RESUMO
BACKGROUND: Alveolar capillary endothelial cell (EC) injury has a pivotal role in driving acute respiratory distress syndrome (ARDS) progression and maintaining endothelial homeostasis. A previous ex vivo study revealed that overexpression of homeobox B4 (HOXB4) in bone marrow mesenchymal stem cells (BMSCs) enhanced protection against lipopolysaccharide (LPS)-induced EC injury by activating the Wnt/ß-catenin pathway. This in vivo study was performed to verify whether BMSCs overexpressing HOXB4 exert similar protective effects on LPS-induced acute lung injury (ALI) in an animal model. METHODS: The ALI rat model was established by intraperitoneal injection of LPS. Wildtype BMSCs or BMSCs overexpressing HOXB4 were then injected via the tail vein. The lung characteristics of rats were visualized by computed tomography. Lung histopathological characteristics and collagen deposition were assessed by hematoxylin-eosin and Masson's staining, respectively, which were combined with the lung wet/dry ratio and proinflammatory factor levels in bronchoalveolar lavage fluid to further evaluate therapeutic effects. Expression of ß-catenin and VE-cadherin was assessed by western blotting and immunofluorescence. RESULTS: Compared with wildtype BMSCs, overexpression of HOXB4 optimized the therapeutic effects of BMSCs, which manifested as improvements in lung exudation and histopathological features, reduced lung collagen deposition, amelioration of lung permeability, attenuation of lung inflammation, and enhanced expression of ß-catenin and VE-cadherin proteins. CONCLUSIONS: HOXB4-overexpressing BMSCs optimized the protective effect against LPS-induced ALI by partially activating Wnt/ß-catenin signaling.
RESUMO
Background: To date, no studies have investigated the association between red blood cell distribution width (RDW)-to-platelet ratio (RPR) and readmission rates among patients with heart failure (HF). As such, the present study aimed to examine the relationship between RPR and readmission rates in patients with HF. Methods: Data for this study were obtained from the Fourth People's Hospital (Zigong, Sichuan Province, China). Patients were diagnosed with HF in accordance with European Society of Cardiology criteria. The primary outcome was the 28-day readmission rate. Various logistic regression models were constructed to explore the association between RPR and the 28-day readmission rate. Results: The study comprised 1978 patients with HF, with a 28-day readmission rate of 6.98%. RPR emerged as an independent risk factor for 28-day readmission, evidenced by consistent results across the various regression-adjusted models. The covariate-adjusted propensity score model demonstrated that every 0.1 increase in RPR was associated with an 8.2% increase in 28-day readmission rate (odds ratio [OR] 1.082 [95% confidence interval (CI) 1.012-1.158]; P = 0.0212). Similarly, each 0.1 change in RPR was associated with a 9.8% (OR 1.098 [95% CI 1.014-1.188]) and 7.3% (OR 1.073 [95% CI 0.991-1.161]) increase in 3- and 6-month readmission rates, respectively. However, RPR was not statistically associated with the 6-month readmission rate. Curve fit plots illustrated a nonlinear positive correlation between RPR and 28-day, and 3- and 6-month readmissions. Moreover, the effects of RPR on 28-day, and 3- and 6-month readmission rates remained robust across subgroup variables in stratified analysis. Finally, the effect sizes of pooled multiply imputed data were consistent with the original data, suggesting robust results. Conclusion: RPR was an independent risk factor for 28-day readmission among patients with HF and also demonstrated modest predictive value for readmissions at 3 and 6 months, despite being non-significant for the 6-month readmission rate. Early identification of patients with HF with elevated RPR would facilitate management and may confer favorable effects on prognosis.
RESUMO
Background: Observational studies have reported an association between circulating cytokines and sepsis. However, the precise causal relationship between these factors remains unclear. The objective of this study was to explore the causal link between circulating cytokines and sepsis using genetic data within the framework of Mendelian Randomization (MR). Methods: We performed a two-sample MR analysis to investigate this causality relationship in individuals of European ancestry. The publicly available genome-wide association studies (GWAS) statistics were used. We selected eligible instrumental single nucleotide polymorphisms (SNPs) that were significantly related to the circulating cytokines. Multiple MR analysis approaches were carried out, which included inverse variance weighted (IVW), Weighted Median, MR-Egger, Weighted Mode, Simple Mode, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods. Results: We found evidence to support the causal role of genetically predicted circulating levels on decreased risk of sepsis, including RANTES (OR = 0.920, 95% CI: 0.849-0.997, P = 0.041) and basic fibroblast growth factor (basic-FGF) (OR = 0.869, 95% CI: 0.766-0.986, P = 0.029). Additionally, MR analysis positive causal association of between beta-nerve growth factor (ß-NGF) and sepsis (OR = 1.120, 95% CI: 1.037-1.211, P = 0.004). The results of MR-Egger, Weighted Median, Weighted Mode, and Simple Mode methods were consistent with the IVW estimates. Sensitivity analysis showed no horizontal pleiotropy to bias the causal estimates. Conclusion: This MR study provides first novel evidence that genetically predicted causal association of circulating levels of RANTES, basic-FGF, and ß-NGF with altered sepsis risk. The findings shed light on the potential involvement of these cytokines in sepsis pathogenesis. Although requiring additional confirmation, the results contribute new insights into cytokine mediators in sepsis and suggest promising future research directions.
