RESUMEN
Urinary tract infections (UTIs) are a leading hospital-acquired infection. Although timely detection of causative pathogens of UTIs is important, rapid and accurate measures assisting UTI diagnosis and bacterial determination are poorly developed. By reading infrared spectra of urine samples, Fourier-transform infrared spectroscopy (FTIR) may help detect urine compounds, but its role in UTI diagnosis remains uncertain. In this pilot study, we proposed a characterization method in attenuated total reflection (ATR)-FTIR spectra to evaluate urine samples and assessed the correlation between ATR-FTIR patterns, UTI diagnosis, and causative pathogens. We enrolled patients with a catheter-associated UTI in a subacute-care unit and non-UTI controls (total n = 18), and used urine culture to confirm the causative pathogens of the UTIs. In the ATR-FTIR analysis, the spectral variation between the UTI group and non-UTI, as well as that between various pathogens, was found in a range of 1800-900 cm-1, referring to the presence of specific constituents of the bacterial cell wall. The results indicated that the relative ratios between different area zones of vibration, as well as multivariate analysis, can be used as a clue to discriminate between UTI and non-UTI, as well as different causative pathogens of UTIs. This warrants a further large-scale study to validate the findings of this pilot research.
Asunto(s)
Infección Hospitalaria , Infecciones Urinarias , Proteínas de la Ataxia Telangiectasia Mutada , Bacterias , Humanos , Proyectos Piloto , Espectroscopía Infrarroja por Transformada de Fourier , Infecciones Urinarias/diagnóstico , Infecciones Urinarias/microbiologíaRESUMEN
BACKGROUND/PURPOSE: T-helper cell 17 (Th17) is a distinct subset of CD4+ T lymphocytes that is important in the pathogenesis of Mycobacterium tuberculosis infection. This study aims to investigate the characteristics of interleukin (IL)-17A and Th17-related cytokines after stimulation with phytohemagglutinin in patients with active tuberculosis (TB). METHODS: This prospective cohort study enrolled patients with culture-confirmed active TB. QuantiFERON-TB Gold In-Tube (QFT-GIT) assay was performed upon TB diagnosis and at 2 months after TB treatment. Their non-TB-specific secretion of IL-17A and Th17-related cytokines were measured in supernatants of mitogen tubes in QFT-GIT and compared to those of active TB contacts with or without latent TB infection. We analyzed the association between IL-17A secretions and TB presentation and treatment outcomes. RESULTS: A total of 108 patients with TB and 64 non-TB cases were enrolled. The secretion of IL-17A, IL-21, IL-23, and IL-6 were lower in active TB patients upon TB diagnosis. In active TB patients, lower IL-17A secretions were associated with higher grades of sputum smear. In the multivariate analysis, lower IL-17A secretions served as an independent factor associated with 2-month culture non-conversion (odds ratio 23.04, 95% confidence interval [CI] 1.69-84.78) and on-treatment mortality (hazard ratio 28.54, 95% CI 1.30-99.25). The levels of IL-23, and IL-6 significantly increased after 2 months of anti-TB treatment. CONCLUSION: The non-TB-specific IL-17A secretions were lower in active TB patients upon TB diagnosis and associated with higher disease severity and worse treatment outcomes. Trend of recovery of the depressed Th17-related cytokines was noted after effective anti-TB treatment.
