Mechanisms and targeted reversion/prevention of hepatic fibrosis caused by the non-hereditary toxicity of benzo(a)pyrene.

The effect of long term exposure to low concentrations of environmental pollutants on hepatic disorders is a major public health concern worldwide. Polycyclic aromatic hydrocarbons (PAHs) are a class of persistent organic pollutants. In recent years, an increasing number of studies have focused on the deleterious effects of low concentrations of PAHs in the initiation or exacerbation of the progression of chronic liver disease. However, the underlying molecular mechanisms and effective intervention methods remain unclear. Here, we found that in hepatocytes, a low concentration of benzo(a)pyrene (B[a]P, an indicator of PAHs) chronic exposure continuously activated 14-3-3η via an epigenetic accumulation of DNA demethylation. As a "switch like" factor, 14-3-3η activated its downstream PI3K/Akt signal, which in turn promoted vascular endothelial growth factor (VEGF) production and secretion. As the characteristic fibrogenic paracrine factor regulated by B[a]P/14-3-3η, VEGF significantly induced the neovascularization and activation of hepatic stellate cells, leading to the development of hepatic fibrosis. Importantly, targeted 14-3-3η by using its specific inhibitor invented by our lab could prevent B[a]P-induced hepatic fibrosis, and could even reverse existent hepatic fibrosis caused by B[a]P. The present study not only revealed novel mechanisms, but also proposed an innovative approach for the targeted reversion/prevention of the harmful effects of exposure to PAHs on chronic liver disease.

Identification of key genes with prognostic value in gastric cancer by bioinformatics analysis.

Background: Gastric cancer (GC) is a digestive system tumor with high morbidity and mortality. It is urgently required to identify genes to elucidate the underlying molecular mechanisms. The aim of this study is to identify the key genes which may affect the prognosis of GC patients and be a therapeutic strategy for GC patients by bioinformatic analysis. Methods: The significant prognostic differentially expressed genes (DEGs) were screened out from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) datasets. The protein-protein interaction (PPI) network was established by STRING and screening key genes by MCODE and CytoNCA plug-ins in Cytoscape. Functional enrichment analysis, construction of a prognostic risk model, and nomograms verify key genes as potential therapeutic targets. Results: In total, 997 genes and 805 genes were related to the prognosis of GC in the GSE84437 and TCGA datasets, respectively. We define the 128 genes shared by the two datasets as prognostic DEGs (P-DEGs). Then, the first four genes (MYLK, MYL9, LUM, and CAV1) with great node importance in the PPI network of P-DEGs were identified as key genes. Independent prognostic risk analysis found that patients with high key gene expression had a poor prognosis, excluding their age, gender, and TNM stage. GO and KEGG enrichment analyses showed that key genes may exert influence through the PI3K-Akt pathway, in which extracellular matrix organization and focal adhesion may play important roles in key genes influencing the prognosis of GC patients. Conclusion: We found that MYLK, MYL9, LUM, and CAV1 are potential and reliable prognostic key genes that affect the invasion and migration of gastric cancer.

Identification of an Immune-Related Prognostic Risk Model in Glioblastoma.

Background: Glioblastoma (GBM) is the most common and malignant type of brain tumor. A large number of studies have shown that the immunotherapy of tumors is effective, but the immunotherapy effect of GBM is not poor. Thus, further research on the immune-related hub genes of GBM is extremely important. Methods: The GBM highly correlated gene clusters were screened out by differential expression, mutation analysis, and weighted gene co-expression network analysis (WGCNA). Least absolute shrinkage and selection operator (LASSO) and proportional hazards model (COX) regressions were implemented to construct prognostic risk models. Survival, receiver operating characteristic (ROC) curve, and compound difference analyses of tumor mutation burden were used to further verify the prognostic risk model. Then, we predicted GBM patient responses to immunotherapy using the ESTIMATE algorithm, GSEA, and Tumor Immune Dysfunction and Exclusion (TIDE) algorithm. Results: A total of 834 immune-related differentially expressed genes (DEGs) were identified. The five hub genes (STAT3, SEMA4F, GREM2, MDK, and SREBF1) were identified as the prognostic risk model (PRM) screened out by WGCNA and LASSO analysis of DEGs. In addition, the PRM has a significant positive correlation with immune cell infiltration of the tumor microenvironment (TME) and expression of critical immune checkpoints, indicating that the poor prognosis of patients is due to TIDE. Conclusion: We constructed the PRM composed of five hub genes, which provided a new strategy for developing tumor immunotherapy.

