Association between ICU admission (neutrophil + monocyte)/lymphocyte ratio and 30-day mortality in patients with sepsis: a retrospective cohort study.

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.

Pathogenesis of psoriasis via miR-149-5p/AKT1axis by long noncoding RNA BLACAT1.

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.

Ghrelin protects against lipopolysaccharide-induced acute respiratory distress syndrome through the PI3K/AKT pathway.

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.

Overexpression of FoxM1 promotes differentiation of bone marrow mesenchymal stem cells into alveolar type II cells through activating Wnt/ß-catenin signalling.

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.

Ghrelin attenuates sepsis-induced acute lung injury by inhibiting the NF-κB, iNOS, and Akt signaling in alveolar macrophages.

Ghrelin has proven to be protective against sepsis-induced acute lung injury (ALI) via anti-inflammatory effects. However, its mechanisms remain poorly understood. Alveolar macrophages (AMs) play a key role in mediating inflammatory responses during sepsis-induced ALI by secretion of cytokines and chemokines. This study was undertaken to investigate whether ghrelin suppresses inflammatory effects of AMs and therefore may help to attenuate sepsis-induced ALI. A sepsis model in rats was achieved using cecal ligation and puncture. Ghrelin treatment markedly improved histopathological changes in the lungs and reduced pulmonary inflammation in septic rats. NF-κB translocation and p-Akt and inducible nitric oxide synthase (iNOS) activities in AMs from septic rats were suppressed by ghrelin. In vitro data indicated that ghrelin decreased the levels of LPS-induced IL-1ß, TNF-α, and IL-6, NF-κB translocation, and iNOS and Akt activities of AMs. Furthermore, the NF-κB/iNOS pathway or Akt signaling was positively correlated with LPS-induced inflammatory production of AMs in vitro. In conclusion, ghrelin exerts a protective role against sepsis-induced ALI probably by reducing the production of inflammatory cytokines from AMs via inhibition of the NF-κB/iNOS pathway or Akt signaling.

Effects of Ghrelin on iNOS-Derived NO Promoted LPS-Induced Pulmonary Alveolar Epithelial A549 Cells Apoptosis.

BACKGROUND/AIMS: In the process of abnormal apoptosis of pulmonary alveolar type II epithelial A549 cells in acute respiratory distress syndrome (ARDS), inducible nitric oxide synthase (iNOS) activity in the lung, nitric oxide (NO) production, and the level of protein S-nitrosylation were increased. However, the role of excessive NO production in sepsis-induced ARDS is controversial. Additionally, ghrelin is a growth hormone that exerts an inhibitory role in cell apoptosis. We examined the effect of NO and S-nitrosylation on apoptosis of A549 cells induced by Lipopolysaccharide (LPS) and molecular mechanism underlying the anti-apoptotic effect of ghrelin in this process. METHODS: Flow cytometry and qPCR were used to detect lentiviral infection efficiency and iNOS gene level, respectively. Extracellular and intracellular NO levels were observed by Griess assay kit and DAF-FM DA. Mitochondrial transmembrane potential, apoptosis rate and SNO levels were determined by flow cytometry, Biotin-Switch method and immunofluoresence staining. The expression of iNOS, apoptotic proteins and JNK were assessed by immunoblot analysis. RESULTS: The results showed about two times increase in iNOS expression and intracellular NO levels response to LPS exposure at 24 hours (P< 0.05), while not in extracellular NO levels. NO donors, S-nitroso-N-acetylpenicillamine (SNAP) significantly raised (36.7%, P< 0.05; 38.4%, P< 0.05; 41.8%, P< 0.05) extracellular NO levels without influencing the intracellular NO levels. LPS increased the apoptosis rate (42.4%±2.6% vs 2.8%±1%, P< 0.05) of A549 accompanied by increased Bax levels and decreased Bcl-2 levels through activating JNK signaling, which was reversed when we diminished the iNOS expression in A549 cells using lentiviral vectors encoding iNOS shRNA in the presence of LPS (24.8%±3.8% vs 42.4%±2.6%, P< 0.05). However, the apoptosis rate was increased when SNAP was added (38.8%±1.3% vs 24.8%±3.8%, P< 0.05). Furthermore, we investigated whether ghrelin exert a protective role against LPS-induced apoptosis and the potential mechanism involved in. Ghrelin alone appeared to decrease iNOS expression (32.3%, P< 0.05; 42.3%, P< 0.05), which showed no signifiant difference between LPS+ghrelin group and LPS group. However, this study showed that ghrelin decreased the intracellular NO production (38.9%, P< 0.05), protein S-nitrosylation levels (33.5%, P< 0.05), Bax protein expression (70.2%, P< 0.05), whereas increasing Bcl-2 protein expression (14.1%, P< 0.05) and mitochondrial transmembrane potential (∆ΨM) (20.7%, P< 0.05) in the presence of LPS. CONCLUSION: The data suggested that NO derived from iNOS induced by LPS stimulation exerts an important role in promoting apoptosis of A549 cells, and ghrelin abolished intracellular NO production and protein S-nitrosylation levels, abrogating the apoptosis of A549 cells partly through inhibiting mitochondrial-dependent pathways.