Asunto(s)
Tuberculosis Latente , Mycobacterium tuberculosis , Tuberculosis , Depresión , Humanos , Interleucina-17 , Tuberculosis Latente/diagnóstico , Mitógenos , Estudios Prospectivos , Prueba de Tuberculina , Tuberculosis/diagnóstico , Tuberculosis/tratamiento farmacológicoRESUMEN
Pulmonary fibrosis is a fatal respiratory disease that gradually leads to dyspnea, mainly accompanied by excessive collagen production in the fibroblast and myofibroblast through mechanisms such as abnormal alveolar epithelial cells remodeling and stimulation of the extracellular matrix (ECM). Our results show that a small molecule, butylidenephthalide (BP), reduces type I collagen (COL1) expression in Transforming Growth Factor beta (TGF-ß)-induced lung fibroblast without altering downstream pathways of TGF-ß, such as Smad phosphorylation. Treatment of BP also reduces the expression of transcription factor Sex Determining Region Y-box 2 (SOX2), and the ectopic expression of SOX2 overcomes the inhibitory actions of BP on COL1 expression. We also found that serial deletion of the SOX2 binding site on 3'COL1 promoter results in a marked reduction in luciferase activity. Moreover, chromatin immunoprecipitation, which was found on the SOX2 binding site of the COL1 promoter, decreases in BP-treated cells. In an in vivo study using a bleomycin-induced pulmonary fibrosis C57BL/6 mice model, mice treated with BP displayed reduced lung fibrosis and collagen deposition, recovering in their pulmonary ventilation function. The reduction of SOX2 expression in BP-treated lung tissues is consistent with our findings in the fibroblast. This is the first report that reveals a non-canonical regulation of COL1 promoter via SOX2 binding, and contributes to the amelioration of pulmonary fibrosis by BP treatment.
Asunto(s)
Anhídridos Ftálicos/farmacología , Fibrosis Pulmonar/metabolismo , Animales , Línea Celular , Colágeno Tipo I/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Anhídridos Ftálicos/uso terapéutico , Regiones Promotoras Genéticas , Fibrosis Pulmonar/tratamiento farmacológico , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismoRESUMEN
Developing an effective drug for treating human glioblastoma multiform (GBM) has been investigated persistently. A pure compound butylidenephthalide (BP), isolated from Angelica sinensis, has been shown the activities to arrest the growth and initiate apoptosis of GBM in our previous reports. In this study, we further demonstrated that BP treatment accelerates the cell senescence in a dose-dependent manner in vitro and in vivo. S-phase kinase-associated protein 2 (Skp2), a proto-oncogene, is generally upregulated in cancer. We found that it was downregulated in BP-treated GBM cells. The downregulation of Skp2 is parallel with increasing p16 and p21 expression which causes G0/G1 arrest and tumor cell senescence. We also found that restoring the Skp2 protein level by exogenous overexpression prevents the BP-induced cell senescence. Therefore, the linkage between cell senescence and Skp2 expression is strengthened. Promoter binding analysis further detailed that the BP-mediated SP1 reduction might involve in the Skp2 downregulation. In summary, these results emphasize that BP-triggered senescence in GBM cells is highly associated with its control on Skp2 regulation.
Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Anhídridos Ftálicos/farmacología , Proteínas Quinasas Asociadas a Fase-S/fisiología , Animales , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Regulación hacia Abajo , Glioblastoma/patología , Humanos , Ratones , Ratones Desnudos , Proto-Oncogenes Mas , Proteínas Quinasas Asociadas a Fase-S/antagonistas & inhibidores , Factor de Transcripción Sp1/metabolismoRESUMEN
In spite of numerous advances, the 5-year survival rate for head and neck squamous cell cancer has remained largely stagnant and few new anti-tumor drugs have been developed. PCH4, a derivative of n-butylidenephthalide, has been investigated for its anti-tumor effects on oral squamous cell carcinoma (OSCC). The aim of this study was to investigate the anti-tumor mechanism of a potential target gene, Nur77, in OSCC cells, which can be induced by PCH4 treatment. Data show that PCH4 promoted Nur77 translocation from the nucleus to the cytoplasm and induced cell apoptosis in OSCC cells. When Nur77 translocation was blocked, the degree of tumor apoptosis caused by PCH4 was significantly inhibited (p < 0.05). Within the MAPK pathway, PCH4 only induced JNK phosphorylation. Furthermore, treatment with a JNK inhibitor significantly reduced PCH4-induced apoptosis (p < 0.05) and decreased PCH4-induced Nur77 expression (p < 0.05). In a xenograft animal model, administration of PCH4 also showed anti-tumor effects. We have demonstrated that OSCC cells are sensitive to PCH4 and that Nur77 protein translocation from the nucleus to the cytoplasm might be associated with the induction of apoptosis by PCH4. These results indicate that PCH4 may serve as a potential anti-tumor drug for OSCC therapy.