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BACKGROUND: We previously identified ezetimibe, an inhibitor of Niemann-Pick C1-like intracellular cholesterol transporter 1 and European Medicines Agency-approved lipid-lowering agent, as a potent autophagy activator. However, its efficacy against pulmonary fibrosis has not yet been evaluated. This study aimed to determine whether ezetimibe has therapeutic potential against idiopathic pulmonary fibrosis. METHODS: Primary lung fibroblasts isolated from both humans and mice were employed for mechanistic in vitro experiments. mRNA sequencing of human lung fibroblasts and gene set enrichment analysis were performed to explore the therapeutic mechanism of ezetimibe. A bleomycin-induced pulmonary fibrosis mouse model was used to examine in vivo efficacy of the drug. Tandem fluorescent-tagged microtubule-associated protein 1 light chain 3 transgenic mice were used to measure autophagic flux. Finally, the medical records of patients with idiopathic pulmonary fibrosis from three different hospitals were reviewed retrospectively, and analyses on survival and lung function were conducted to determine the benefits of ezetimibe. RESULTS: Ezetimibe inhibited myofibroblast differentiation by restoring the mechanistic target of rapamycin complex 1-autophagy axis with fine control of intracellular cholesterol distribution. Serum response factor, a potential autophagic substrate, was identified as a primary downstream effector in this process. Similarly, ezetimibe ameliorated bleomycin-induced pulmonary fibrosis in mice by inhibiting mechanistic target of rapamycin complex 1 activity and increasing autophagic flux, as observed in mouse lung samples. Patients with idiopathic pulmonary fibrosis who regularly used ezetimibe showed decreased rates of all-cause mortality and lung function decline. CONCLUSION: Our study presents ezetimibe as a potential novel therapeutic for idiopathic pulmonary fibrosis.
Assuntos
Anticolesterolemiantes , Autofagia , Modelos Animais de Doenças , Reposicionamento de Medicamentos , Ezetimiba , Fibrose Pulmonar Idiopática , Ezetimiba/uso terapêutico , Ezetimiba/farmacologia , Animais , Fibrose Pulmonar Idiopática/tratamento farmacológico , Humanos , Camundongos , Autofagia/efeitos dos fármacos , Masculino , Anticolesterolemiantes/uso terapêutico , Anticolesterolemiantes/farmacologia , Feminino , Camundongos Transgênicos , Bleomicina , Pulmão/patologia , Pulmão/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Estudos Retrospectivos , Idoso , Pessoa de Meia-Idade , Camundongos Endogâmicos C57BL , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Colesterol/metabolismoRESUMO
BACKGROUND: Whether COVID-19-induced acute respiratory distress syndrome (ARDS) should be approached differently in terms of mechanical ventilation therapy compared to other virus-induced ARDS is debatable. Therefore, we aimed to ascertain whether the respiratory mechanical characteristics of COVID-19-induced ARDS differ from those of influenza A induced ARDS, in order to establish a rationale for mechanical ventilation therapy in COVID-19-induced ARDS. METHODS: This was a retrospective cohort study comparing patients with COVID-19-induced ARDS and influenza A induced ARDS. We included intensive care unit (ICU) patients with COVID-19 or Influenza A aged ≥ 19, who were diagnosed with ARDS according to the Berlin definition between January 2015 and July 2021. Ventilation parameters for respiratory mechanics were collected at specific times on days one, three, and seven after intubation. RESULTS: The median age of the 87 participants was 71.0 (62.0-78.0) years old, and 63.2% were male. The ratio of partial pressure of oxygen in arterial blood to the fractional of inspiratory oxygen concentration in COVID-19-induced ARDS was lower than that in influenza A induced ARDS during the initial stages of mechanical ventilation (influenza A induced ARDS 216.1 vs. COVID-19-induced ARDS 167.9, p = 0.009, day 1). The positive end expiratory pressure remained consistently higher in the COVID-19 group throughout the follow-up period (7.0 vs. 10.0, p < 0.001, day 1). COVID-19 and influenza A initially showed different directions for peak inspiratory pressure and dynamic compliance; however, after day 3, both groups exhibited similar directions. Dynamic driving pressure exhibited opposite trends between the two groups during mechanical ventilation. CONCLUSIONS: Respiratory mechanics show clear differences between COVID-19-induced ARDS and influenza A induced ARDS. Based on these findings, we can consider future treatment strategies for COVID-19-induced ARDS.