[Efficacy analysis of inferior vena cava variability combined with difference of central venous-to-arterial partial pressure of carbon dioxide on guiding fluid resuscitation in patients with septic shock].

OBJECTIVE: To investigate the effect of inferior vena cava variability (IVCV) combined with difference of central venous-to-arterial partial pressure of carbon dioxide (Pcv-aCO2) on guiding fluid resuscitation in septic shock. METHODS: Patients with septic shock admitted to the department of critical care medicine of Jiangxi Provincial People's Hospital from January 1, 2018 to December 31, 2020 were enrolled, and they were divided into control group and observation group according to random number table method. Patients in both groups were given fluid resuscitation according to septic shock fluid resuscitation guidelines. The patients in the control group received fluid resuscitation strictly according to the early goal-directed therapy (EGDT) strategy. Resuscitation target: central venous pressure (CVP) 12-15 cmH2O (1 cmH2O≈0.098 kPa), mean arterial pressure (MAP) > 65 mmHg (1 mmHg≈0.133 kPa), mean urine volume (UO) > 0.5 mL×kg-1×h-1, central venous oxygen saturation (ScvO2) > 0.70. In the observation group, the endpoint of resuscitation was evaluated by IVCV dynamically monitored by bedside ultrasound and Pcv-aCO2. Resuscitation target: fixed filling of inferior vena cava with diameter > 2 cm, IVCV < 18%, and Pcv-aCO2 < 6 mmHg. The changes in recovery indexes before and 6 hours and 24 hours of resuscitation of the two groups were recorded, and the 6-hour efficiency of fluid resuscitation, 6-hour lactate clearance rate (LCR) and 6-hour and 24-hour total volume of resuscitation were also recorded; at the same time, the duration of mechanical ventilation, length of intensive care unit (ICU) stay, 28-day mortality and the incidence of acute renal failure and acute pulmonary edema between the two groups were compared. RESULTS: A total of 80 patients were enrolled in the analysis, with 40 in the control group and 40 in the observation group. The MAP, CVP and ScvO2 at 6 hours and 24 hours of resuscitation in the two groups were significantly higher than those before resuscitation, while Pcv-aCO2 and blood lactic acid (Lac) were significantly decreased, and UO was increased gradually with the extension of resuscitation time, indicating that both resuscitation endpoint evaluation schemes could alleviate the shock state of patients. Compared with before resuscitation, IVCV at 6 hours and 24 hours of resuscitation in the observation group were decreased significantly [(17.54±4.52)%, (18.32±3.64)% vs. (27.49±10.56)%, both P < 0.05]. Compared with the control group, MAP and ScvO2 at 6 hours of resuscitation in the observation group were significantly increased [MAP (mmHg): 69.09±4.64 vs. 66.37±4.32, ScvO2: 0.666±0.033 vs. 0.645±0.035, both P < 0.05], 24-hour MAP was increased significantly (mmHg: 75.16±3.28 vs. 70.12±2.18, P < 0.05), but CVP was relatively lowered (cmH2O: 9.25±1.49 vs. 10.25±1.05, P < 0.05), indicating that the fluid resuscitation efficiency was higher in the observation group. Compared with the control group, 6-hour LCR in the observation group was significantly increased [(55.64±6.23)% vs. (52.45±4.52)%, P < 0.05], 6-hour and 24-hour total volume of resuscitation was significantly decreased (mL: 2 860.73±658.32 vs. 3 568.54±856.43, 4 768.65±1 085.65 vs. 5 385.34±1 354.83, both P < 0.05), the duration of mechanical ventilation was significantly shortened (days: 6.78±3.45 vs. 8.45±2.85, P < 0.05), while the incidence of acute pulmonary edema was significantly decreased [2.5% (1/40) vs. 20.0% (8/40), P < 0.05]. There was no significant difference in the length of ICU stay, 28-day mortality or incidence of acute renal failure between the two groups. CONCLUSIONS: Dynamic monitoring of IVCV and Pcv-aCO2 can effectively guide the early fluid resuscitation of patients with septic shock, and compared with EGDT, it can significantly shorten the duration of mechanical ventilation, reduce the amount of fluid resuscitation, and reduce the incidence of acute pulmonary edema. Combined with its non-invasive characteristics, it has certain clinical advantages.

