODS: Oxidized low-density lipoprotein (oxLDL)-induced macrophage foam cells were used as an in vitro model. Apolipoprotein E-deficient (apoE-/-) hyperlipidemic mice were used as an in vivo model. Western blot analysis was used to evaluate protein expression. Luciferase reporter assays were used to assess the activity of promoters and transcription factors. Conventional assay kits were used to measure the levels of ADMA, cholesterol, triglycerides, and cytokines. RESULTS: Treatment with oxLDL decreased the protein expression of dimethylarginine dimethylaminohydrolase-2 (DDAH-2) but not DDAH-1. Incubation with ADMA markedly increased oxLDL-induced lipid accumulation in macrophages. ADMA impaired cholesterol efflux following oxLDL challenge and downregulated the expression of ATP-binding cassette transporter A1 (ABCA1) and ABCG1 by interfering with liver X receptor α (LXRα) expression and activity. Additionally, this inhibitory effect of ADMA on cholesterol metabolism was mediated through the activation of the NADPH oxidase/reactive oxygen species pathway. In vivo experiments revealed that chronic administration of ADMA for 4 weeks exacerbated systemic inflammation, decreased the aortic protein levels of ABCA1 and ABCG1, and impaired the capacity of reverse cholesterol transport, ultimately, leading to the progression of atherosclerosis in apoE-/- mice. CONCLUSION: Our findings suggest that the ADMA/DDAH-2 axis plays a crucial role in regulating cholesterol metabolism in macrophage foam cells and atherosclerotic progression.

7.
Sci Rep ; 9(1): 9539, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266972

RESUMO

This retrospective, observational cohort study aimed to determine the independent risk factors and impact of prolonged non-invasive positive pressure ventilation (NIPPV) after extubation among patients in the intensive care unit following cardiac surgery. Patients who received prophylactic NIPPV after extubation were categorized into prolonged (NIPPV duration >3 days, n = 83) and non-prolonged groups (NIPPV duration ≤3 days, n = 105). The perioperative characteristics and hospital outcomes were recorded. The multivariate analyses identified the preoperative residual volume/total lung capacity (RV/TLC) ratio (adjusted odds ratio [AOR]: 1.10; 95% CI:1.01-1.19, p = 0.022) and postoperative acute kidney injury (AKI) with Kidney Disease Improving Global Outcomes (KDIGO) stage 2-3, 48 h after surgery (AOR: 3.87; 95% CI:1.21-12.37, p = 0.023) as independent predictors of prolonged NIPPV. Patients with both RV/TLC ratio > 46.5% and KDIGO stage 2-3 showed a highly increased risk of prolonged NIPPV (HR 27.17, p = 0.010), which was in turn associated with higher risk of postoperative complications and prolonged ICU and hospital stays. Preoperative RV/TLC ratio and postoperative AKI could identify patients at higher risk for prolonged NIPPV associated with poor outcomes. These findings may allow early recognition of patients who are at a higher risk for prolonged NIPPV, and help refine the perioperative management and critical care.

8.
NPJ Prim Care Respir Med ; 29(1): 22, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138809

RESUMO

Underuse or unavailability of spirometry is one of the most important factors causing underdiagnosis of COPD. We reported the development of a COPD prediction model to identify at-risk, undiagnosed COPD patients when spirometry was unavailable. This cross-sectional study enrolled subjects aged ≥40 years with respiratory symptoms and a smoking history (≥20 pack-years) in a medical center in two separate periods (development and validation cohorts). All subjects completed COPD assessment test (CAT), peak expiratory flow rate (PEFR) measurement, and confirmatory spirometry. A binary logistic model with calibration (Hosmer-Lemeshow test) and discrimination (area under receiver operating characteristic curve [AUROC]) was implemented. Three hundred and one subjects (development cohort) completed the study, including non-COPD (154, 51.2%) and COPD cases (147; stage I, 27.2%; II, 55.8%; III-IV, 17%). Compared with non-COPD and GOLD I cases, GOLD II-IV patients exhibited significantly higher CAT scores and lower lung function, and were considered clinically significant for COPD. Four independent variables (age, smoking pack-years, CAT score, and percent predicted PEFR) were incorporated developing the prediction model, which estimated the COPD probability (PCOPD). This model demonstrated favorable discrimination (AUROC: 0.866/0.828; 95% CI 0.825-0.906/0.751-0.904) and calibration (Hosmer-Lemeshow P = 0.332/0.668) for the development and validation cohorts, respectively. Bootstrap validation with 1000 replicates yielded an AUROC of 0.866 (95% CI 0.821-0.905). A PCOPD of ≥0.65 identified COPD patients with high specificity (90%) and a large proportion (91.4%) of patients with clinically significant COPD (development cohort). Our prediction model can help physicians effectively identify at-risk, undiagnosed COPD patients for further diagnostic evaluation and timely treatment when spirometry is unavailable.