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COVID-19 , Influenza Humana , Síndrome do Desconforto Respiratório , Humanos , Masculino , Idoso , Feminino , Respiração Artificial , Influenza Humana/diagnóstico , Influenza Humana/epidemiologia , Influenza Humana/terapia , Estudos Retrospectivos , COVID-19/terapia , Síndrome do Desconforto Respiratório/diagnóstico , Síndrome do Desconforto Respiratório/epidemiologia , Síndrome do Desconforto Respiratório/terapia , Mecânica Respiratória , OxigênioRESUMO
A Gram-stain-positive, aerobic bacterium, designated as YPD9-1T, was isolated from the gut contents of a spotty belly greenling, Hexagrammos agrammus, collected near Dokdo island, South Korea. The rod-shaped cells were oxidase-positive, and catalase-negative. The major cellular fatty acids were anteiso-C15â:â0, iso-C15â:â0, C16â:â0, iso-C16â:â0 and iso-C17: 0. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and two unidentified lipids. The DNA G+C content was 47.6 mol% and the predominant respiratory quinone was menaquinone MK-7. The 16S rRNA gene sequence of YPD9-1T showed low sequence similarities to species of the genus Paenibacillus, Paenibacillus pocheonensis Gsoil 1138T (97.21â% of sequence similarity), Paenibacillus aestuarii CJ25T (97.12â%) and Paenibacillus allorhizoplanae JJ-42T (96.89â%). The results of phylogenetic analysis based on 16S rRNA gene sequences indicated that YPD9-1T formed a distinct branch among other species of the genus Paenibacillus. The digital DNA-DNA hybridisation, average nucleotide identity, and average amino acid identity values between YPD9-1T and the related species were in the ranges of 15.3-16.2â%, 74.1-78.4â%, and 71.1-71.9â%, respectively, which are below the species cutoff values. On the basis of the results of the polyphasic analysis, we conclude that strain YPD9-1T represents a novel species of the genus Paenibacillus, for which the name Paenibacillus hexagrammi sp. nov. is proposed. The type strain of Paenibacillus hexagrammi is YPD9-1T (=KCTC 43424T =LMG 32988T).
Assuntos
Técnicas de Tipagem Bacteriana , Composição de Bases , DNA Bacteriano , Ácidos Graxos , Paenibacillus , Filogenia , RNA Ribossômico 16S , Análise de Sequência de DNA , Vitamina K 2 , RNA Ribossômico 16S/genética , DNA Bacteriano/genética , República da Coreia , Ácidos Graxos/análise , Ácidos Graxos/química , Paenibacillus/isolamento & purificação , Paenibacillus/classificação , Paenibacillus/genética , Vitamina K 2/análogos & derivados , Vitamina K 2/análise , Animais , Hibridização de Ácido Nucleico , Fosfolipídeos/análise , Fosfolipídeos/químicaRESUMO
The EGF-containing fibulin-like extracellular matrix protein 2 (EFEMP2) is involved in connective tissue development, elastic fiber formation, and tumor growth. In this study, we characterized the cDNA of EFEMP2 (PoEFEMP2), a member of the fibulin family of ECM proteins, in the olive flounder Paralichthys olivaceus. The coding region of PoEFEMP2 encodes a protein that contains six calcium-binding EGF-like (EGF-CA) domains and four complement Clr-like EGF-like (cEGF) domains. PoEFEMP2 shows 67.51-96.77 % similarities to orthologs in a variety of fish species. PoEFEMP2 mRNA was detected in all tissues examined; the highest levels of PoEFEMP2 mRNA expression were observed in the heart, testis, ovary and muscle. The PoEFEMP2 mRNA level increases during early development. In addition, the PoEFEMP2 mRNA level increased at 3 h post-infection (hpi) and decreased from 6 to 48 hpi in flounder Hirame natural embryo (HINAE) cells infected with viral hemorrhagic septicemia virus (VHSV). Disruption of PoEFEMP2 using the clustered regularly interspaced short palindromic repeats/CRISPR-associated-9 (CRISPR/Cas9) system resulted in a significant upregulation of VHSV G mRNA levels and immune-related genes expression in knockout cells. These findings implicate PoEFEMP2 in antiviral responses in P. olivaceus.
Assuntos
Sequência de Aminoácidos , Proteínas da Matriz Extracelular , Proteínas de Peixes , Regulação da Expressão Gênica , Septicemia Hemorrágica Viral , Imunidade Inata , Novirhabdovirus , Filogenia , Animais , Novirhabdovirus/fisiologia , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/imunologia , Septicemia Hemorrágica Viral/imunologia , Septicemia Hemorrágica Viral/genética , Imunidade Inata/genética , Regulação da Expressão Gênica/imunologia , Alinhamento de Sequência/veterinária , Doenças dos Peixes/imunologia , Doenças dos Peixes/virologia , Perfilação da Expressão Gênica/veterinária , Linguados/imunologia , Linguados/genéticaRESUMO
BACKGROUND: Dermatophytosis is a common and major public health concern worldwide. Despite the increasing availability of antifungal drugs, relapses and untreated cases of dermatophyte infections are reported. Therefore, novel antifungal agents are required. Aminopyrrolnitrin (APRN) shows promise for dermatophytosis treatment because of its antifungal activity. OBJECTIVES: This study aimed to assess the antifungal properties of APRN against Trichophyton verrucosum (T. verrucosum), in both laboratory settings and a guinea pig model. METHODS: The minimum inhibitory concentrations (MICs) of APRN and enilconazole against T. verrucosum were determined according to the CLSI M38 method. The skins of 16 male guinea pigs were infected with 1.0 × 108 conidia of T. verrucosum and the animals were grouped into sets of four: negative control group (NC) received normal saline; positive control group (PC) received 2 µg/mL of enilconazole; and APRN4 and APRN8 received 4 and 8 µg/mL of APRN, respectively. Clinical, mycological and histological efficacies were measured after 10 days. RESULTS: The MIC90 of APRN and enilconazole against T. verrucosum was 4 and 2 µg/mL, respectively. The clinical scores of PC, APRN4, and APRN8 were significantly lower than those of NC. Clinical and mycological efficacies were higher for APRN8, APRN4 and PC. No fungi were observed in the skin tissues of APRN4 and APRN8, while fungi were observed in 50% of the PC. CONCLUSION: APRN showed antifungal activity against T. verrucosum in vitro and in vivo and is a potential candidate for the treatment of dermatophytosis.