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Benzofuranos/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Etilaminas/farmacología , Neoplasias de la Boca/tratamiento farmacológico , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Anhídridos Ftálicos/farmacología , Transporte Activo de Núcleo Celular , Animales , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias de la Boca/genética , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/patología , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , ARN Mensajero/metabolismo , Factores de Tiempo , Carga Tumoral/efectos de los fármacos , Regulación hacia Arriba , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Telomerase is widely expressed in most human cancers, but is almost undetectable in normal somatic cells and is therefore a potential drug target. Using the human telomerase promoter platform, the naturally occurring compound butylidenephthalide (BP) was selected for subsequent investigation of antitumor activity in vitro and in vivo. METHODS: We treated human glioblastoma cells with BP and found a dose-dependent decrease in human telomerase reverse transcriptase (hTERT) mRNA expression and a concomitant increase in p16 and p21 expression. Because c-Myc and Sp1 are involved in transcriptional regulation of hTERT, the effect of BP on c-Myc and Sp1 expression was examined. RESULTS: Using electrophoretic mobility shift assays and western blotting, we showed that BP represses hTERT transcriptional activity via downregulation of Sp1 expression. Using the telomerase repeat amplification protocol, an association between BP concentration and suppression of telomerase activity, induction of human glioblastoma senescence, and inhibition of cellular proliferation was identified. This was supported by a mouse xenograft model, in which BP repressed telomerase and inhibited tumor proliferation, resulting in tumor senescence. Overexpression of hTERT restored telomerase activity in human glioblastoma cells and overcame replicative senescence. CONCLUSIONS: These findings suggest that BP inhibits proliferation and induces senescence in human glioblastomas by downregulating hTERT expression and consequently telomerase activity. This is the first study to describe regulation of telomerase activity by BP in human glioblastomas.
Asunto(s)
Neoplasias Encefálicas/enzimología , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Glioblastoma/enzimología , Anhídridos Ftálicos/farmacología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Telomerasa/metabolismo , Animales , Western Blotting , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Senescencia Celular/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Ensayo de Cambio de Movilidad Electroforética , Citometría de Flujo , Genes p16 , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Humanos , Técnicas para Inmunoenzimas , Ratones , Ratones Desnudos , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-myc/genética , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Telomerasa/antagonistas & inhibidores , Telomerasa/genética , Transcripción Genética , Células Tumorales CultivadasRESUMEN
BACKGROUND: In previous study, n-butylidenephthalide (BP), a natural compound from Angelica sinensis, has anti-glioblastoma multiform (GBM) cell effects. In this study, we modified BP structure to increase anti-GBM cell effects. The anti-GBM cell effects of one derivative of BP, (Z)-N-(2-(dimethylamino)ethyl)-2-(3-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)phenoxy)acetamide (PCH4) were tested in vitro and in vivo. METHODS: MTT assay and PI/Annexin V assay were performed to evaluate the anti-GBM effects of PCH4. The Nur77 expression and translocation were assayed by RT-PCR and Western blot. The Nur77 siRNA was used to downregulate the Nur77 expression. The JNK inhibitor (SP600125) was used to block the JNK pathway. RESULTS: The anti-GBM effect of PCH4 is four times more than BP. The IC(50) of PCH4 on DBTRG-05MG cells was 50 µg/ml. Nur77 expression and translocation from the nucleus to the cytoplasm were important in PCH4-induced apoptosis. Furthermore, the downregulation of PCH4-induced Nur77 expression by Nur77 siRNA reduced PCH4-induced apoptosis. In addition, PCH4-induced apoptosis was associated with the JNK pathway. The JNK inhibitor, SP600125, inhibited Nur77 mRNA expression and reduced PCH4-induced apoptosis. CONCLUSIONS: In conclusion, PCH4, a derivative of BP, induced Nur77-mediated apoptosis via the JNK pathway and this mechanism, which is different from that of BP, may explain the increase in the anti-tumor effects on GBM.