Assuntos
Estudo de Associação Genômica Ampla , Sepse , Humanos , Análise da Randomização Mendeliana , Fator de Crescimento Neural , Sepse/genética , Citocinas/genética , Fator 2 de Crescimento de FibroblastosRESUMO
BACKGROUND: Sepsis is an important public health issue, and it is urgent to develop valuable indicators to predict the prognosis of sepsis. Our study aims to assess the predictive value of ICU admission (Neutrophil + Monocyte)/lymphocyte ratio (NMLR) on the 30-day mortality of sepsis patients. METHODS: A retrospective analysis was conducted in septic patients, and the data were collected from Medical Information Mart for Intensive Care IV (MIMIC-IV). Univariate and multivariate Cox regression analyses were conducted to investigate the relation between ICU admission NMLR and 30-day mortality. Restricted cubic spline (RCS) was performed to determine the optimum cut-off value of ICU admission NMLR. Survival outcomes of the two groups with different ICU admission NMLR levels were estimated using the Kaplan-Meier method and compared by the log-rank test. RESULTS: Finally, 7292 patients were recruited in the study, of which 1601 died within 30 days of discharge. The non-survival group had higher ICU admission NMLR values than patients in the survival group (12.24 [6.44-23.67] vs. 8.71 [4.81-16.26], P < 0.001). Univariate and multivariate Cox regression analysis demonstrated that ICU admission NMLR was an independent prognostic predictor on 30-day mortality (Univariate: P < 0.001; multivariate: P = 0.011). The RCS model demonstrated the upturn and non-linear relationship between ICU admission NMLR and 30-day mortality (Nonlinearity: P = 0.0124). According to the KM curve analysis,30-day survival was worse in the higher ICU admission NMLR group than that in the lower ICU admission NMLR group (Log rank test, P < 0.0001). CONCLUSION: The elevated ICU admission NMLR level is an independent risk factor for high 30-day mortality in patients with sepsis.
Assuntos
Monócitos , Sepse , Humanos , Estudos Retrospectivos , Neutrófilos , Unidades de Terapia Intensiva , Curva ROC , Prognóstico , LinfócitosRESUMO
Background: Sepsis is an important public health issue, and it is urgent to develop valuable indicators to predict the prognosis of sepsis. Our study aims to assess the predictive value of ICU admission (Neutrophil + Monocyte)/lymphocyte ratio (NMLR) on the 30-day mortality of sepsis patients. Methods: A retrospective analysis was conducted in septic patients, and the data were collected from Medical Information Mart for Intensive Care IV (MIMIC-IV). Univariate and multivariate Cox regression analyses were conducted to investigate the relation between ICU admission NMLR and 30-day mortality. Restricted cubic spline (RCS) was performed to determine the optimum cut-off value of ICU admission NMLR. Survival outcomes of the two groups with different ICU admission NMLR levels were estimated using the Kaplan-Meier method and compared by the log-rank test. Results: Finally, 7292 patients were recruited in the study, of which 1601 died within 30 days of discharge. The non-survival group had higher ICU admission NMLR values than patients in the survival group (12.24 [6.44-23.67] vs. 8.71 [4.81-16.26], P < 0.001). Univariate and multivariate Cox regression analysis demonstrated that ICU admission NMLR was an independent prognostic predictor on 30-day mortality (Univariate: P < 0.001; multivariate: P=0.011). The RCS model demonstrated the upturn and non-linear relationship between ICU admission NMLR and 30-day mortality (Nonlinearity: P=0.0124). According to the KM curve analysis,30-day survival was worse in the higher ICU admission NMLR group than that in the lower ICU admission NMLR group (Log rank test, P<0.0001). Conclusion: The elevated ICU admission NMLR level is an independent risk factor for high 30-day mortality in patients with sepsis.