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Antifúngicos , Modelos Animais de Doenças , Testes de Sensibilidade Microbiana , Tinha , Trichophyton , Animais , Cobaias , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Trichophyton/efeitos dos fármacos , Tinha/tratamento farmacológico , Tinha/microbiologia , Masculino , Pele/microbiologiaRESUMO
BACKGROUND: Coinfections with multiple nontuberculous mycobacterial (NTM) species have not been widely studied. We aimed to evaluate the clinical characteristics and treatment outcomes in patients with NTM-pulmonary disease (PD) caused by coinfection with multiple NTM species. METHODS: We retrospectively reviewed patients with NTM-PD at a tertiary referral hospital in Korea between March 2012 and December 2018. Coinfection was defined as two or more species of NTM pathogens isolated from the same respiratory specimen or different specimens within three months. RESULTS: Among 1,009 patients with NTM-PD, 147 (14.6%) NTM coinfections were observed (average age 64.7 years, 69.4% women). NTM species were identified more frequently (median 6 vs. 3 times, P < 0.001) in the coinfection group than in the single species group, and follow-up duration was also longer in the coinfection group (median 44.9 vs. 27.1 months, P < 0.001). Mycobacterium avium complex (MAC) and M. abscessus and M. massiliense (MAB) were the dominant combinations (n = 71, 48.3%). For patients treated for over six months in the MAC plus MAB group (n = 31), sputum culture conversion and microbiological cure were achieved in 67.7% and 41.9% of patients, respectively. We divided the MAC plus MAB coinfection group into three subgroups according to the target mycobacteria; however, no statistical differences were found in the treatment outcomes. CONCLUSION: In NTM-PD cases, a significant number of multiple NTM species coinfections occurred. Proper identification of all cultured NTM species through follow-up is necessary to detect multispecies coinfections. Further research is needed to understand the nature of NTM-PD in such cases.
Assuntos
Coinfecção , Pneumopatias , Infecções por Mycobacterium não Tuberculosas , Micobactérias não Tuberculosas , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/complicações , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Idoso , Coinfecção/microbiologia , Micobactérias não Tuberculosas/isolamento & purificação , Resultado do Tratamento , Pneumopatias/microbiologia , Pneumopatias/complicações , Complexo Mycobacterium avium/isolamento & purificação , Antibacterianos/uso terapêutico , República da CoreiaRESUMO
BACKGROUND: The treatment success rate for tuberculosis (TB) has stagnated at 80-81% in South Korea, indicating unsatisfactory outcomes. Enhancing treatment success rate necessitates the development of individualized treatment approaches for each patient. This study aimed to identify the risk factors associated with unfavorable treatment outcomes to facilitate tailored TB care. METHODS: We retrospectively analyzed the data of patients with active TB between January 2019 and December 2020 at a single tertiary referral center. We classified unfavorable treatment outcomes according to the 2021 World Health Organization guidelines as follows: "lost to follow-up" (LTFU), "not evaluated" (NE), "death," and "treatment failure" (TF). Moreover, we analyzed risk factors for each unfavorable outcome using Cox proportional hazard regression analysis. RESULTS: A total of 659 patients (median age 62 years; male 54.3%) were included in the study. The total unfavorable outcomes were 28.1%: 4.6% LTFU, 9.6% NE, 9.1% deaths, and 4.9% TF. Multivariate analysis showed that a culture-confirmed diagnosis of TB was associated with a lower risk of LTFU (adjusted hazard ratio [aHR], 0.25; 95% confidence interval [CI], 0.10-0.63), whereas the occurrence of adverse drug reactions (ADRs) significantly increased the risk of LTFU (aHR, 6.63; 95% CI, 2.63-16.69). Patients living far from the hospital (aHR, 4.47; 95% CI, 2.50-7.97) and those with chronic kidney disease (aHR, 3.21; 95% CI, 1.33-7.75) were at higher risk of being transferred out to other health institutions (NE). Higher mortality was associated with older age (aHR, 1.06; 95% CI, 1.04-1.09) and comorbidities. The ADRs that occurred during TB treatment were a risk factor for TF (aHR, 6.88; 95% CI, 2.24-21.13). CONCLUSION: Unfavorable outcomes of patients with TB were substantial at a tertiary referral center, and the risk factors for each unfavorable outcome varied. To improve treatment outcomes, close monitoring and the provision of tailored care for patients with TB are necessary.