Asunto(s)
Apoptosis/efectos de los fármacos , Benzofuranos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Etilaminas/farmacología , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Transporte de Proteínas/efectos de los fármacos , Angelica sinensis/química , Animales , Western Blotting , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Citometría de Flujo , Glioblastoma/metabolismo , Humanos , Luciferasas/metabolismo , MAP Quinasa Quinasa 4/antagonistas & inhibidores , MAP Quinasa Quinasa 4/metabolismo , Ratones , Ratones Desnudos , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/antagonistas & inhibidores , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/antagonistas & inhibidores , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Anhídridos Ftálicos/química , Anhídridos Ftálicos/farmacología , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Receptores de Esteroides/antagonistas & inhibidores , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Receptores de Hormona Tiroidea/antagonistas & inhibidores , Receptores de Hormona Tiroidea/genética , Receptores de Hormona Tiroidea/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Delayed extubation is one of postoperative pulmonary complications (PPCs). Preoperative pulmonary function test (PFT) is an important assessment for patients undergoing lung resection. Volume-oriented incentive spirometry (IS) is one of physiotherapies to prevent PPCs. Preoperative PFT and IS volume (IS-v) can reflect the physiologic conditions of respiratory system in patients planning to undergo lung resection. However, the relationship between preoperative PFT/IS-v and delayed extubation in patients undergoing lung resection remains unclear. The study investigated the risk factors and impact of delayed extubation after lung resection. We aimed to achieve early recognition of patients being at a higher risk for developing postoperative delayed extubation after lung resection. METHODS: This retrospective observational 4-year cohort study was conducted in a medical center, Taiwan. A total of 353 enrolled patients receiving thoracic surgery for lung resection were further categorized into the delayed extubation (n = 142, 40%) and non-delayed extubation (n = 211, 60%) groups. RESULTS: In multivariate logistic regression analyses, age >65 years (adjusted odds ratio [AOR]: 2.60; 95% confidence interval [CI], 1.52-4.45), American Society of Anesthesiologists score >2 (AOR: 1.72; 95% CI, 1.05-2.82), anesthesia time >6hrs (AOR: 1.80; 95% CI, 1.13-2.88), pneumonectomy (AOR: 5.58; 95% CI, 1.62-19.19), and IS-v/inspiratory capacity (IC) ratio (AOR: 2.07; 95% CI, 1.16-3.68) were associated with delayed extubation after lung resection (all p < 0.05). Patients with delayed extubation were significantly associated with a higher proportion of other pulmonary complications, reintubation, mortality, and prolonged intensive care unit and hospital stays. CONCLUSION: Older age, poor general health status, longer anesthesia time, pneumonectomy, and IS-v/IC ratio could be the independent factors predictive for delayed extubation after lung resection, which was in turn associated with worse outcomes. Preoperative PFT and IS-v were valuable for early recognition of patients being at a higher risk for developing postoperative delayed extubation after lung resection.
Asunto(s)
Extubación Traqueal , Neumonectomía/métodos , Pruebas de Función Respiratoria , Espirometría , Anciano , Femenino , Humanos , Pulmón/cirugía , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
COVID-19 has spread worldwide, including the United States, United Kingdom, and Italy, along with its site of origin in China, since 2020. The virus was first found in the Wuhan seafood market at the end of 2019, with a controversial source. The clinical symptoms of COVID-19 include fever, cough, and respiratory tract inflammation, with some severe patients developing an acute and chronic lung injury, such as acute respiratory distress syndrome (ARDS) and pulmonary fibrosis (PF). It has already claimed approximately 300 thousand human lives and the number is still on the rise; the only way to prevent the infection is to be safe till vaccines and reliable treatments develop. In previous studies, the use of mesenchymal stem cells (MSCs) in clinical trials had been proven to be effective in immune modulation and tissue repair promotion; however, their efficacy in treating COVID-19 remains underestimated. Here, we report the findings from past experiences of SARS and MSCs, and how SARS could also induce PF. Such studies may help to understand the rationale for the recent cell-based therapies for COVID-19.