RESUMO
BACKGROUND: Psoriasis is a chronic, complicated, and recurrent inflammatory skin disease, whose precise molecular mechanisms need to be further explored. The lncRNA bladder cancer-associated transcript 1 (BLACAT1) is aberrantly expressed in many cancers and associated with cellular hyperproliferation and may play a role in the pathogenesis of psoriasis. Thus, this study aimed at identifying the primary mechanism associated with BLACAT1 in psoriasis pathogenesis. MATERIALS AND METHODS: Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was performed to detect the expression of BLACAT1 in psoriasis tissues. Cell proliferation and apoptosis were assessed using cell counting kit-8 and apoptosis assays, respectively. In vivo experiments and histopathological examinations were performed to investigate the effects of BLACAT1 on psoriasis. Dual-luciferase Reporter and RNA immunoprecipitation assays were used to evaluate the relationship among BLACAT1 and miR-149-5p and AKT1. RESULTS: BLACAT1 was upregulated in psoriasis tissues. Overexpression exacerbated the clinical manifestation of psoriasis and increased the epidermal thickness in imiquimod-induced mice. BLACAT1 could promote proliferation and inhibit apoptosis of keratinocytes. Further studies demonstrated that BLACAT1 positively regulated AKT1 expression, functioning as a competing endogenous RNA (ceRNA) by sponging miR-149-5p. CONCLUSIONS: The combination of lncRNA BLACAT1 and miR-149-5p regulates AKT1 expression and promotes psoriasis formation thus may provide a new direction for psoriasis treatment.
Assuntos
MicroRNAs , Psoríase , RNA Longo não Codificante , Neoplasias da Bexiga Urinária , Animais , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Psoríase/genética , Queratinócitos/metabolismo , Apoptose/genética , Proliferação de CélulasRESUMO
Background: Mesenchymal stem cell- (MSC-) based cell and gene therapies have made remarkable progress in alleviating acute lung injury/acute respiratory distress syndrome (ALI/ARDS). However, the benefits of Forkhead box protein M1 (FoxM1) gene-modified MSCs in the treatment of ALI have not been studied. Methods: We evaluated the therapeutic effects of FoxM1-modified MSCs in ALI mice induced by lipopolysaccharide (LPS) by quantifying the survival rate, lung weight ratio (wet/dry), and contents of bronchoalveolar lavage fluid. In addition, microcomputed tomography, histopathology, Evans Blue assay, and quantification of apoptosis were performed. We also explored the underlying mechanism by assessing Wnt/ß-catenin signaling following the treatment of mice with FoxM1-modified MSCs utilizing the Wnt/ß-catenin inhibitor XAV-939. Results: Compared with unmodified MSCs, transplantation of FoxM1-modified MSCs improved survival and vascular permeability; reduced total cell counts, leukocyte counts, total protein concentrations, and inflammatory cytokines in BALF; attenuated lung pathological impairments and fibrosis; and inhibited apoptosis in LPS-induced ALI/ARDS mice. Furthermore, FoxM1-modified MSCs maintained vascular integrity during ALI/ARDS by upregulating Wnt/ß-catenin signaling, which was partly reversed via a pathway inhibitor. Conclusion: Overexpression of FoxM1 optimizes the treatment action of MSCs on ALI/ARDS by inhibiting inflammation and apoptosis and restoring vascular integrity partially through Wnt/ß-catenin signaling pathway stimulation.
Assuntos
Lesão Pulmonar Aguda , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Síndrome do Desconforto Respiratório , Animais , Camundongos , Lesão Pulmonar Aguda/induzido quimicamente , beta Catenina/metabolismo , Medula Óssea/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/patologia , Células-Tronco Mesenquimais/metabolismo , Síndrome do Desconforto Respiratório/metabolismo , Via de Sinalização Wnt , Microtomografia por Raio-XRESUMO
BACKGROUND: Injury of alveolar epithelial cells and capillary endothelial cells is crucial in the pathogenesis of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Mesenchymal stem cells (MSCs) are a promising cell source for ALI/ARDS treatment. Overexpression of Fork head box protein M1 (FoxM1) facilitates MSC differentiation into alveolar type II (AT II) cells in vitro. Moreover, FoxM1 has been shown to repair the endothelial barrier. Therefore, this study explored whether overexpression of FoxM1 promotes the therapeutic effect of bone marrow-derived MSCs (BMSCs) on ARDS by differentiation of BMSCs into AT II cells or a paracrine mechanism. METHODS: A septic ALI model was established in mice by intraperitoneal administration of lipopolysaccharide. The protective effect of BMSCs-FoxM1 