9.
Geriatr Gerontol Int ; 19(4): 317-322, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30788891

RESUMO

AIM: The older adult population is continuously growing worldwide and there is increasing use of medical recourse in older patients, especially for those requiring intensive care unit (ICU) care and mechanical ventilation (MV). The present study aimed to investigate the burden and predictors of post-ICU respiratory failure in older ICU patients weaned from MV. METHODS: In the present retrospective study, older ICU patients aged ≥60 years, who were successfully weaned from MV and discharged to the general ward from the ICU of Taipei Veterans General Hospital, Taipei, Taiwan, in 2011, were included. Biomarkers on ICU discharge, as well as the National Early Warning Score (NEWS) were recorded and calculated. The outcome measure was post-ICU respiratory failure before day 14 (PIRF-14) requiring reinstitution of MV. Logistical regression was used to assess the predictors for PIRF-14. RESULTS: Of 272 patients included, 23 (8.5%) developed PIRF-14. The post-ICU in-hospital mortality rates were 47.8% and 6.8% in patients with and without PIRF-14 (adjusted OR 12.597, 95% CI 4.368-36.331). In a multivariate analysis, the levels of NEWS and hemoglobin on ICU discharge were independent predictors for PIRF-14 (adjusted OR 1.273, 95% CI 1.076-1.507 and 0.645, 95% CI 0.474-0.879). In particular, patients with a NEWS of ≥10 and subsequent PIRF-14 had a 15-fold increased risk of mortality as compared with those without both factors (adjusted OR 15.418, 95% CI 4.344-54.720). CONCLUSIONS: PIRF-14 is associated with high mortality in older ICU patients, and NEWS is a significant predictor for PIRF-14, which could be used to early identify patients at risk of post-ICU respiratory failure in the specific population. Geriatr Gerontol Int 2019; 19: 317-322.


Assuntos
Unidades de Terapia Intensiva/estatística & dados numéricos , Alta do Paciente/estatística & dados numéricos , Insuficiência Respiratória , Medição de Risco/métodos , Desmame do Respirador/efeitos adversos , Idoso , Diagnóstico Precoce , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Projetos de Pesquisa , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/mortalidade , Estudos Retrospectivos , Taiwan/epidemiologia
10.
Respir Physiol Neurobiol ; 249: 16-22, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29289575

RESUMO

The effects of long-acting muscarinic receptor antagonists (LAMAs) have not been evaluated in a model with simultaneous lung inflammation and small airway remodeling induced by cigarette smoke (CS). We exposed the mice to CS for four weeks with daily treatment with a LAMA (glycopyrronium bromide, NVA237) or its vehicle. Human bronchial epithelial cells (PBECs) and lung fibroblasts were exposed to CS extract (CSE) or acetylcholine with or without NVA237 treatment. We found that NVA237, but not its vehicle, suppressed elevations in inflammatory score, epithelial thickness, and peribronchial collagen deposition in CS-exposed mice. NVA237 alleviated CS-induced increased levels of chemokines, inflammatory cells, and total protein in the bronchoalveolar lavage fluid. NVA237 suppressed acetylcholine- or CSE-induced elevations in IL-8 production in PBECs and elevations in proliferation and collagen production in lung fibroblasts. These phenomena were also prevented by a p44/42 MAPK inhibitor. In conclusion, NVA237 exerted a potent suppressive effect on lung inflammation and small airway remodeling induced by subchronic CS exposure.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Fumar Cigarros/fisiopatologia , Glicopirrolato/uso terapêutico , Antagonistas Muscarínicos/uso terapêutico , Pneumonia/tratamento farmacológico , Pneumonia/etiologia , Análise de Variância , Animais , Líquido da Lavagem Broncoalveolar , Células Cultivadas , Fumar Cigarros/patologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Humanos , Pulmão/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
11.
Chest ; 153(6): 1347-1357, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29253553