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COVID-19/complicaciones , Trasplante de Células Madre Mesenquimatosas , Fibrosis Pulmonar/etiología , Animales , COVID-19/sangre , COVID-19/patología , COVID-19/terapia , Coronavirus/aislamiento & purificación , Humanos , Trasplante de Células Madre Mesenquimatosas/métodos , Fibrosis Pulmonar/sangre , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/terapia , Sistema Renina-Angiotensina , SARS-CoV-2/aislamiento & purificación , Síndrome Respiratorio Agudo Grave/sangre , Síndrome Respiratorio Agudo Grave/complicaciones , Síndrome Respiratorio Agudo Grave/patología , Síndrome Respiratorio Agudo Grave/terapia , Factor de Crecimiento Transformador beta/sangreRESUMEN
Leukocyte esterase (LE) is a useful marker that can be used in establishing a diagnosis of urinary tract infections (UTIs). The development of a UTI diagnostic method with quantitative determinations of biomarkers across all age groups is becoming more important. In this report, microfluidic resistance sensors based on silver ink (Ag ink) and silver ink mixed with ZnO nanoparticles (Ag-ZnO ink) were synthesized and coated on cellulose paper, namely LE-Ag-µPADs and LE-Ag-ZnO-µPADs, respectively, for the sensitive detection of LE. The microfluidic design increases the precision of data and further allows for quantitative determination and early detection of LE in human urine. The quantification of LE relies on the change in the resistance readout coating with Ag ink as well as Ag-ZnO ink in the detection zone. A mixture of 3-(N-tosyl-l-alaninyloxy)-5-phenylpyrrole (PE) and 1-diazo-2-naphthol-4-sulfonic acid (DAS) was deposited in the sample zone to selectively recognize LE, and the resulting nonconductive products, i.e., azo compounds, further reacted with the Ag ink and Ag-ZnO ink to increase resistance. The quantitative detectable LE concentrations between 2 to 32 (×5.2 U mL-1), i.e. ≈12 to 108 µg L-1, cover the commercial dipstick range of trace, +1 and +2. The minimum detectable concentration of LE in urine was 1 (×5.2 U mL-1). The lower concentrations of LE detectable by LE-Ag-µPADs (1-8 × 5.2 U mL-1) are below the value achieved with the ELISA LE kit. Urine samples from inpatients with indwelling urinary catheters were used, and the LE levels measured by the present device were highly correlated with those determined by a commercial urine analyser.
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Hidrolasas de Éster Carboxílico/orina , Infecciones Urinarias/diagnóstico , Hidrolasas de Éster Carboxílico/química , Humanos , Tinta , Dispositivos Laboratorio en un Chip , Técnicas Analíticas Microfluídicas , Nanopartículas/química , Naftalenosulfonatos/química , Papel , Pirroles/química , Plata/química , Infecciones Urinarias/orina , Óxido de Zinc/químicaRESUMEN
The commercially-available colorimetric urine dipstic for the early detection of urinary tract infection (UTI) has several limitations. The quantitative determination of urinary leukocyte esterase (LE) for predicting UTI remains uncertain. This study presents a paper-based analytical device to detect LE (LE-PAD) as a point-of-care quantitative test for UTI. The LE-PAD is composed of a coating of mixed 3-(N-tosyl-L-alaninyloxy)-5-phenylpyrrole (PE) and 1-diazo-2-naphthol-4-sulfonic acid (DAS) deposited onto a silver conducting film (Ag film). The LE/urine reacts with the PE and DAS, and the resulting products in turn react with the silver coating, causing a change in resistivity. The quantitative calibration curve was established in this study and has been used to analyse urine samples from inpatients with urinary catheters (n = 21). The results revealed that the level of LE determined by LE-PADs was predictive of UTI diagnosis with an area under the receiver operating characteristic curve of 0.875 (95% confidence interval, 0.704-1.000). Using an appropriate cut-off value, the sensitivity and specificity of UTI diagnosis by LE-PAD were 87.5% and 92.3%, while the LE-positivities of urine dipstics were 62.5% and 76.9%, respectively. For UTI diagnosis, the LE-PAD demonstrated positive and negative likelihood ratios of 11.38 and 0.14, suggesting that the novel LE-PAD is a reliable test.
RESUMEN
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.