Assuntos
Antituberculosos , Tuberculose , Humanos , Masculino , Pessoa de Meia-Idade , Antituberculosos/efeitos adversos , Estudos Retrospectivos , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia , Fatores de Risco , Resultado do Tratamento , República da Coreia/epidemiologia , Assistência Centrada no PacienteRESUMO
Inflammation after surgical incisions is related to the degree of tissue damage. Healing with low inflammation is desirable, especially in patients with compromised healing potential. This experimental study was conducted to assess the degree of inflammatory reaction and scar formation from incisions made by an ultra-polished scalpel (UPS). Two paravertebral incisions were made with a conventional scalpel (CS) and a UPS in 18 individual rats with diabetes. The fibrotic tissue (scar) area and expression levels of collagen, transforming growth factor, and matrix metalloproteinases were quantified on postoperative days 3, 7, and 30. The scar widths and areas were significantly lower in the UPS group than in the CS group. The scar widths were 64.3 ± 14.7 µm and 86.8 ± 12.1 µm in the UPS and CS groups, respectively (P = 0.03). The scar areas were 11,398 ± 1595 µm2 in the UPS group and 17,433 ± 3487 µm2 in the CS group (P = 0.014). The UPS group had less inflammation on day 3, less transforming growth factor synthesis on days 3 and 7, lower levels of matrix metalloproteinases, and less collagen synthesis on day 7 than did the CS group. The UPS achieved less local inflammation by reducing the local tissue damage in diabetic rat models, enabling better healing, and resulting in less scar formation. The UPS warrants further clinical study as it may bring beneficial outcomes for patients with impaired healing capability and patients who seek to reduce scarring.
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BACKGROUND: The longitudinal relationship between adiposity and lung function is controversial. We aimed to investigate the long-term association between adiposity changes and lung function in a middle-aged general Asian population. METHODS: In total, 5011 participants (average age, 54 years; 45% men) were enrolled from a community-based prospective cohort. During the follow-up period (median 8 years), both spirometry and bio-electrical impedance analysis were performed biannually. Individual slopes of the fat mass index (FMI; fat mass divided by the square of height in meters) and waist-to-hip ratio (WHR) were calculated using linear regression analysis. Multivariate linear mixed regression analysis was used to determine the long-term association between adiposity changes and lung function. RESULTS: The FMI was inversely associated with forced vital capacity (FVC) (estimated: - 31.8 mL in men, - 27.8 mL in women) and forced expiratory volume in 1 s (FEV1) (estimated: - 38.2 mL in men, - 17.8 mL in women) after adjusting for baseline age, height, residential area, smoking exposure (pack-years, men only), initial adiposity indices, and baseline lung function. The WHR was also inversely associated with FVC (estimated = - 1242.2 mL) and FEV1 (estimated = - 849.8 mL) in men. The WHR-increased group showed a more rapid decline in lung function than the WHR-decreased group in both the fat-gain and fat-loss groups. CONCLUSION: Adiposity was associated with the long-term impairment of lung function. Central obesity was the main driver of lung function impairment in the middle-aged general Asian population, regardless of fat mass changes.
Assuntos
Adiposidade , Pulmão , Masculino , Pessoa de Meia-Idade , Humanos , Feminino , Estudos Prospectivos , Índice de Massa Corporal , Obesidade/epidemiologia , Capacidade Vital , Volume Expiratório ForçadoRESUMO
BACKGROUND: In the global trend of population aging, age is one of the significant factors to be considered in critically ill patients. However, the impact of age on clinical outcomes and long-term prognosis in this population varies across different studies. METHODS: We conducted a retrospective cohort analysis for patients admitted to the medical intensive care unit (ICU) (30 beds) between January 2017 and December 2020 at the tertiary referral hospital in Korea. Patients were classified into three groups according to age: <65 years, old age (65-79 years), and very old age (≥ 80 years). Subsequently, enrolled patients were analyzed for acute mortality and long-term prognosis. RESULTS: Among the 1584 patients, the median age was 67.0 (57.0-76.0) years, and 65.2% were male. Median ICU length of stay (LOS) (8, 9, and 10 days in < 65, 65-79, and ≥ 80 years, respectively; p = 0.006) and the proportion of patients who were transferred to long-term care hospital at the time of discharge (12.9% vs. 28.3% vs. 39.4%, respectively; p < 0.001) increased with age. Multivariable logistic analysis showed no significant difference in the 28-day mortality in the old age (adjusted odds ratio [aOR] 0.88; 95% confidence interval [CI] 0.65-1.17) and very old age (aOR 1.05; 95% CI 0.71-1.55) groups compared to that in patients with age < 65 years. However, the relevance of the proportion of ICU LOS ≥ 7 days and transfers to other hospitals after discharge increased with age. CONCLUSIONS: Age did not affect acute mortality in critical illness patients. However, surviving older age groups required more long-term care facilities compared to patients younger than 65 years after acute management. These results indicate that in an aging society, the importance of not only acute management but also long-term care facilities may increase for critical illness patients.