on ALI was explored by detecting pathological variations in the lung, total protein concentration in bronchoalveolar lavage fluid (BALF), wet/dry (W/D) lung weight ratio, oxidative stress levels, cytokine levels, and retention of BMSCs in the lung. In addition, we assessed whether FoxM1 overexpression promoted the therapeutic effect of BMSCs on ALI/ARDS by differentiating into AT II cells using SPC-/- mice. Furthermore, the protective effect of BMSCs-FoxM1 on lipopolysaccharide-induced endothelial cell (EC) injury was explored by detecting EC proliferation, apoptosis, scratch wounds, tube formation, permeability, and oxidative stress, and analyzing whether the Wnt/ß-catenin pathway contributes to the regulatory mechanism in vitro using a pathway inhibitor. RESULTS: Compared with BMSCs-Vector, treatment with BMSCs-FoxM1 significantly decreased the W/D lung weight ratio, total BALF protein level, lung injury score, oxidative stress, and cytokine levels. With the detected track of BMSCs-FoxM1, we observed a low residency rate and short duration of residency in the lung. Notably, SPC was not expressed in SPC-/- mice injected with BMSCs-FoxM1. Furthermore, BMSCs-FoxM1 enhanced EC proliferation, migration, and tube formation; inhibited EC apoptosis and inflammation; and maintained vascular integrity through activation of the Wnt/ß-catenin pathway, which was partially reversed by XAV-939. CONCLUSION: Overexpression of FoxM1 enhanced the therapeutic effect of BMSCs on ARDS, possibly through a paracrine mechanism rather than by promoting BMSC differentiation into AT II cells in vivo, and prevented LPS-induced EC barrier disruption partially through activating the Wnt/ß-catenin signaling pathway in vitro.
Assuntos
Proteína Forkhead Box M1 , Lesão Pulmonar , Células-Tronco Mesenquimais , Síndrome do Desconforto Respiratório , Animais , Camundongos , beta Catenina/metabolismo , Células da Medula Óssea , Citocinas/metabolismo , Células Endoteliais/metabolismo , Lipopolissacarídeos/toxicidade , Células-Tronco Mesenquimais/metabolismo , Síndrome do Desconforto Respiratório/terapia , Proteína Forkhead Box M1/genéticaRESUMO
Livedoid vasculopathy is a chronic, recurrent skin disorder. It seriously affects the quality of patients' life. However, the pathogenesis has not been fully identified yet. Here, this retrospective study describes the successful use of anti-TNF-α agent adalimumab in three cases of refractory livedoid vasculopathy, which has not been reported previously. In addition, we provide some clinical evidence that adalimumab therapy is efficient in improving skin lesions and relieving the pain of livedoid vasculopathy.
RESUMO
BACKGROUND: Lung endothelial barrier injury plays a crucial role in the pathophysiology of acute respiratory distress syndrome. It has been demonstrated that bone marrow-derived mesenchymal stem cells-conditioned medium (BMSCs-CM) and ghrelin have a protective effect. This study investigated if ghrelin pretreatment enhanced the protective effect of BMSCs-CM on lipopolysaccharide (LPS)-induced endothelial cell injury. METHODS: BMSCs were isolated from rat bone marrow, expanded, then phenotypically tested for mesenchymal stem cell-identifying criteria by flow cytometry. The effects of the conditioned medium derived from ghrelin-pretreated BMSCs (BMSCs-ghrelin-pretreated-CM) on LPS-injured endothelial cells were evaluated by migration, apoptosis, permeability, and pro-inflammatory factor (e.g., tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6) assays in endothelial cells. Further, AKT/GSK3ß pathway activation in endothelial cells was examined by Western blot, and the gene expression profiles of ghrelin-pretreated BMSCs were examined by RNA sequencing. RESULTS: BMSCs-ghrelin-pretreated-CM had a greater protective effect on LPS-induced endothelial cell injury than BMSCs-CM by improving cell migration, alleviating apoptosis, and reducing endothelial permeability and the release of pro-inflammatory factors in endothelial cells. The mechanism is partly related to AKT/GSK3ß pathway activation after BMSCs-ghrelin-pretreated-CM treatment. There were five upregulated candidate genes (Wnt5a [i.e., Wnt Family Member 5A], S100b [i.e., S100 Calcium-Binding Protein B], Bmp2 [i.e., Bone Morphogenetic Protein 2], Id4 [i.e., Inhibitor Of DNA Binding 4], and PTHLH [i.e., Parathyroid Hormone Like Hormone]) in BMSCs after ghrelin treatment, and all were associated with AKT pathway activation and endothelial function. CONCLUSIONS: Ghrelin pretreatment enhanced the protective effect of BMSCs-CM on LPS-induced endothelial cell injury, partly by activating the AKT/GSK3ß pathway.
Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Animais , Medula Óssea , Células da Medula Óssea , Meios de Cultivo Condicionados/farmacologia , Células Endoteliais/metabolismo , Grelina/metabolismo , Grelina/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Lipopolissacarídeos/farmacologia , Células-Tronco Mesenquimais/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de SinaisRESUMO
Background: Hyperglycemia is one of the poor prognostic factors in critical ill sepsis patients with diabetes. We aimed to assess the interaction between admission glucose level and clinical endpoints in sepsis patients with diabetes admitted in the intensive care unit (ICU). Methods: Data from the Medical Information Mart Intensive Care III database were used in this study. The study primary endpoint was 28-day mortality after ICU admission. Multivariate Cox regression models were used to explore the association between admission glucose level and the primary endpoint. Results: We included 3,500 sepsis patients with diabetes. Of participants with no hyperglycemia, mild hyperglycemia, and severe hyperglycemia, no differences were evident in hospital mortality, ICU mortality, or 28-day mortality (all P >0.05). The multivariable Cox regression analysis demonstrated that severe hyperglycemia did not increase the risk of 28-day mortality (hazard ratio [HR]=1.06, 95% confidence interval [CI]: 0.86-1.31, P=0.5880). Threshold effects analysis identified the inflection points for 28-day mortality as 110 mg/dl and 240 mg/dl. The HRs for 28-day mortality were 0.980 in the <110 mg/dl and 1.008 in the >240 mg/dl. A short-term survival advantage was observed in the 110-240 mg/dl group compared with that in the <110 mg/dl group; meanwhile, no adverse hazard was detected in the >240 mg/dl group. In the stratified analyses, the association effect between the three glucose groups (<110 mg/dl, 110-240 mg/dl, and ≥240 mg/dl) and 28-day mortality was consistent in terms of different sequential organ failure assessment (SOFA) scores and infection sites. The 28-day mortality of the 110-240 mg/dl group with a SOFA score of ≥10 was lower than that of the <110 mg/dl group (HR=0.61, 95% CI: 0.38-0.98). Conclusion: Admission hyperglycemia was not a risk factor for short-term prognosis in critical ill sepsis patients with diabetes; a lower admission blood glucose level was associated with increased risk of poor prognosis. The potential benefit of higher admission glucose level on 28-day mortality in patients with a more severe condition remains a concern.
Assuntos
Diabetes Mellitus , Hiperglicemia , Sepse , Humanos , Estado Terminal/terapia , Estudos Retrospectivos , Hiperglicemia/complicações , Diabetes Mellitus/epidemiologia , Sepse/complicações , GlucoseRESUMO
Pulmonary endothelial barrier dysfunction is a major pathophysiology observed in acute respiratory distress syndrome (ARDS). Ghrelin, a key regulator of metabolism, has been shown to play protective roles in the respiratory system. However, its effects on lipopolysaccharide (LPS)-induced pulmonary endothelial barrier injury are unknown. In this study, the effects of ghrelin on LPS-induced ARDS and endothelial cell injury were evaluated in vivo and in vitro. In vivo, mice treated with LPS (3 mg/kg intranasal application) were used to establish the ARDS model. Annexin V/propidium iodide apoptosis assay, scratch-wound assay, tube formation assay, transwell permeability assay, and Western blotting experiment were performed to reveal in vitro effects and underlying mechanisms of ghrelin on endothelial barrier function. Our results showed that ghrelin had protective effects on LPS-induced ARDS and endothelial barrier disruption by inhibiting apoptosis, promoting cell migration and tube formation, and activating the PI3K/AKT signaling pathway. Furthermore, ghrelin stabilized LPS-induced endothelial barrier function by decreasing endothelial permeability and increasing the expression of the intercellular junction protein vascular endothelial cadherin. LY294002, a specific inhibitor of the PI3K pathway, reversed the protective effects of ghrelin on the endothelial cell barrier. In conclusion, our findings indicated that ghrelin protected against LPS-induced ARDS by impairing the pulmonary endothelial barrier partly through activating the PI3K/AKT pathway. Thus, ghrelin may be a valuable therapeutic strategy for the prevention or treatment of ARDS.