[Celastrol alleviates sepsis-induced acute lung injury in rats by inhibiting the Toll-like receptor 4/nuclear factor-κB inflammatory pathway].

OBJECTIVE: To investigate the protective effect and mechanism of celastrol in acute lung injury (ALI) of septic rats. METHODS: According to random number table, 24 male Sprague-Dawley (SD) rats were divided into control group (Con group), Sham operation group (Sham group), sepsis-induced ALI group by cecal ligation and perforation (CLP group) and celastrol intervention group (CLP+celastrol group, 2 mg/kg intraperitoneal administration 1 hour before surgery), 6 rats in each group. The abdominal aortic blood of the rats was collected for blood gas analysis 24 hours after the surgery, and then the rats were sacrificed and the lung tissues were taken to calculate the lung wet to dry weight ratio (W/D). The pathological characteristics of lung tissues were observed under light microscope and calculated the lung injury score. The protein levels of Toll-like receptor 4 (TLR4), interleukins (IL-6, IL-10), and nuclear factor-κB (NF-κB) of cytoplasm and nucleus in lung tissues were detected by enzyme linked immunosorbent assay (ELISA). RESULTS: The partial arterial oxygen pressure (PaO2), lung W/D ratio, lung injury score and the protein levels of inflammatory factor in lung tissues had no differences between Con group and Sham group. Compared with the Con group, PaO2 in the CLP group was significantly decreased [mmHg (1 mmHg = 0.133 kPa): 60.33±2.01 vs. 109.20±2.99], the lung W/D ratio and lung injury score were significantly increased (lung W/D ratio: 4.44±0.05 vs. 3.27±0.04, lung injury score: 10.67±0.42 vs. 0.50±0.22), and the protein levels of TLR4, IL-6, IL-10 and the nucleus NF-κB in the lung tissues were significantly increased [TLR4 (pg/L): 21.87±0.66 vs. 3.27±0.09, IL-6 (ng/L): 861.10±8.28 vs. 120.30±3.91, IL-10 (ng/L): 212.40±2.57 vs. 41.73±1.02, nuclear NF-κB (ng/L): 707.70±16.82 vs. 403.30±7.46], but the protein level of cytoplasm NF-κB was significantly decreased (ng/L: 213.70±8.67 vs. 408.30±8.71), with statistically significant differences (all P < 0.05). Compared with the CLP group, PaO2 in CLP+celastrol group was significantly increased (mmHg: 76.83±3.21 vs. 60.33±2.01), the lung W/D ratio and lung injury score were significantly decreased (lung W/D ratio: 3.82±0.03 vs. 4.44±0.05, lung injury score: 5.00±0.37 vs. 10.67±0.42), and the protein levels of TLR4, IL-6, IL-10 and nucleus NF-κB in the lung tissue were significantly decreased [TLR4 (pg/L): 7.57±0.21 vs. 21.87±0.66, IL-6 (ng/L): 380.90±6.55 vs. 861.10±8.28, nuclear NF-κB (ng/L): 533.80±9.42 vs. 707.70±16.82], and the protein level of cytoplasm NF-κB was significantly increased (ng/L: 342.70±14.96 vs. 213.70±8.67), with statistically significant differences (all P < 0.05), while the protein level of IL-10 in lung tissues had no significant difference (ng/L: 210.50±3.16 vs. 212.40±2.57, P > 0.05). CONCLUSIONS: Celastrol may regulate the expression and release of inflammatory factors by inhibiting the TLR4/NF-κB pathway, thereby alleviating the ALI induced by sepsis in rats.