Assuntos
Estado Terminal , Assistência de Longa Duração , Humanos , Masculino , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudos Retrospectivos , Estado Terminal/terapia , Unidades de Terapia Intensiva , Hospitalização , Tempo de Internação , Mortalidade HospitalarRESUMO
BACKGROUND: Sarcopenia is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD), but its relationship with chronic obstructive pulmonary disease (COPD) has not been fully determined. This study is aimed to investigate the association between sarcopenia and risk for ASCVD in patients with COPD, independent of central obesity and fat mass. METHODS: Data regarding 704 men with COPD (mean age: 63.4 years) were extracted from the 2008 to 2011 Korean National Health and Nutrition Examination Surveys. Sarcopenia index and fat mass were assessed using dual-energy X-ray absorptiometry. Sarcopenia was defined according to the presence of sarcopenia index values < 1 standard deviation from the cutoff (0.774) among the study participants. ASCVD risk was evaluated using American College of Cardiology/American Heart Association guidelines. High probability of ASCVD was defined as ASCVD risk > 20%. RESULTS: The quartile-stratified sarcopenia index was negatively associated with ASCVD risk (P < 0.001). ASCVD risk and prevalence of high ASCVD risk were significantly greater in sarcopenic participants than in non-sarcopenic participants, regardless of central obesity and fat mass (all P < 0.001). Multivariate regression analyses demonstrated an independent association between sarcopenia and ASCVD risk (estimated ± standard error = 3.63 ± 0.77%, P < 0.001) and high ASCVD risk (odds ratio [OR] = 2.32, 95% confidence interval [CI] 1.05-5.15, P = 0.039). Furthermore, sarcopenia was an independent factor for high ASCVD risk in participants with moderate to very severe airflow limitation (OR = 2.97, 95% CI 1.06-8.36, P < 0.001). CONCLUSIONS: Sarcopenia was significantly associated with an increased risk for ASCVD in men with COPD, independent of central obesity and fat mass. High ASCVD risk was significantly associated with sarcopenia, particularly in participants with moderate to very severe airflow limitation.
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Doenças Cardiovasculares , Doença Pulmonar Obstrutiva Crônica , Sarcopenia , Absorciometria de Fóton , Adiposidade , Índice de Massa Corporal , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Fatores de Risco de Doenças Cardíacas , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Obesidade/diagnóstico , Obesidade/epidemiologia , Obesidade Abdominal/diagnóstico , Obesidade Abdominal/epidemiologia , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Fatores de Risco , Sarcopenia/diagnóstico por imagem , Sarcopenia/epidemiologiaRESUMO
BACKGROUND: For patients with acute respiratory distress syndrome, a ventilator is essential to supply oxygen to tissues, but it may also cause lung damage. In this study, we investigated the role of NOX4 using NOX4 knockout (KO) mice and NOX4 inhibitors in a ventilator-induced lung injury (VILI) model. METHODS: Wild-type (WT) male C57BL/6J mice and NOX4 knockout (KO) male mice were divided into five groups: (1) control group; (2) high tidal ventilation (HTV) group: WT mice + HTV ± DMSO; (3) NOX4 KO group; (4) NOX4 KO with HTV group; (5) NOX4 inhibitor group: WT mice + HTV + NOX4 inhibitor. In the VILI model, the supine position was maintained at 24 mL/kg volume, 0 cm H2O PEEP, 100/min respiratory rate, and 0.21 inspired oxygen fraction. In the NOX4 inhibitor group, 50 µL anti-GKT 137831 inhibitor was injected intraperitoneally, 2 h after ventilator use. After 5 h of HTV, mice in the ventilator group were euthanized, and their lung tissues were obtained for further analysis. In addition, the relationship between EphA2 (which is related to lung injury) and NOX4 was investigated using EphA2 KO mice, and NOX4 and EphA2 levels in the bronchoalveolar lavage fluid (BALF) of 38 patients with pneumonia were examined. RESULTS: Cell counts from BALFs were significantly lower in the NOX4 KO with HTV group (p < 0.01) and EphA2 KO with HTV group (p < 0.001) compared to that in the HTV group. In the NOX4 inhibitor group, cell counts and protein concentrations from BALF were significantly lower than those in the HTV group (both, p < 0.001). In the NOX4 KO group and the NOX4 inhibitor group, EphA2 levels were significantly lower than those in the HTV group (p < 0.001). In patients with respiratory disease, NOX4 and EphA2 levels were significantly higher in patients with pneumonia and patients who received ventilator treatment in the intensive care unit. CONCLUSION: In the VILI model with high tidal volume, NOX4 KO, EphA2 KO or monoclonal antibodies attenuated the VILI. NOX4 and EphA2 levels were significantly higher in patients with pneumonia and especially in mechanical ventilated in the ICU. Inhibition of Nox4 is a potential therapeutic target for the prevention and reduction of VILI.