Assuntos
Grelina/metabolismo , Síndrome do Desconforto Respiratório/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Feminino , Grelina/genética , Grelina/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/metabolismo , Junções Intercelulares/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Síndrome do Desconforto Respiratório/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
PURPOSE: Pulmonary vascular endothelial cell (EC) injury is recognized as one of the pathological factors of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Bone marrow mesenchymal stem cell (BMSC)-based cytotherapy has attracted substantial attention over recent years as a promising therapeutic approach for ALI/ARDS; however, its use remains limited due to inconsistent efficacy. Currently, gene modification techniques are widely applied to MSCs. In the present study, we aimed to investigate the effect of BMSCs overexpressing Homeobox B4 (HOXB4) on lipopolysaccharide (LPS)-induced EC injury. METHODS: We used LPS to induce EC injury and established EC-BMSC coculture system using transwell chambers. The effect of BMSCs on ECs was explored by detecting EC proliferation, apoptosis, migration, tube formation, and permeability, and determining whether the Wnt/ß-catenin pathway is involved in the regulatory mechanism using XAV-939, inhibitor of Wnt/ ß-catenin. RESULTS: As compared to BMSCWT, BMSCHOXB4 coculture promoted EC proliferation, migration, and tube formation after LPS stimulation and attenuated LPS-induced EC apoptosis and vascular permeability. Mechanistically, BMSCHOXB4 coculture prevented LPS-induced EC injury by activating the Wnt/ß-catenin pathway, which is partially reversible by XAV-939. When cocultured with BMSCHOXB4, pro-inflammatory factors were dramatically decreased and anti-inflammatory factors were greatly increased in the EC medium compared to those in the LPS group (P<0.05). Additionally, when compared to BMSCWT coculture, the BMSCHOXB4 coculture showed an enhanced modulation of IL-6, TNF-α, and IL-10, but there was no statistically significant effect on IL-1ß and IL-4. CONCLUSION: Coculturing of BMSCHOXB4 prevented LPS-induced EC injury by reversing the inactivation of the Wnt/ß-catenin signaling pathway. An in vivo study remains warranted to ascertain whether engraftment of BMSCHOXB4 can be an attractive strategy for the treatment of ALI/ARDS.
RESUMO
PURPOSE: To investigate the association of cardiac Troponin T (cTnT) with prognosis in critically ill patients without myocardial infarction. METHODS: Adult patients admitted to the intensive care units (ICUs) of the Beth Israel Deaconess Medical Center between 2008 and 2019 who were free of myocardial infarction with a length of ICU stay ≥24 hours and available cTnT records within 24 hours before and after ICU admission were included. The association between cTnT on ICU admission and hospital mortality was evaluated by multivariable logistic regression analysis. The discrimination capacity of cTnT on ICU admission for predicting hospital mortality was examined by receiver operating characteristic (ROC) analysis. RESULTS: A total of 2960 patients were included. Elevated cTnT (>0.01 ng/mL) was observed in 2730 (92.23%) patients with a higher hospital mortality compared to normal cTnT (11.21% versus 7.39%, P=0.075). There was no statistically significant association between elevated cTnT on ICU admission and hospital mortality (adjusted odds ratio 1.50, 95% confidence interval (CI) 0.88-2.57). Poor discrimination capacity was found for cTnT on ICU admission to predict hospital mortality (area under the ROC curve 0.48, 95% CI 0.44-0.53). CONCLUSION: cTnT on ICU admission has limited prognostic value in critically ill patients without myocardial infarction.
RESUMO
BACKGROUND: Currently, there have been studies showing a correlation between sex differences and prognosis. Nevertheless, the conclusions of clinical studies on sex-based differences are controversial. We aimed to evaluate the effect of sex on the short- and long-term survival of critically ill patients with sepsis. METHODS: We use the critical care database of the healthcare information mart. Cox models were conducted to determine the relationship of 28-day and 1-year mortality with a different sex. Interaction and stratified analyses were conducted to test whether the effect of sex differed across age and sequential organ failure assessment (SOFA) score subgroups. RESULTS: A total of 12,321 patients were enrolled in this study. The Cox regression analysis showed that the 28-day and 1-year mortality rates of female patients were significantly lower than those of male patients by 10% and 8%, respectively (hazard ratio [HR]=0.90, 95% confidence interval [CI] 0.83-0.98, and HR=0.92, 95% CI 0.87-0.97, respectively). The effects of the association between sex and 28-day and 1-year mortality were broadly consistent for age and the SOFA subgroup variables. Only age was observed to have significant interactions in the 1-year mortality (P=0.0177). Compared with male patients, female patients aged <50 years had a long-term survival advantage (HR=0.77, 95% CI 0.62-0.95). In contrast, we did not find sex-based differences in the short- and long-term survival for patients aged ≥50 years. CONCLUSION: In the current retrospective large database review, the 28-day and 1-year mortality were significantly lower in females than in male patients among critically ill patients with sepsis. Notably, there was an interaction between age and sex, and whether female-associated hormones or other contributing factors affect the clinical outcomes of patients with sepsis needs to be further researched.