[Study on the effect of sedation strategy guided by driving pressure on prognosis of patients with mechanical ventilation].

OBJECTIVE: To evaluate the effect of airway driving pressure (ΔP) guided sedation strategy on the prognosis of patients with mechanical ventilation. METHODS: Patients who needed invasive mechanical ventilation and admitted to the department of intensive care unit (ICU) of Jiangxi Provincial People's Hospital from January 2017 to December 2018 were enrolled. The patients were divided into study group and control group according to the random number table. After informed consent of patients or their families, both groups received routine treatment in ICU. The control group was treated with light sedation strategy, the Richmond agitation sedation score (RASS) was performed every 4 hours, and the target was RASS > -3. ΔP in the study group was measured once a day, and the sedative target of patients with low driving pressure (ΔP ≤ 14 cmH2O, 1 cmH2O = 0.098 kPa) was RASS > -3, while the patients with high driving pressure (ΔP > 14 cmH2O) was RASS ≤ -3. The evaluation was conducted at 28 days after admission to ICU, and the patients were followed up to 60 days. The main outcome was days without mechanical ventilation in 28 days. The secondary outcomes were the rate of extubation, discharge outcome, incidence of ventilator associated pneumonia (VAP) and delirium, and 60-day survival rate. RESULTS: A total of 60 patients with respiratory failure due to various reasons were recruited, 30 in each group. There was no significant difference in gender, age, primary disease, severity of disease or ΔP between the two groups. The days without mechanical ventilation within 28 days in the study group were significantly more than that in the control group [days: 20 (0, 23) vs. 12 (0, 16), P = 0.018], and the incidences of VAP (3.3% vs. 16.7%, P = 0.045) and delirium (0% vs. 10.0%, P = 0.038) were significantly lower than that in the control group. There were no significant differences in the rate of extubation (73.3% vs. 66.7%, P = 0.273), discharge outcome [improvement (cases): 24 vs. 21, unhealed (cases): 2 vs. 5, deaths (cases): 4 vs. 4, P = 0.506] and 60-day survival rate (83.3% vs. 76.7%, P = 0.519) between the study group and control group. CONCLUSIONS: Compared with light sedation strategy, ΔP directed sedation strategy can effectively shorten the duration of mechanical ventilation and reduce the incidence of VAP and delirium in the ICU patients.

Inhibition of JAK2/STAT3/SOCS3 signaling attenuates atherosclerosis in rabbit.

BACKGROUND: Previous studies have indicated that the JAK/STAT signaling pathway is involved in modulating arterial adventitia inflammation response. In this study, we designed experiments to further investigate the effect of JAK2/STAT3/SOCS3 signaling in rabbit atherosclerosis process. METHODS: Atherosclerosis was induced in the abdominal arteries of rabbits by balloon injury of the aorta supplemented by the atherogenic diet. Simultaneously, in the process of atherosclerosis, animals underwent either ruxolitinib treatment or not for 12 weeks. At the end of the experimental period, all rabbits were sacrificed. The plaque areas in abdominal artery, the lipid burden of plaque and the calcium burden of plaque were detected by H&E staining, Oil Red O staining and Alizarin Red staining, respectively. In addition, rabbit plasma lipids and inflammatory cytokines were measured by biochemical test kits or ELISA kits. Finally, the expression and phosphorylation levels of JAK2/STAT3/SOCS3 pathway-related proteins were detected by RT-qPCR, western blot and immunohistochemistry assays. RESULTS: H&E staining and CT scan analysis showed that rabbit atherosclerosis model was constructed successfully. Ruxolitinib, an inhibitor of the Janus kinase 2 (JAK2), substantially reduced the area of atherosclerotic plaques in rabbits treated with high fat diet and balloon injury of the aorta. Moreover, ruxolitinib significantly decreased IL-6, IL-1ß, IFN-γ and TNF-α, but increased IL-10 and IL-17 levels in plasma of atherosclerotic rabbits. Additionally, ruxolitinib reduced plasma TC, TG and LDL-C contents and AIP value, while enhanced HDL-C level in atherosclerotic rabbits. Furthermore, we found that JAK2 and STAT3 phosphorylation were up-regulated in rabbits with atherosclerosis when compared with those of the control group, followed by the expression of SOCS3 was also increased due to the activation of JAK2 and STAT3. Interestingly, ruxolitinib could inactivate JAK2 and STAT3 pathway and decrease SOCS3 expression. CONCLUSION: Taken together, the inhibition of JAK2/STAT3/SOCS3 signaling pathway may be a novel method for the clinical treatment of artery atherosclerosis.