RESUMO

BACKGROUND: Metformin and the sulfonylureas are common initial antidiabetic agents; the former has demonstrated anti-TB action in in vitro and animal studies. The comparative effect of metformin vs the sulfonylureas on TB risk in patients with type 2 diabetes mellitus (T2DM) remains unclear. METHODS: In this retrospective cohort study, patients without chronic kidney disease who received a T2DM diagnosis during 2003 to 2013 were identified from the Taiwan National Health Insurance Research Database. Participants with ≥ 2 years of follow-up were reviewed and observed for TB until December 2013. Patients receiving metformin ≥ 60 cumulative defined daily dose (cDDD) and sulfonylureas < 15 cDDD in the initial 2 years were defined as metformin majors; it was the inverse for sulfonylurea majors. The two groups were matched 1:1 by propensity score and compared for TB risk by multivariate Cox regression analysis. RESULTS: Among 40,179 patients with T2DM, 263 acquired TB (0.65%) over a mean follow-up of 6.1 years. In multivariate analysis, the initial 2-year dosage of metformin, but not that of the sulfonylureas, was an independent predictor of TB (60-cDDD increase (adjusted hazard ratio [HR], 0.931; 95% CI, 0.877-0.990) after adjustment by cofactors, including adapted diabetes complication severity index. Metformin majors had a significantly lower TB risk than that of sulfonylurea majors before and after matching (HR, 0.477; 95% CI, 0.268-0.850 and HR, 0.337; 95% CI, 0.169-0.673; matched pairs, n = 3,161). Compared with the reference group (initial 2-year metformin < 60 cDDD), metformin treatment showed a dose-dependent association with TB risk (60-219 cDDD; HR, 0.860; 95% CI, 0.637-1.161; 220-479 cDDD, HR, 0.706; 95% CI, 0.485-1.028; ≥ 480 cDDD, HR, 0.319; 95% CI, 0.118-0.863). CONCLUSIONS: Metformin use in the initial 2 years was associated with a decreased risk of TB, and metformin users had a reduced risk compared with their sulfonylurea comparators.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Tuberculose Latente/epidemiologia , Metformina/efeitos adversos , Pontuação de Propensão , Medição de Risco/métodos , Compostos de Sulfonilureia/efeitos adversos , Idoso , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Seguimentos , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Incidência , Tuberculose Latente/etiologia , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Compostos de Sulfonilureia/uso terapêutico , Taiwan/epidemiologia
12.
Front Physiol ; 9: 1817, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30618827