Ghrelin ameliorates the human alveolar epithelial A549 cell apoptosis induced by lipopolysaccharide.

Ghrelin is a gastric acyl-peptide that plays an inhibitory role in cell apoptosis. Herein we investigate the protective effects of ghrelin in LPS-induced apoptosis of human alveolar epithelial A549 cells, along with the possible molecular mechanisms. LPS exposure impaired cell viability and increased apoptosis of A549 cells significantly in concentration- and time-dependent manners embodied in increased Bax and cleaved caspase-3 production, coupled with decreased Bcl-2 levels. Simultaneously, LPS remarkably decreased the expression of phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) and extracellular signal-regulated kinas (ERK) in A549 cells. However, ghrelin'pretreatment ameliorated LPS-caused alterations in the ratio of Bax/Bcl-2 and cleaved caspase-3 expression, whereas activated the PI3K/Akt and ERK signaling. These results demonstrate that ghrelin lightens LPS-induced apoptosis of human alveolar epithelial cells partly through activating the PI3K/Akt and ERK pathway and thereby might benefit alleviating septic ALI.

Clinical value of soluble urokinase-type plasminogen activator receptor in the diagnosis, prognosis, and therapeutic guidance of sepsis.

OBJECTIVES: The level of soluble urokinase-type plasminogen activator receptor (suPAR) is significantly increased in sepsis. We investigated whether suPAR could be a valuable biomarker in sepsis. METHODS: We measured suPAR and procalcitonin (PCT) levels, recorded the Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment scores of engaged subjects, and drew Receiver Operating Characteristics curves. RESULTS: The plasma suPAR and serum PCT levels of the sepsis group were higher than those of the systemic inflammatory response syndrome and control groups. Using suPAR to distinguish systemic inflammatory response syndrome from sepsis on day 1, the area under the curve (AUC) curve was 0.817, and when suPAR and PCT were used in combination to diagnose sepsis, the AUC was 0.927. At a cutoff point of 9.52 ng/mL, the sensitivity and specificity for diagnosis of sepsis using suPAR were 71.93% and 95.46%, respectively. At a cutoff point of 12.01 ng/mL, the sensitivity and specificity for distinguishing survival and mortality by suPAR were 87.1% and 72.5%, respectively. When suPAR and the APACHE II score were combined to distinguish survival from mortality, the AUC was 0.857. The plasma suPAR level was positively correlated with the serum PCT level (r = 0.326, P < .001), APACHE II score (r = 0.492, P < .001), and Sequential Organ Failure Assessment score (r = 0.386, P < .001). CONCLUSIONS: Use of both plasma suPAR and PCT levels enhanced the efficiency of sepsis diagnosis, and the combination of plasma suPAR and APACHE II score improved mortality prediction.

Bone marrow mesenchymal stem cells protect alveolar macrophages from lipopolysaccharide-induced apoptosis partially by inhibiting the Wnt/ß-catenin pathway.

Apoptosis of alveolar macrophages (AMs) plays a pathogenic role in acute lung injury (ALI) and its severe type, acute respiratory distress syndrome (ARDS). Mesenchymal stem cells (MSCs) are promising therapeutic cells for preventing apoptosis and eliminating cellular injury. We investigated the effects of rat bone marrow mesenchymal stem cells (BMSCs) on lipopolysaccharide (LPS)-induced apoptosis in AMs using transwell experiments, and examined the underlying mechanisms LPS induced AMs apoptosis in a dose- and time-dependent fashion, whereas BMSCs reduced AMs apoptosis when co-cultured at appropriate ratios. BMSCs decreased expression of cleaved caspase-3 and the pro-apoptotic protein, Bax, whilst increased levels of the anti-apoptotic protein, Bcl-2, prolonging the lifespan of AMs in vitro. Promotion of AMs survival by BMSCs required down-regulation of p-GSK-3ß and ß-catenin in AMs. The anti-apoptosis action of BMSCs was reversed by SB216763, a specific inhibitor of GSK-3ß that also activates Wnt/ß-catenin signaling. In conclusion, BMSCs can attenuate AM apoptosis partially by suppressing the Wnt/ß-catenin pathway.