Serum retinol-binding protein 4 as a predictor of cardiovascular events in elderly patients with chronic heart failure.

AIMS: RBP4 is an adipokine with adverse effects on cardiovascular system. Increased circulating retinol-binding protein 4 (RBP4) has been linked to chronic heart failure (CHF). However, whether elevated RBP4 is correlated with a poor prognosis in elderly patients with CHF remains unclear. The aim of this study was to evaluate the prognostic value of serum RBP4 in elderly patients with CHF. METHODS AND RESULTS: We enrolled 934 consecutive elderly patients (aged 60 years and older) with CHF and 138 age-matched and sex-matched control subjects in a prospective cohort study and explored the association of serum RBP4 levels with the clinical outcomes using multivariate Cox regression analyses. Serum RBP4 levels were elevated in CHF patients when compared with controls (46.66 ± 12.38 µg/mL vs. 40.71 ± 7.2 µg/mL, P < 0.001). Patients with the highest RBP4 concentrations had higher N terminal pro brain natriuretic peptide (NT-proBNP) levels but lower left ventricular eject fraction (LVEF) and estimated glomerular filtration rate (P < 0.001). Serum RBP4 levels were increased as the New York Heart Association functional class increased and LVEF decreased (P < 0.001) and were negatively correlated with LVEF (r = -0.154, P < 0.001) but positively correlated with NT-proBNP levels (r = 0.074, P = 0.023). Multivariate Cox regression analysis suggested that log RBP4 was an independent predictor for major adverse cardiac event(s) [hazard ratio (HR) = 2.61, 95% confidence interval (CI) = 1.19-5.70], together with age, male, LVEF, log NT-proBNP, and estimated glomerular filtration rate. Moreover, log RBP4 was also an independent predictor for cardiovascular mortality (HR = 2.24, 95% CI = 1.35-5.39) and CHF rehospitalization (HR = 2.54, 95% CI = 1.09-5.60) even after adjustment for the established adverse prognostic factors for CHF. The Kaplan-Meier survival curves showed that high concentration of RBP4 was a prognostic indicator of major adverse cardiac event(s) in patients with CHF. CONCLUSIONS: Our findings demonstrate for the first time that elevated serum RBP4 is correlated with worse outcome in elderly patients with CHF.

Kaempferol Improves Lung Ischemia-Reperfusion Injury via Antiinflammation and Antioxidative Stress Regulated by SIRT1/HMGB1/NF-κB Axis.