RESUMO

In smokers with chronic obstructive pulmonary disease, more severe lung inflammation is associated with menthol cigarette smoking compared to non-menthol cigarette smoking. However, the mechanisms remain unclear. Menthol is an activator of transient receptor potential melastatin-8 (TRPM8), which is also sensitive to reactive oxygen species (ROS). Our recent in vitro study demonstrated that the extracts of menthol cigarette smoke (M-CS) can induce greater ROS-sensitive, TRPM8-mediated, mitogen-activated protein kinase (MAPK)-dependent inflammatory responses in lung epithelial cells than the extracts of non-menthol cigarette smoke (Non-M-CS) can. In this study, we tested the hypothesis that M-CS can induce more severe lung inflammation than Non-M-CS can via the additional action of menthol in M-CS on epithelial and lung TRPM8 in mice. Compared with Non-M-CS exposure, subchronic M-CS exposure for 7 days up-regulated the epithelial and lung expression of TRPM8, induced more vigorous activation of epithelial and lung MAPKs, and caused more severe lung inflammation. The MAPK activation was evidenced by the increased expression of phosphor-extracellular signal-regulated and phosphor-c-Jun N-terminal kinases. The lung inflammation was evidenced by pathohistological findings and increases in several inflammatory indices. Moreover, treatment with a TRPM8 antagonist (N-(3-aminopropyl)-2-{[(3-methylphenyl)methyl]oxy}-N-(2-thienylmethyl)benzamide; AMTB) greatly suppressed the MAPK activation and lung inflammation induced by Non-M-CS and M-CS, and the residual responses to these two types of CS did not differ. Conversely, the levels of biomarkers of acute CS exposure (20 min), including carboxyhemoglobin and cotinine (a nicotine metabolite) in blood plasma, and superoxide and hydrogen peroxide (two major types of ROS) in bronchoalveolar lavage fluid, did not show significant differences in the mice with Non-M-CS and M-CS exposure. We concluded that M-CS could induce greater TRPM8-mediated activation of MAPKs and lung inflammation than Non-M-CS could in mice with subchronic exposure. The augmented inflammatory effects of M-CS are unlikely due to a larger total amount of CS inhaled, but may be caused by an additional stimulation of epithelial and lung TRPM8 by menthol in M-CS. A common stimulant (presumably ROS) generated by both CS types may also stimulate TRPM8, activate MAPKs, and induce lung inflammation because treatment with AMTB could reduce these responses to Non-M-CS.

13.
PLoS One ; 12(8): e0182252, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28767690

RESUMO

BACKGROUND: To investigate the effect of a simplified prevention bundle with alcohol-based, dual hand hygiene (HH) audit on the incidence of early-onset ventilation-associated pneumonia (VAP). METHODS: This 3-year, quasi-experimental study with interrupted time-series analysis was conducted in two cardiovascular surgery intensive care units in a medical center. Unaware external HH audit (eHH) performed by non-unit-based observers was a routine task before and after bundle implementation. Based on the realistic ICU settings, we implemented a 3-component bundle, which included: a compulsory education program, a knowing internal HH audit (iHH) performed by unit-based observers, and a standardized oral care (OC) protocol with 0.1% chlorhexidine gluconate. The study periods comprised 4 phases: 12-month pre-implementation phase 1 (eHH+/education-/iHH-/OC-), 3-month run-in phase 2 (eHH+/education+/iHH+/OC+), 15-month implementation phase 3 (eHH+/education+/iHH+/OC+), and 6-month post-implementation phase 4 (eHH+/education-/iHH+/OC-). RESULTS: A total of 2553 ventilator-days were observed. VAP incidences (events/1000 ventilator days) in phase 1-4 were 39.1, 40.5, 15.9, and 20.4, respectively. VAP was significantly reduced by 59% in phase 3 (vs. phase 1, incidence rate ratio [IRR] 0.41, P = 0.002), but rebounded in phase 4. Moreover, VAP incidence was inversely correlated to compliance of OC (r2 = 0.531, P = 0.001) and eHH (r2 = 0.878, P < 0.001), but not applied for iHH, despite iHH compliance was higher than eHH compliance during phase 2 to 4. Compared to eHH, iHH provided more efficient and faster improvements for standard HH practice. The minimal compliances required for significant VAP reduction were 85% and 75% for OC and eHH (both P < 0.05, IRR 0.28 and 0.42, respectively). CONCLUSIONS: This simplified prevention bundle effectively reduces early-onset VAP incidence. An unaware HH compliance correlates with VAP incidence. A knowing HH audit provides better improvement in HH practice. Accordingly, we suggest dual HH audit and consistent bundle performance does matter in quality-of-care VAP prevention.