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Unidades de Cuidados Intensivos/estadística & datos numéricos , Alta del Paciente/estadística & datos numéricos , Insuficiencia Respiratoria , Medición de Riesgo/métodos , Desconexión del Ventilador/efectos adversos , Anciano , Diagnóstico Precoz , Femenino , Humanos , Masculino , Valor Predictivo de las Pruebas , Proyectos de Investigación , Insuficiencia Respiratoria/diagnóstico , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/mortalidad , Estudios Retrospectivos , Taiwán/epidemiologíaRESUMEN
Although the clinical application of new drugs has been shown to be effective in slowing disease progression and improving the quality of life in patients with pulmonary fibrosis, the damaged lung tissue does not recover with these drugs. Thus, there is an urgent need to establish regenerative therapy, such as stem cell therapy or tissue engineering. Moreover, the clinical application of mesenchymal stem cell (MSC) therapy has been shown to be safe in humans with idiopathic pulmonary fibrosis (IPF). It seems that a combination of MSC transplantation and pharmaceutical therapy might have additional benefits; however, the experimental design for its efficacy is still lacking. In this review, we provide an overview of the mechanisms that were identified when IPF was treated with MSC transplantation or new drugs. To maximize the therapeutic effect, we suggest that MSC transplantation is combined with drug application for synergistic effects. This review provides clinicians and scientists with the most efficient medical options, in the hope that this will spur on future research and lead to an eventual cure for this disease.
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Life-long smoking cessation is a critical public health objective, but it is difficult for numerous people. This study aimed to identify the independent predictors of 1-year abstinence in smokers motivated to quit and participating in an intervention program. This 6-year retrospective observational cohort study was conducted in smokers who participated in an intervention program. The exhaled carbon monoxide (CO) was sequentially measured on day 1, 8, 15, and 22 of the intervention program. The primary outcome measure was smoking status at 1 year of follow-up. A total of 162 participants were enrolled and divided into a successful quit group (n = 52) and unsuccessful quit group (n = 110). Using a multivariate logistic regression analysis, we reported that the intention to quit (adjusted odds ratio [AOR] = 1.475, 95% confidence interval [CI] = 1.169-1.862, P-value = 0.001), varenicline use (AOR = 3.199, 95% CI = 1.290-7.934, P -value = 0.012) and the exhaled CO level on day 8 (AOR = 0.937, 95% CI = 0.885-0.992, P-value = 0.025) independently predicted 1-year smoking cessation. Moreover, the level of exhaled CO < 4.5 parts per million on day 8 significantly predict successful 1-year smoking cessation (area under curve 0.761, sensitivity 88.2%, and specificity 57.8%, P-value < 0.001). These independent predictors including intention to quit, varenicline use, and exhaled CO level on day 8, may help primary care physicians rearrange resources and refine the strategies for intervention programs to achieve a higher rate of long-term smoking cessation. QUITTING SMOKING: IDENTIFYING PREDICTORS OF SUCCESS: Researchers in Korea identify key predictors that pinpoint people most likely to quit smoking successfully during intervention programs. Millions are spent each year supporting people to quit smoking. However, successful quitters remain in the minority, with only 9-35 per cent of those in intervention programs abstaining for at least a year. Hsin-Kuo Ko at Taipei Veterans General Hospital and co-workers identified key independent indicators of successful abstinence in 162 smokers attending an intervention program. Alongside having a high intention to quit and using varenicline medication, a potential predictor is having an exhaled carbon monoxide (CO) level of less than 4.5 parts-per-million by day 8 of the course. Exhaled CO is higher in smokers than in non-smokers. Measuring CO levels one week into courses may be a useful biomarker to identify those fully committed to quit.