RESUMO
BACKGROUND: Sepsis patients hospitalized in the intensive care unit (ICU) often have comorbid diabetes mellitus (DM). However, the clinical impact of DM on the clinical outcomes of critically ill sepsis patients has yet to be determined. Therefore, the current study aimed to analyze the association of comorbid DM with the prognosis of sepsis patients in the ICU. METHODS: Data of patients with sepsis and comorbid DM were obtained from a large-scale intensive care database. The primary outcome was 28-day mortality after ICU admission. Associations of comorbid DM with the primary outcome were assessed using a multivariable Cox regression model. Different adjusted models, such as the propensity score method, were used to determine the prognosis of the patients. RESULTS: Overall, 12,321 sepsis patients were enrolled, including 3,509 (28.48%) with comorbid DM. After adjusting and matching, we found that comorbid DM was not an independent risk factor for 28-day mortality in critically ill sepsis patients and was even associated with lower mortality. Propensity score matching showed a dramatically lower 28-day mortality for sepsis patients with comorbid DM in comparison to patients without comorbid DM [hazard ratio (HR): 0.86, 95% confidence interval (CI): 0.77-0.97, P=0.0167]. The relationship of comorbid DM with 28-day mortality was broadly consistent for all subgroup variables. In the stratified analysis, a significant interaction was observed only for glucose concentration (P<0.0001). Patients with comorbid DM and a glucose level of 140-200 mg/dL (7.8-11.1 mmol/L) or ≥200 mg/dL (11.1 mmol/L) had a significantly lower 28-day mortality rate (HR 0.83, 95% CI: 0.71-0.98, P=0.0250 and HR: 0.49, 95% CI: 0.38-0.64, P<0.0001, respectively). CONCLUSIONS: Critically ill patients with sepsis and comorbid DM were not found to have increased 28-day mortality compared to those without comorbid DM, and may even have a lower risk of mortality. Notably, this association remained in the setting of hyperglycemia.
RESUMO
BACKGROUND: Association of diabetes and admission glucose on the short-term prognosis in patients with critical illnesses are currently ambiguous. We aimed to determine whether diabetes and admission glucose affects short-term prognosis of critically ill patients. METHODS: We performed a retrospective analysis of data on 46,476 critically ill patients from the critical care database. Association of diabetes with 28-day mortality was assessed by inverse probability weighting based on the propensity score. Smoothing splines and threshold effect analysis were applied to explore the relationship between admission glucose and clinical outcomes. RESULTS: Of the 33,680 patients enrolled in the study, 8,701 (25.83%) had diabetes. In the main analysis, the 28-day mortality was reduced by 29% (hazard ratio (HR)=0.71, 95% confidence interval (CI) 0.67-0.76) in patients with diabetes compared to those without diabetes. The E-value of 2.17 indicated robustness to unmeasured confounders. Significant interactions were observed for glucose at ICU admission, admission type, and insulin use (Interaction P <0.05). A V-shaped relationship was observed between admission glucose and 28-day mortality in non-diabetic patients, with the lowest 28-day mortality corresponding to a glucose level of 101.75 mg/dl (95% CI 94.64-105.80 mg/dl), and admission hypoglycemia or hyperglycemia should be avoided, especially in patients admitted to the surgical intensive care unit (SICU), cardiac surgery recovery unit (CSRU), and coronary care unit (CCU); for diabetic patients, elevated admission glucose does not appear to be associated with a poor prognosis and perhaps may be beneficial except for CCU and CSRU. CONCLUSION: The non-detrimental effect of diabetes on the short-term prognosis of critically ill patients was further confirmed, which would reduce 28-day mortality by approximately 29%. For non-diabetic patients, the admission glucose level corresponding to the lowest 28-day mortality was 101.75 mg/dl (95% CI 94.64-105.80 mg/dl); however, for diabetics, the appropriate admission glucose threshold remains unresolved.
RESUMO
BACKGROUND: Obesity is now recognized as one of the major public health threats, especially for patients with a critical illness. However, studies regarding whether and how body mass index (BMI) affects clinical outcomes in patients with sepsis are still scarce and controversial. The aim of our study was to determine the effect of BMI on critically ill patients with sepsis. MATERIALS AND METHODS: We performed this study using data from the Medical Information Center for Intensive Care III database. A multivariate Cox regression model was used to assess the independent association of BMI with the primary outcome. RESULTS: A total of 7,967 patients were enrolled in this study. Firstly, we found that the 28-day mortality was reduced by 22% (HR = 0.78, 95% CI 0.69-0.88) and 13% (HR = 0.87, 95% CI 0.78-0.98) for obese and overweight compared to normal weight, respectively. Subsequently, a U-shaped association of BMI with 28-day mortality was observed in sepsis patients, with the lowest 28-day mortality at the BMI range of 30-40 kg/m2. Finally, significant interactions were observed only for sex (P = 0.0071). Male patients with a BMI of 25-30 kg/m2 (HR = 0.74, 95% CI 0.63-0.86) and 30-40 kg/m2 (HR = 0.63, 95% CI 0.53-0.76) had a significantly lower risk of 28-day mortality. CONCLUSIONS: A U-shaped association of BMI with 28-day mortality in critically ill sepsis patients was found, with the lowest 28-day mortality at a BMI range of 30-40 kg/m2. Notably, male patients were protected by a higher BMI more effectively than female patients as males had a significantly lower mortality risk.