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NADPH Oxidase 4 , Lesão Pulmonar Induzida por Ventilação Mecânica , Animais , Humanos , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidase 4/genética , NADPH Oxidase 4/metabolismo , Transdução de Sinais , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismoRESUMO
Tripartite motif-containing (TRIM) proteins are conserved throughout the metazoan kingdom, and the TRIM subset finTRIM is highly diversified in fish. We isolated TRIM16 cDNA, a member of the finTRIM family, from the olive flounder Paralichthys olivaceus (PoTRIM16). PoTRIM16 contained a 1,725-bp coding sequence encoding a 574-amino acid polypeptide, which in turn contained a really interesting new gene (RING) finger domain, B-box-type zinc finger (B-BOX), nuclease SbcCD subunit C (SbcC), structural maintenance of chromosome (SMC prok B), and stonustoxin (SNTX) subunit alpha (SPRY-PRY-SNTX). Multiple alignment of related sequences revealed that PoTRIM16 showed 86.63-97.40% identity with fish orthologues, and a phylogenetic tree was constructed of vertebrates. PoTRIM16 mRNA was detected in all tissues examined; levels were highest in the eye and ovary. PoTRIM16 mRNA expression was investigated during early development. Under VHSV infection, PoTRIM16 mRNA was downregulated in the liver of P. olivaceus. This is the first study to characterize fish-specific finTRIM in P. olivaceus, which may play a role in the immune response against virus infection.
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Doenças dos Peixes , Linguado , Novirhabdovirus , Animais , Feminino , Novirhabdovirus/fisiologia , Filogenia , RNA Mensageiro/metabolismoRESUMO
BACKGROUND: Pneumocystis jirovecii pneumonia (PCP) with acute respiratory failure can result in development of pneumothorax during treatment. This study aimed to identify the incidence and related factors of pneumothorax in patients with PCP and acute respiratory failure and to analyze their prognosis. METHODS: We retrospectively reviewed the occurrence of pneumothorax, including clinical characteristics and results of other examinations, in 119 non-human immunodeficiency virus patients with PCP and respiratory failure requiring mechanical ventilator treatment in a medical intensive care unit (ICU) at a tertiary-care center between July 2016 and April 2019. RESULTS: During follow up duration, twenty-two patients (18.5%) developed pneumothorax during ventilator treatment, with 45 (37.8%) eventually requiring a tracheostomy due to weaning failure. Cytomegalovirus co-infection (odds ratio 13.9; p = 0.013) was related with occurrence of pneumothorax in multivariate analysis. And development of pneumothorax was not associated with need for tracheostomy and mortality. Furthermore, analysis of survivor after 28 days in ICU, patients without pneumothorax were significantly more successful in weaning from mechanical ventilator than the patients with pneumothorax (44% vs. 13.3%, p = 0.037). PCP patients without pneumothorax showed successful home discharges compared to those who without pneumothorax (p = 0.010). CONCLUSIONS: The development of pneumothorax increased in PCP patient with cytomegalovirus co-infection, pneumothorax might have difficulty in and prolonged weaning from mechanical ventilators, which clinicians should be aware of when planning treatment for such patients.
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Pneumonia por Pneumocystis/complicações , Pneumotórax/complicações , Pneumotórax/epidemiologia , Idoso , Estudos de Coortes , Feminino , Infecções por HIV , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Pneumocystis carinii , Pneumotórax/terapia , Prognóstico , República da Coreia/epidemiologia , Respiração Artificial , Insuficiência Respiratória/complicações , Estudos Retrospectivos , Fatores de RiscoRESUMO
Cognitive impairment has high prevalence in older adults with airway diseases, and may influence their competence in inhaler use, thereby negatively affecting patient prognosis. We aimed to evaluate the relationship between cognitive function and competence in inhaler technique. We enrolled 108 inhaler naïve older adults (≥60 years) with airway disease in this prospective observational study and performed the Korean version of the Mini-Mental State Examination (K-MMSE). After explaining the inhaler technique, we scored its competence. While the total K-MMSE score was unrelated to the inhaler score, the orientation for place (estimates=0.62, p = 0.009), registration (estimates=0.988, p = 0.037), and recall (estimates=0.161, p = 0.048) were positively associated with the score. Low K-MMSE scores were associated with lower odds ratio for the competence of the "exhale" step (adjusted odds ratio= 0.23, p = 0.018). Thus, a K-MMSE-mediated evaluation of cognitive function in older adults with airway disease can be a useful tool to predict inhaler competence.
Assuntos
Disfunção Cognitiva , Nebulizadores e Vaporizadores , Idoso , Cognição , Disfunção Cognitiva/psicologia , Humanos , Estudos ProspectivosRESUMO
BACKGROUND: As lung transplantation (LTx) is becoming a standard treatment for end-stage lung disease, the use of bridging with extracorporeal membrane oxygenation (ECMO) is increasing. We examined the clinical impact of being awake during ECMO as bridging therapy in patients awaiting LTx. METHODS: In this single-center study, we retrospectively reviewed 241 consecutive LTx patients between October 2012 and March 2019; 64 patients received ECMO support while awaiting LTx. We divided into awake and non-awake groups and compared. RESULTS: Twenty-five patients (39.1%) were awake, and 39 (61.0%) were non-awake. The median age of awake patients was 59.0 (interquartile range, 52.5-63.0) years, and 80% of the group was men. The awake group had better post-operative outcomes than the non-awake group: statistically shorter post-operative intensive care unit length of stay [awake vs. non-awake, 6 (4-8.5) vs. 18 (11-36), p < 0.001], longer ventilator free days [awake vs. non-awake, 24 (17-26) vs. 0 (0-15), p < 0.001], and higher gait ability after LTx (awake vs. non-awake, 92% vs. 59%, p = 0.004), leading to higher 6-month and 1-year lung function (forced expiratory volume in 1 s: awake vs. non-awake, 6-month, 77.5% vs. 61%, p = 0.004, 1-year, 75% vs. 57%, p = 0.013). Furthermore, the awake group had significantly lower 6-month and 1-year mortality rates than the non-awake group (6-month 12% vs. 38.5%, p = 0.022, 1-year 24% vs. 53.8%, p = 0.018). CONCLUSIONS: In patients with end-stage lung disease, considering the long-term and short-term impacts, the awake ECMO strategy could be useful compared with the non-awake ECMO strategy.