Assuntos
Controle de Infecções/métodos , Unidades de Terapia Intensiva/normas , Pneumonia Associada à Ventilação Mecânica/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Feminino , Higiene das Mãos/métodos , Humanos , Incidência , Análise de Séries Temporais Interrompida , Masculino , Pessoa de Meia-Idade , Pneumonia Associada à Ventilação Mecânica/epidemiologia
14.
Pediatr Pulmonol ; 52(7): 891-899, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28608650

RESUMO

BACKGROUND: Severe inflammation plays a vital role in the pathogenesis of meconium aspiration syndrome (MAS). Intratracheal (IT) instillation of corticosteroids may be beneficial for MAS in optimizing local effect and reducing systemic adverse effects, but the optimum dosing course remains open to question. METHODS: Thirty meconium-injured newborn piglets were enrolled into six study groups. The first four groups consisted of the IT instillation of 0.25/0.5 mg/kg using either one (IT-B251/IT-B501) or two (IT-B252/IT-B502) doses of budesonide, while the other two groups were the intravenous (IV) dexamethasone (0.5 mg/kg) (IV-Dex) group and the control group (Ctrl). Vital signs and cardiopulmonary functions were monitored throughout the experiments. Pulmonary histology was examined after completing the experiments. RESULTS: Both the IV-Dex and IT-B501 groups got significant improvement in oxygenation (P < 0.05). Lung compliance became worse after one dose of 0.25 mg/kg of IT budesonide. Pulmonary histology revealed that there were significantly lower lung injury scores for all treatment groups compared to control group, especially at the non-dependent sites of both the IT-B501 and IT-B502 groups. There was no significant difference between double- and single-dose groups, no matter whether 0.25 or 0.5 mg/kg of budesonide was used. CONCLUSIONS: IT instillation of one dose of 0.5 mg/kg budesonide is beneficial in treating meconium-injured piglet lungs during the first 8 h of injury, but a second dose at an interval of 4 h does not have a superior beneficial effect compared to one dose.


Assuntos
Corticosteroides/administração & dosagem , Budesonida/administração & dosagem , Síndrome de Aspiração de Mecônio/tratamento farmacológico , Administração por Inalação , Corticosteroides/uso terapêutico , Animais , Animais Recém-Nascidos , Budesonida/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiopatologia , Complacência Pulmonar/efeitos dos fármacos , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/patologia , Lesão Pulmonar/fisiopatologia , Masculino , Síndrome de Aspiração de Mecônio/patologia , Síndrome de Aspiração de Mecônio/fisiopatologia , Suínos
15.
Front Physiol ; 8: 263, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28496415

RESUMO

Clinical studies suggest that smokers with chronic obstructive pulmonary disease who use menthol cigarettes may display more severe lung inflammation than those who smoke non-menthol cigarette. However, the mechanisms for this difference remain unclear. Menthol is a ligand of transient receptor potential melastatin-8 (TRPM8), a Ca2+-permeant channel sensitive to reactive oxygen species (ROS). We previously reported that exposure of human bronchial epithelial cells (HBECs) to non-menthol cigarette smoke extract (Non-M-CSE) triggers a cascade of inflammatory signaling leading to IL-8 induction. In this study, we used this in vitro model to compare the inflammatory effects of menthol cigarette smoke extract (M-CSE) and Non-M-CSE and delineate the mechanisms underlying the differences in their impacts. Compared with Non-M-CSE, M-CSE initially increased a similar level of extracellular ROS, suggesting the equivalent oxidant potency. However, M-CSE subsequently produced more remarkable elevations in intracellular Ca2+, activation of the mitogen-activated protein kinases (MAPKs)/nuclear factor-κB (NF-κB) signaling, and IL-8 induction. The extracellular ROS responses to both CSE types were totally inhibited by N-acetyl-cysteine (NAC; a ROS scavenger). The intracellular Ca2+ responses to both CSE types were also totally prevented by NAC, AMTB (a TRPM8 antagonist), or EGTA (an extracellular Ca2+ chelator). The activation of the MAPK/NF-κB signaling and induction of IL-8 to both CSE types were suppressed to similar levels by NAC, AMTB, or EGTA. These results suggest that, in addition to ROS generated by both CSE types, the menthol in M-CSE may act as another stimulus to further activate TRPM8 and induce the observed responses. We also found that menthol combined with Non-M-CSE induced greater responses of intracellular Ca2+ and IL-8 compared with Non-M-CSE alone. Moreover, we confirmed the essential role of TRPM8 in these responses to Non-M-CSE or M-CSE and the difference in these responses between the both CSE types using HBECs with TRPM8 knockdown and TRPM8 knockout, and using HEK293 cells transfected with hTRPM8. Thus, compared with exposure to Non-M-CSE, exposure to M-CSE induced greater TRPM8-mediated inflammatory responses in HBECs. These augmented effects may be due to a double-hit on lung epithelial TRPM8 by ROS generated from CSE and the menthol in M-CSE.