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Monóxido de Carbono/análisis , Cese del Hábito de Fumar/estadística & datos numéricos , Factores de Edad , Espiración , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores Sexuales , Fumar/epidemiología , Prevención del Hábito de Fumar/métodosRESUMEN
The endoplasmic reticulum (ER) is a major site of cellular homeostasis regulation. Under the ER stress condition, Glioblastoma multiform (GBM) cells activate the unfolded protein response. In this study, we discovered isochaihulactone, a natural compound extracted from the Chinese traditional herb Nan-Chai-Hu, which can disrupt ER homeostasis in GBM cell lines. It can induce DNA damage inducible transcript 3 (DDIT3) expression which is independent of 78 kDa glucose-regulated protein (GRP78) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) expression. Flow cytometry results revealed that isochaihulactone trigger the cell cycle arrest at G2/M phase and apoptosis in GBM cells. Isochaihulactone induced DDIT3 led to the expression of NAG-1. The in vivo study showed that isochaihulactone suppressed tumor growth, and DDIT3 and Caspase3 overexpressed in the xenograft model, which is consistent with the in vitro study. Overall, the data revealed that isochaihulactone disrupted ER homeostasis in cancer cells by increasing DDIT3 and NAG-1 expression. Our finding also provides a therapeutic strategy by using isochaihulactone for GBM treatment.
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4-Butirolactona/análogos & derivados , Antineoplásicos Fitogénicos/administración & dosificación , Benzodioxoles/administración & dosificación , Glioblastoma/tratamiento farmacológico , Factor de Transcripción CHOP/metabolismo , eIF-2 Quinasa/metabolismo , 4-Butirolactona/administración & dosificación , 4-Butirolactona/farmacología , Animales , Antineoplásicos Fitogénicos/farmacología , Benzodioxoles/farmacología , Caspasa 3/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/metabolismo , Factor 15 de Diferenciación de Crecimiento/metabolismo , Humanos , Ratones , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The treatment of liver fibrosis has clinical limitations because of its multiple etiologies, such as epithelial-mesenchymal transition (EMT) promotion, cell regeneration and remodeling dysfunction, inflammatory cell activation, and scar tissue deposition. These factors might be considered as a new target for the fibrotic microenvironment, leading to increased fibrogenesis and liver fibrosis. Here, we investigate a small molecule named butylidenephthalide (BP) and its multiple effects on liver fibrosis treatment. Thioacetamide was used in vivo to induce chronic liver fibrosis. BP was administered orally in rats for a period of 2 and 4 weeks, which resulted in a significantly reduced fibrosis score (p < 0.05) and (p < 0.001), respectively. The inflammatory reaction of macrophage infiltration were reduced in the administration of BP, which led to the decrease in the transaminase levels. Moreover, we also found liver functions recovering (due to the increased serum albumin and reduced prothrombin time) where liver cells regenerated, which can be seen in the increase of Ki-67 on Oval cell. In addition, the fibrotic scar was also reduced, along with the expression of matrix metalloprotease by hepatic stellate cell. Furthermore, regarding the mechanism/study of EMT reduced by BP, the knockdown of BMP-7, which could reduce α-SMA expression, was mediated by the regulation of TGF-ß, which implies its major role on EMT. Finally, in the in vivo study, BP treatment of liver fibrosis was reduced by Bmp7 knockdown in zebrafish, suggesting that BP leads to the reduction of liver fibrosis, which also depends on BMP-7 induction. These results suggest that BP had multiple targets for treating liver fibrosis in the following ways: reduction of EMT, decreasing inflammatory reaction, and liver cell proliferation. This multiple targets approach provided a new mechanism to treat liver injury and fibrosis.
RESUMEN
INTRODUCTION: Respiratory neuromuscular impairment severity is known to predict weaning outcome among patients with cervical spinal cord injury; however, the impact of non-neuromuscular complications remains unexplored. This study was to evaluate possible neuromuscular and non-neuromuscular factors that may negatively impact weaning outcome. METHODS: From September 2002 to October 2012, acute traumatic cervical spinal cord injury patients who had received mechanical ventilation for >48h were enrolled and divided into successful (n=54) and unsuccessful weaning groups (n=19). Various neuromuscular, non-neuromuscular factors and events during the intensive care unit stay were extracted from medical charts and electronic medical records. Variables presenting with a significant difference (p<0.2) between these two groups were included in the univariate analysis. Following univariate analysis, those significantly different variables (p<0.05) were subjected to multivariate logistic regression to identify independent predictors of unsuccessful weaning. RESULTS: Compared to successful weaning patients, unsuccessful weaning patients were older; more often had high level of cervical spinal cord injury (C1-3), lower pulse rates, and lower Glasgow Coma Scale score on admission, higher peak blood urea nitrogen, lower trough albumin, and lower trough blood leukocyte counts. Furthermore, unsuccessful weaning patients had a higher incidence of pneumonia, acute respiratory distress syndrome, shock and acute kidney injury during the intensive care unit stay. Multivariate logistic regression analysis revealed acute kidney injury and high level of cervical spinal cord injury were independent risk factors for failure of weaning. Importantly, patients with both risk factors showed a large increase in odds ratio for unsuccessful weaning from mechanical ventilation (p<0.001). CONCLUSIONS: The presence of acute kidney injury during the intensive care unit stay and high level of cervical spinal injury are two independent risk factors that synergistically work together producing a negative impact on weaning outcome.