Assuntos
Oxigenação por Membrana Extracorpórea/métodos , Pneumopatias/terapia , Transplante de Pulmão , Pulmão/fisiopatologia , Cuidados Pré-Operatórios/métodos , Vigília/fisiologia , Feminino , Seguimentos , Humanos , Pneumopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Testes de Função Respiratória , Estudos Retrospectivos , Fatores de TempoRESUMO
BACKGROUND: Lung cancer is the primary cause of cancer-related deaths worldwide. The human lung serves as a niche to a unique and dynamic bacterial community that is related to the development of multiple diseases. Here, we investigated the differences in the lung microbiomes of patients with lung cancer. METHODS: 16S rRNA sequencing was performed to evaluate the respiratory tract microbiome present in the bronchoalveolar lavage fluid. Patients were stratified based on programmed death-ligand 1 (PD-L1) expression levels and immunotherapy responses. RESULTS: In total, 84 patients were prospectively analyzed, of which 59 showed low (< 10%), and 25 showed high (≥ 10%) PD-L1 expression levels. The alpha and beta diversities did not significantly differ between the two groups. Veillonella dispar was dominant in the high-PD-L1 group; the population of Neisseria was significantly higher in the low-PD-L1 group than in the high-PD-L1 group. In the immunotherapy responder group, V. dispar was dominant, while Haemophilus influenzae and Neisseria perflava were dominant in the non-responder group. CONCLUSION: The abundances of Neisseria and V. dispar differed significantly in relation to PD-L1 expression levels and immunotherapy responses.
Assuntos
Antígeno B7-H1/biossíntese , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Imunoterapia/métodos , Neoplasias Pulmonares/metabolismo , Microbiota/fisiologia , Idoso , Antineoplásicos Imunológicos , Antígeno B7-H1/genética , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Feminino , Humanos , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
BACKGROUND: Pirfenidone is an anti-fibrotic agent shown to slow the progression of idiopathic pulmonary fibrosis (IPF). However, its effectiveness in association with serological autoimmune features in IPF remains unclear. METHODS: We retrospectively reviewed the medical records of patients with IPF treated at a tertiary care hospital in South Korea. The autoantibody status was defined as positive if we detected autoantibodies meeting the serological domain criteria for interstitial pneumonia with autoimmune features or anti-neutrophil cytoplasmic antibodies. RESULTS: We included 142 patients with IPF treated with pirfenidone for over six months (93 were autoantibody-positive and 49 were autoantibody-negative). The mean age was 69.5 ± 7.3 years, and 77.5% of the patients were male. The adjusted mean changes over one year were - 34.4 and - 112.2 mL (p = 0.168) in forced vital capacity (FVC), and - 0.53 and - 0.72 mL/mmHg/min (p = 0.356) in the lungs diffusion capacity for carbon monoxide (DLCO) in the autoantibody-negative and autoantibody-positive groups, respectively. CONCLUSIONS: Reductions in FVC and DLCO were similar in autoantibody-positive and autoantibody-negative patients with IPF treated with pirfenidone. Pirfenidone is effective in attenuating the progression of IPF, irrespective of the autoantibody status.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Anticorpos Anticitoplasma de Neutrófilos/sangue , Fibrose Pulmonar Idiopática/tratamento farmacológico , Piridonas/uso terapêutico , Idoso , Monóxido de Carbono/sangue , Feminino , Humanos , Fibrose Pulmonar Idiopática/sangue , Masculino , Pessoa de Meia-Idade , Capacidade de Difusão Pulmonar , República da Coreia , Estudos Retrospectivos , Resultado do Tratamento , Capacidade Vital/efeitos dos fármacosRESUMO
BACKGROUND: Cumulative evidence regarding the use of brain magnetic resonance imaging (MRI) for predicting prognosis of unconscious out-of-hospital cardiac arrest (OHCA) survivors treated with targeted temperature management (TTM) is available. Theoretically, these patients are at a high risk of developing cerebral infarction. However, there is a paucity of reports regarding the characteristics of cerebral infarction in this population. Thus, we performed a pilot study to identify the characteristics and risk factors of cerebral infarction and to evaluate whether this infarction is associated with clinical outcomes. METHODS: A single-center, retrospective, registry-based cohort study was conducted at Severance Hospital, a tertiary center. Unconscious OHCA survivors were registered and treated with TTM between September 2011 and December 2015. We included patients who underwent brain MRI in the first week after the return of spontaneous circulation. We excluded patients who underwent any endovascular interventions to focus on "procedure-unrelated" cerebral infarctions. We assessed hypoxic-ischemic encephalopathy (HIE) and procedure-unrelated cerebral infarction separately on MRI. Patients