Association between red blood cell distribution width-to-platelet ratio and post-discharge readmission rate in patients with heart failure: A retrospective cohort study.

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.

Homeobox B4 optimizes the therapeutic effect of bone marrow mesenchymal stem cells on endotoxin-associated acute lung injury in rats.

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.

Causal association of circulating cytokines with sepsis: a Mendelian randomization study.

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.

Overexpression of FoxM1 optimizes the therapeutic effect of bone marrow mesenchymal stem cells on acute respiratory distress syndrome.

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.

Association Between ICU admission (Neutrophil + Monocyte)/Lymphocyte Ratio And 30-Day Mortality in Patients with Sepsis: A Retrospective Study from MIMIC-IV.

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.

Overexpression of FoxM1 Enhanced the Protective Effect of Bone Marrow-Derived Mesenchymal Stem Cells on Lipopolysaccharide-Induced Acute Lung Injury through the Activation of Wnt/ß-Catenin Signaling.

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.

[The effects of rosiglitazone combined ceftazidime on peroxisome proliferator activated receptor γ activity and interleukin in septic rats].

OBJECTIVE: To observe the effects of rosiglitazone (RSG) and ceftazidime (CAZ) on peroxisome proliferator activated receptor γ (PPARγ) activity in nucleated cells and interleukin (IL-4, IL-6) levels in plasma in septic rats. METHODS: According to randomized digital table, 180 male Sprague-Dawley (SD) rats were assigned to control group, sham operation group, sepsis group, CAZ group, RSG group and combined CAZ and RSG group. Sepsis model was established by cecal ligation and puncture (CLP). Drugs were administered by intraperitoneal injection at 3-hour post-operation, once every 12-hour. The PPARγ activity in nucleated cells and IL-4, IL-6 levels in plasma were detected by enzyme linked immunosorbent assay (ELISA) at 12, 24 and 48 hours post-operation. RESULTS: There was no difference in PPARγ activity and levels of IL-4 and IL-6 at each time point post-operation between control group and sham operation group. Compared with control group and sham operation group, PPARγ activity [absorbance (A) value] in nucleated cells in sepsis group, where downward trend was seen as time went on, significantly reduced (0.263±0.017 vs. 0.292±0.005, 0.294±0.007, both P<0.05). PPARγ activity was significantly higher in CAZ group, RSG group and CAZ + RSG group than in sepsis group (0.282±0.008, 0.336±0.020, 0.347±0.007 vs. 0.263±0.017, all P<0.05), CAZ + RSG group>RSG group >CAZ group (both P<0.05). Plasma IL-6 and IL-4 levels were higher in sepsis group than in control group and sham operation group (IL-6: 436.77±62.28 ng/L vs. 45.11±10.42 ng/L, 42.28±7.54 ng/L; IL-4: 89.24±25.06 ng/L vs. 41.34±7.08 ng/L, 41.49±7.27 ng/L, all P<0.05) and reached peak at 24 hours and 48 hours post-operation, respectively. Compared with sepsis group, IL-6 and IL-4 levels in CAZ group, RSG group and CAZ + RSG group were significantly decreased (IL-6: 273.48±12.13 ng/L, 317.64±14.10 ng/L, 253.94±13.57 ng/L vs. 436.77±62.28 ng/L; IL-4: 59.12±7.03 ng/L, 68.37±8.28 ng/L, 53.81±8.34 ng/L vs. 89.24±25.06 ng/L, all P<0.05), CAZ + RSG group < CAZ group < RSG group (all P<0.05). CONCLUSION: In septic rats, PPARγ activity in nucleated cells was decreased. On the basis of effective antibiotic treatment, RSG might play a role in improving PPARγ activity in nucleated cells and reducing the levels of inflammation mediators and anti-inflammatory in plasma.

Association between hyperglycemia and adverse clinical outcomes of sepsis patients with diabetes.

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.

Ghrelin pretreatment enhanced the protective effect of bone marrow-derived mesenchymal stem cell-conditioned medium on lipopolysaccharide-induced endothelial cell injury.

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.

Adalimumab in Treating Refractory Livedoid Vasculopathy.

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.

Association of Cardiac Troponin T Concentration on Admission with Prognosis in Critically Ill Patients without Myocardial Infarction: A Cohort Study.

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.