16.
Front Physiol ; 8: 193, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28408888

RESUMO

Pulmonary fibrosis is a severe and progressive disease that is characterized by an abnormal deposition of extracellular matrix, such as collagens. The pathogenesis of this disease may be initiated by oxidative damage of lung epithelial cells by fibrogenic stimuli, leading to lung inflammation, which in turn promotes various lung fibrotic responses. The profibrogenic effect of transforming growth factor-ß1 (TGF-ß1) on lung fibroblasts is crucial for the pathogenesis of this disease. Paeonol, the main phenolic compound present in the Chinese herb Paeonia suffruticosa, has antioxidant and anti-inflammatory properties. However, whether paeonol has therapeutic effects against pulmonary fibrosis remains unclear. Using a murine model, we showed that 21 days after the insult, intratracheal bleomycin caused pulmonary inflammation and fibrosis, as evidenced by lung histopathological manifestations and increase in various indices. The inflammatory indices included an increase in total cell count, differential cell count, and total protein concentration in bronchoalveolar lavage fluid. The fibrotic indices included an increase in lung levels of TGF-ß1, total collagen, type 1α1 collagen (COL1A1), and α-smooth muscle actin (α-SMA; a marker of myofibroblasts). Bleomycin also was found to cause an increase in oxidative stress as reflected by increased levels of malondialdehyde and 4-hydroxynonenal in the lungs. Importantly, all these pathophysiological events were suppressed by daily treatment with paeonol. Using human lung fibroblasts, we further demonstrated that exposure of human lung fibroblasts to TGF-ß1 increased productions of α-SMA and COL1A1, both of which were inhibited by inhibitors of Jun N-terminal kinase (JNK), p38, and Smad3. JNK and p38 are two subfamily members of mitogen-activated protein kinases (MAPKs), whereas Smad3 is a transcription factor. TGF-ß1 exposure also increased the phosphorylation of JNK, p38, and Smad3 prior to the induction of α-SMA and COL1A1. Notably, all these TGF-ß1-induced cellular events were suppressed by paeonol treatment. Our findings suggest that paeonol has antioxidant, anti-inflammatory, and anti-fibrotic functions against bleomycin-induced pulmonary fibrosis in mice. The beneficial effect of paeonol may be, at least in part, mediated through the inhibition of the MAPKs/Smad3 signaling.

17.
Eur Child Adolesc Psychiatry ; 26(11): 1351-1359, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28417257

RESUMO

In this retrospective nationwide population-based case-control study, we investigated the impact of congenital heart disease (CHD) on the development of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), which remains unclear. Children aged <18 years that were diagnosed with CHD (n = 3552) between January 1, 1997 and December 31, 2009 were identified from the National Health Insurance Research Database in Taiwan. Non-CHD controls (n = 14,208) matched for age and sex (1:4) were selected from the same dataset. All subjects were observed until December 31, 2011 or their death. Comorbid perinatal conditions and early developmental disorders (EDD) that were diagnosed before ADHD and ASD diagnosis were also analyzed. The incidence rates of perinatal comorbidities, EDD, ADHD, and ASD were higher in the CHD group than in the control group. Multivariate Cox regression analysis revealed that the CHD group had an increased risk of developing ADHD (adjusted hazard ratio [aHR] 2.52, 95% confidence interval CI 1.96-3.25) and ASD (aHR 1.97, 95% CI 1.11-3.52) after adjusting for confounding comorbidities. EDD, but not perinatal comorbidities were also independent risk factors for ADHD and ASD after adjustment. Subgroup analysis indicated that the risk for ADHD (HR 16.59, 95% CI 12.17-22.60) and ASD (HR 80.68, 95% CI 39.96-176.12) was greatly increased in CHD subjects with EDD than in non-CHD subjects without EDD. These findings suggested that CHD at birth and EDD during early childhood were two independent risk factors for ADHD and ASD and that concurrent CHD and EDD might additively increase these risks.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Espectro Autista/diagnóstico , Deficiências do Desenvolvimento/epidemiologia , Cardiopatias Congênitas/epidemiologia , Estudos de Casos e Controles , Pré-Escolar , Comorbidade , Feminino , Humanos , Estudos Longitudinais , Masculino , Gravidez , Estudos Retrospectivos , Fatores de Risco
18.
BMC Infect Dis ; 17(1): 252, 2017 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-28390391