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Lesión Renal Aguda/terapia , Médula Cervical/lesiones , Respiración Artificial , Insuficiencia Respiratoria/terapia , Traumatismos de la Médula Espinal/terapia , Desconexión del Ventilador , Lesión Renal Aguda/mortalidad , Lesión Renal Aguda/fisiopatología , Factores de Edad , Comorbilidad , Femenino , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Selección de Paciente , Valor Predictivo de las Pruebas , Pronóstico , Insuficiencia Respiratoria/mortalidad , Estudios Retrospectivos , Factores de Riesgo , Traumatismos de la Médula Espinal/mortalidad , Traumatismos de la Médula Espinal/fisiopatología , Taiwán/epidemiologíaRESUMEN
Cerebral palsy (CP) is a complicated disease with varying causes and outcomes. It has created significant burden to both affected families and societies, not to mention the quality of life of the patients themselves. There is no cure for the disease; therefore, development of effective therapeutic strategies is in great demand. Recent advances in regenerative medicine suggest that the transplantation of stem cells, including embryonic stem cells, neural stem cells, bone marrow mesenchymal stem cells, induced pluripotent stem cells, umbilical cord blood cells, and human embryonic germ cells, focusing on the root of the problem, may provide the possibility of developing a complete cure in treating CP. However, safety is the first factor to be considered because some stem cells may cause tumorigenesis. Additionally, more preclinical and clinical studies are needed to determine the type of cells, route of delivery, cell dose, timing of transplantation, and combinatorial strategies to achieve an optimal outcome.
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Parálisis Cerebral/terapia , Animales , Parálisis Cerebral/epidemiología , Parálisis Cerebral/fisiopatología , Ensayos Clínicos como Asunto , Trasplante de Células Madre de Sangre del Cordón Umbilical , Modelos Animales de Enfermedad , Células Madre Embrionarias/citología , Células Madre Embrionarias/trasplante , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/trasplante , Trasplante de Células Madre Mesenquimatosas , Células-Madre Neurales/citología , Células-Madre Neurales/trasplante , Factores de RiesgoRESUMEN
The polyglutamine (polyQ) diseases are a group of neurodegenerative disorders caused by expanded cytosine-adenine-guanine (CAG) repeats encoding a long polyQ tract in the respective proteins. To date, a total of nine polyQ disorders have been described: six spinocerebellar ataxias (SCA) types 1, 2, 6, 7, 17; Machado-Joseph disease (MJD/SCA3); Huntington's disease (HD); dentatorubral pallidoluysian atrophy (DRPLA); and spinal and bulbar muscular atrophy, X-linked 1 (SMAX1/SBMA). PolyQ diseases are characterized by the pathological expansion of CAG trinucleotide repeat in the translated region of unrelated genes. The translated polyQ is aggregated in the degenerated neurons leading to the dysfunction and degeneration of specific neuronal subpopulations. Although animal models of polyQ disease for understanding human pathology and accessing disease-modifying therapies in neurodegenerative diseases are available, there is neither a cure nor prevention for these diseases, and only symptomatic treatments for polyQ diseases currently exist. Long-term pharmacological treatment is so far disappointing, probably due to unwanted complications and decreasing drug efficacy. Cellular transplantation of stem cells may provide promising therapeutic avenues for restoration of the functions of degenerative and/or damaged neurons in polyQ diseases.