Assuntos
Estado Terminal/mortalidade , Sepse/mortalidade , Sepse/fisiopatologia , Idoso , Índice de Massa Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/mortalidade , Obesidade/fisiopatologia , Sobrepeso/mortalidade , Sobrepeso/fisiopatologiaRESUMO
BACKGROUND: Acute respiratory distress syndrome (ARDS) becomes a serious challenge in critical care medicine due to the lack of effective therapy. As the damage of alveolar epithelium is a characteristic feature of ARDS, inducing mesenchymal stem cells (MSCs) to differentiate into alveolar epithelial cells turns out to be a promising therapy for ARDS, but the differentiation efficiency is yet to be improved. The study aimed to investigate the effect of overexpressing FoxM1 on MSCs' differentiation into alveolar epithelial cells. METHODS: MSCs were isolated from mouse bone marrow, followed by transfected with lentivirus carrying the FoxM1 plasmid. Small airway epithelial cell growth medium was used as a culture system for inducing MSCs' differentiation into alveolar epithelial cells. Differentiation efficiency was assessed by detecting the expression levels of specific markers of alveolar epithelial cells mainly using quantitative reverse-transcription polymerase chain reaction and Western blot. To examine whether Wnt/ß-catenin signalling was involved in the regulation mechanism, a specific inhibitor of the pathway XAV-939 was used and nuclear and cytoplasmic proteins were also analysed respectively. Co-immunoprecipitation was performed to examine the potential interaction between FoxM1 and ß-catenin. RESULTS: Overexpressing FoxM1 statistically significantly increased the expression levels of specific markers of type II alveolar epithelial cells prosurfactant protein C and surfactant protein B, which was partially reversed by XAV-939 treatment, while the expression levels of specific marker of type I alveolar epithelial cells aquaporin 5 did not change significantly. Overexpressing FoxM1 also increased the nuclear translocation of ß-catenin and its transcriptional activity. A direct interaction between FoxM1 and ß-catenin was found in co-immunoprecipitation assay. CONCLUSION: Overexpression of FoxM1 could improve the efficiency of MSCs' differentiation into type II alveolar epithelial cells partly by activating Wnt/ß-catenin signalling.
Assuntos
Células Epiteliais Alveolares/citologia , Células Epiteliais Alveolares/metabolismo , Diferenciação Celular , Proteína Forkhead Box M1/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Via de Sinalização Wnt , Animais , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacologia , Masculino , Células-Tronco Mesenquimais/ultraestrutura , Camundongos Endogâmicos C57BL , beta Catenina/metabolismoRESUMO
BACKGROUND: The Oxford Acute Severity of Illness Score (OASIS) has shown fair prognosis predictive value in critically ill patients, but its predictive value has not been assessed in septic patients. OBJECTIVE: The aim of this study was to evaluate the performance of the OASIS for the assessment of mortality in septic patients, especially when compared with the Sepsis-related Organ Failure Assessment (SOFA) score. METHODS: A retrospective cohort study was conducted using data from a public database and septic patients were identified using the Sepsis-3 criteria. The primary outcome was hospital mortality. Data were mainly analyzed using multivariable logistic regression and receiver operating characteristic (ROC) curves. Sensitive analyses were performed in patients with an ICD-9-CM code for sepsis and ROC curves analyses were also conducted in septic patients stratified by the Simplified Acute Physiology Score (SAPS) II as subgroup analyses. RESULTS: A total of 10,305 septic patients were included. The OASIS was found to be significantly associated with hospital mortality (odds ratio 1.07 per one-point increase, 95% confidence interval [1.06-1.08]), while ROC curves analyses showed the discriminatory power of the OASIS for hospital mortality was statistically significantly lower than that of the SOFA score (area under the ROC curve: 0.652 vs 0.682, p < 0.001). Results of sensitive analyses were consistent, but the significant difference existed only when the SAPS II was higher than 50 according to results of the subgroup analyses. CONCLUSIONS: The OASIS might serve as an initial predictor of clinical outcomes for septic patients, but one should be circumspect when it is applied to severer patients.