RESUMO

BACKGROUND: While Candida pneumonia is life-threatening, biomarker measurements to early detect suspected Candida pneumonia are lacking. This study compared the diagnostic values of measuring levels of (1, 3)-ß-D-glucan in endotracheal aspirate, bronchoalveolar lavage fluid, and serum to detect suspected Candida pneumonia in immunocompromised and critically ill patients. METHODS: This prospective, observational study enrolled immunocompromised, critically ill, and ventilated patients with suspected fungal pneumonia in mixed intensive care units from November 2010 to October 2011. Patients with D-glucan confounding factors or other fungal infection were excluded. Endotracheal aspirate, bronchoalveolar lavage fluid and serum were collected from each patient to perform a fungal smear, culture, and D-glucan assay. RESULTS: After screening 166 patients, 31 patients completed the study and were categorized into non-Candida pneumonia/non-candidemia (n = 18), suspected Candida pneumonia (n = 9), and non-Candida pneumonia/candidemia groups (n = 4). D-glucan levels in endotracheal aspirate or bronchoalveolar lavage were highest in suspected Candida pneumonia, while the serum D-glucan level was highest in non-Candida pneumonia/candidemia. In all patients, the D-glucan value in endotracheal aspirate was positively correlated with that in bronchoalveolar lavage fluid. For the detection of suspected Candida pneumonia, the predictive performance (sensitivity/specificity/D-glucan cutoff [pg/ml]) of D-glucan in endotracheal aspirate and bronchoalveolar lavage fluid was 67%/82%/120 and 89%/86%/130, respectively, accounting for areas under the receiver operating characteristic curve of 0.833 and 0.939 (both P < 0.05), respectively. Measuring serum D-glucan was of no diagnostic value (area under curve =0.510, P = 0.931) for the detection of suspected Candida pneumonia in the absence of concurrent candidemia. CONCLUSIONS: D-glucan levels in both endotracheal aspirate and bronchoalveolar lavage, but not in serum, provide good diagnostic values to detect suspected Candida pneumonia and to serve as potential biomarkers for early detection in this patient population.


Assuntos
Líquido da Lavagem Broncoalveolar , Candidíase/diagnóstico , Pneumonia/diagnóstico , beta-Glucanas/análise , Adulto , Idoso , Biomarcadores/análise , Candidemia/diagnóstico , Estado Terminal , Diagnóstico Precoce , Feminino , Humanos , Hospedeiro Imunocomprometido , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Pneumonia/microbiologia , Estudos Prospectivos , Sensibilidade e Especificidade
19.
Front Physiol ; 7: 263, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27445853