were categorized into the following groups based on MRI findings: HIE (-)/infarction (-), infarction-only, and HIE (+) groups. Conventional vascular risk factors showing p < 0.05 in univariate analyses were entered into multivariate logistic regression. We also evaluated if the presence of this procedure-unrelated cerebral infarction lesion or HIE was associated with a poor clinical outcome at discharge, defined as a cerebral performance category of 3-5. RESULTS: Among 71 unconscious OHCA survivors who completed TTM, underwent MRI, and who did not undergo endovascular interventions, 14 (19.7%) patients had procedure-unrelated cerebral infarction based on MRI. Advancing age [odds ratio (OR) 1.11] and atrial fibrillation (OR 5.78) were independently associated with the occurrence of procedure-unrelated cerebral infarction (both p < 0.05). There were more patients with poor clinical outcomes at discharge in the HIE (+) group (88.1%) than in the infarction-only (30.0%) or HIE (-)/infarction (-) group (15.8%) (p < 0.001). HIE (+) (OR 38.69, p < 0.001) was independently associated with poor clinical outcomes at discharge, whereas infarction-only was not (p > 0.05), compared to HIE (-)/infarction (-). CONCLUSIONS: In this pilot study, procedure-unrelated cerebral infarction was noted in approximately one-fifth of unconscious OHCA survivors who were treated with TTM and underwent MRI. Older age and atrial fibrillation might be associated with the occurrence of procedure-unrelated cerebral infarction, and cerebral infarction was not considered to be associated with clinical outcomes at discharge. Considering that the strict exclusion criteria in this pilot study resulted in a highly selected sample with a relatively small size, further work is needed to verify our findings.
Assuntos
Parada Cardíaca Extra-Hospitalar , Idoso , Encéfalo/diagnóstico por imagem , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/etiologia , Estudos de Coortes , Humanos , Imageamento por Ressonância Magnética , Parada Cardíaca Extra-Hospitalar/diagnóstico por imagem , Parada Cardíaca Extra-Hospitalar/etiologia , Parada Cardíaca Extra-Hospitalar/terapia , Projetos Piloto , Estudos Retrospectivos , SobreviventesRESUMO
BACKGROUND: It is essential to determine the distribution of the causative microorganisms in the region and the status of local antibiotic resistance for the proper treatment of hospital-acquired pneumonia/ventilator-associated pneumonia (HAP/VAP). This study aimed to investigate the occurrence and causative strains of HAP/VAP, distribution of resistant bacteria, use of antibiotics, and the ensuing outcomes of patients in Korea. METHODS: A multicenter prospective observational cohort study was conducted among patients with HAP/VAP admitted to the medical intensive care unit of 5 tertiary referral centers between August 2012 and June 2015. Patients' demographic and clinical data were collected. RESULTS: A total of 381 patients were diagnosed with HAP/VAP. Their median age was 69 (59-76) years and 71% were males. A majority of the patients (88%) had late-onset (> 5 days) HAP/VAP. One-quarter of the patients (n = 99) had at least one risk factor for multidrug-resistant (MDR) pathogens, such as prior intravenous antibiotic use within the last 90 days. Microbiological specimens were mostly obtained noninvasively (87%) using sputum or endotracheal aspirates. Pathogens were identified in 235 (62%) of the 381 patients. The most common bacterial pathogen was Acinetobacter baumannii (n = 89), followed by Staphylococcus aureus (n = 52), Klebsiella pneumoniae (n = 25) and Pseudomonas aeruginosa (n = 22). Most of isolated A. baumannii (97%) and S. aureus (88%) were multidrug resistant. The most commonly used empirical antibiotic regimens were carbapenem-based antibiotics (38%), followed by extended-spectrum penicillin/ß-lactamase inhibitor (34%). Glycopeptide or linezolid were also used in combination in 54% of patients. The 28-day mortality rate of the patients with HAP/VAP was 30% and the 60-day mortality was 46%. Patients who used empirical antibiotics appropriately had significantly lower mortality rates than those who did not (28-day mortality: 25% vs. 40%, P = 0.032; 60-day mortality: 41% vs. 55%, P = 0.032, respectively). Administration of appropriate empirical antibiotics (odds ratio [OR], 0.282; confidence interval [CI], 0.092-0.859; P = 0.026), Day 7 treatment failure (OR, 4.515; CI, 1.545-13.192; P = 0.006), and APACHE II score on day 1 (OR, 1.326; CI, 0.988-1.779; P = 0.012) were the factors that determined the 28-day mortality in patients with HAP who had identified bacteria as pathogens. CONCLUSION: In HAP/VAP patients, there was a large burden of MDR pathogens, and their associated mortality rate was high. Proper selection of empirical antibiotics was significantly associated with the patient's prognosis; however, there was a discrepancy between major pathogens and empirical antibiotic therapy.