RESUMO

Obstructive sleep apnea (OSA), manifested by airway exposure to intermittent hypoxia (IH), is associated with excess reactive oxygen species (ROS) production in airways, airway inflammation, and hyperreactive airway diseases. The cause-effect relationship for these events remains unclear. We investigated the inflammatory role of ROS-sensitive AMP-activated protein kinase (AMPK) in IH-induced airway hypersensitivity mediated by lung vagal C fibers (LVCFs) in rats. Conscious rats were exposed to room air (RA) or IH with or without treatment with N-acetyl-L-cysteine (NAC, an antioxidant), Compound C (an AMPK inhibitor), ibuprofen (a cyclooxygenase inhibitor), or their vehicles. Immediately after exposure (24 h), we found that intravenous capsaicin, phenylbiguanide, or α,ß-methylene-ATP evoked augmented LVCF-mediated apneic responses and LVCF afferent responses in rats subjected to IH exposure in comparison with those in RA rats. The potentiating effect of IH on LVCF responses decreased at 6 h after and vanished at 12 h after the termination of IH exposure. The potentiating effect of IH on LVCF-mediated apneic and LVCF afferent responses was significantly attenuated by treatment with NAC, compound C, or ibuprofen, but not by their vehicles. Further biochemical analysis revealed that rats exposed to IH displayed increased lung levels of lipid peroxidation (an index of oxidative stress), AMPK phosphorylation (an index of AMPK activation), and prostaglandin E2 (a cyclooxygenase metabolite), compared with those exposed to RA. IH-induced increase in lipid peroxidation was considerably suppressed by treatment with NAC but not by compound C or ibuprofen. IH-induced increase in AMPK phosphorylation was totally abolished by NAC or compound C but not by ibuprofen. IH-induced increase in prostaglandin E2 was considerably prevented by any of these three inhibitor treatments. The vehicles of these inhibitors exerted no significant effect on the three IH-induced responses. These results suggest that 24-h IH exposure sensitizes LVCFs, leading to an exaggerated reflex and afferent responses to chemical stimulants in rats. Moreover, this IH-induced LVCF sensitization is mediated through a cascade of inflammatory responses in the airways involving increases in ROS, AMPK activation, and cyclooxygenase metabolite release.

20.
Artigo em Inglês | MEDLINE | ID: mdl-27274227

RESUMO

PURPOSE: COPD is often associated with various comorbidities that may influence its outcomes. Pneumonia, cardiovascular disease (CVD), and cancer are the major causes of death in COPD patients. The objective of this study is to investigate the influence of comorbidities on COPD by using the Taiwan National Health Insurance database. PATIENTS AND METHODS: We retrospectively analyzed the database in 2006 of one million sampling cohort. Newly diagnosed patients with COPD with a controlled cohort that was matched by age, sex, and Charlson comorbidity index (CCI) were included for analysis. RESULTS: In total, 1,491 patients with COPD were included for analysis (61.8% male). Patients with COPD had higher incidences of pneumonia (25.7% vs 10.4%; P<0.0001), CVD (15.1% vs 10.5%; P<0.0001), and mortality rate (26.6% vs 15.8%; P<0.001) compared with the control group in the 4-year follow-up. In patients with COPD, CCI ≥3 have a higher incidence of pneumonia (hazard ratio [HR] 1.61; 95% confidence interval [CI] 1.23-2.09; P<0.0001), CVD (HR 1.73; 95% CI 1.24-2.41; P=0.001), and mortality (HR 1.12; 95% CI 1.12-1.83; P=0.004). Among the major comorbidities of COPD, hyperlipidemia was associated with decreased incidence of pneumonia (HR 0.68; 95% CI 0.5-0.93; P=0.016) and mortality (HR 0.64; 95% CI 0.46-0.90; P=0.009), but was not associated with increased risk of CVD (HR 1.10; 95% CI 0.78-1.55; P=0.588). CONCLUSION: Our results demonstrate that COPD is associated with increased incidence of pneumonia, CVD, and mortality. In patients with COPD, higher CCI is associated with increased incidence of pneumonia, CVD, and mortality. However, COPD with hyperlipidemia is associated with decreased incidence of pneumonia and mortality.


Assuntos
Hiperlipidemias/complicações , Pneumonia/epidemiologia , Pneumonia/etiologia , Doença Pulmonar Obstrutiva Crônica/complicações , Adulto , Idoso , Estudos de Coortes , Bases de Dados Factuais , Feminino , Humanos , Incidência , Seguro Saúde , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/mortalidade , Estudos Retrospectivos , Taiwan
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