Trauma, organ transplantation, and thromboembolism are the main causes of lung ischemia-reperfusion injury (LIRI), and new therapies and drugs are urgent to relieve LIRI. In preliminary experiment, authors found that kaempferol could improve LIRI in rats, and the current study further explored its possible mechanism. The model of rat LIRI was established and appropriate research methods were implemented. Results shown that kaempferol could significantly improve LIRI, inhibit release of inflammatory factors including interleukin (IL) 6 and tumor necrosis factor (TNF) α in bronchoalveolar lavage fluid, and reduce oxidative stress reaction. Western blotting was used to detect protein expression levels and found that kaempferol could up-regulate the protein expressions of phosphorylated (p-) p65 and p65, and down-regulate the protein expression of sirtuin (SIRT) 1. Immunofluorescence was used to localize the expression of high mobility group box (HMGB) 1 and found its higher expression in outside of nucleus. However, the above effects of kaempferol on LIRI markedly attenuated by EX 527, a selective inhibitor of SIRT 1. Taken together, we first reported the protective effect of kaempferol on rat LIRI and confirmed that kaempferol's antiinflammation and antioxidative stress involving the SIRT1/HMGB1/NF-κB axis.

Serum Metrnl is associated with the presence and severity of coronary artery disease.

Meteorin-like (Metrnl) is a novel adipokine that is highly expressed in white adipose tissue. Metrnl stimulates energy expenditure and improves glucose tolerance in rodents. However, whether Metrnl plays a role in coronary artery disease (CAD) remains to be elucidated. The present study aimed to investigate the association of serum Metrnl with CAD in Chinese patients. A total of 193 patients with CAD and 156 control subjects were enrolled in this study. Serum Metrnl concentration was measured by enzyme-linked immunosorbent assay. Anthropometric phenotypes, fasting glucose, serum lipids, and inflammatory cytokines were measured. Serum Metrnl was lower in CAD patients when compared to those controls (132.41 vs 173.17 pg/mL, P < 0.001). Serum Metrnl was negatively correlated with metabolic parameters, including body mass index, total cholesterol, and low-density lipoprotein cholesterol as well as inflammatory markers including high-sensitivity C-reactive protein, IL-1ß, and IL-11 even after adjustment for potential confounding variables (P < 0.05). In multivariable logistic regression analyses, compared to those in the highest tertile of serum Metrnl levels, subjects in the lowest tertile had the highest risks for CAD (adjusted OR = 2.63, 95% CI = 1.46-4.27, P = 0.001). After adjustment for potential confounding variables, serum Metrnl was also decreased as the number of stenosed vessels increased (P < 0.001). Furthermore, decreased Metrnl level was negatively correlated with the severity of CAD quantified by the Gensini score. This first case-control study shows significant associations of serum Metrnl with the presence and severity of CAD, suggesting Metrnl might be a new promising therapeutic target for CAD.

[Influence of air pollution on the development of intensive care unit pneumonia patients: a summary of 2 454 cases from 2014 to 2016 in Nanchang City].

OBJECTIVE: To analyze the main characteristics of air pollution in Nanchang City, and discuss the correlation between air pollution exposure (especially PM2.5) and the development of pneumonia related intensive care unit (ICU) patients and their lag effect. METHODS: 2 454 patients who lived in Nanchang City admitted to ICU of Jiangxi Provincial People's Hospital from January 1st, 2014 to December 31st, 2016 were enrolled. According to the diagnosis, the patients were divided into pneumonia group (156 cases) and non-pneumonia group (2 298 cases). The general clinical characteristics of patients and air pollution concentration in Nanchang in the year between 2014-2016 were collected. Multiple regression model was used to analyze the influence of meteorological factors on the condition of ICU patients associated with pneumonia. Using odds ratio (OR), the correlation intensity of air pollution exposure and pneumonia related ICU patients' development was reflected, and the confidence level of association intensity was reflected by the 95% confidence interval (95%CI). The distribution lag nonlinear model (DLNM) was established to evaluate the effect of air mass parameters on the time lag effect. RESULTS: The results of air pollution analysis in Nanchang City in the year between 2014-2016 showed that the annual average concentration of carbon monoxide (CO), sulfur dioxide (SO2) and nitrogen dioxide (NO2) was low and maintained at the same level in the year between 2014-2016. The annual average concentration of CO and NO2 increased in the year between 2014-2016, but the average annual concentration of SO2 decreased rapidly in the year between 2014-2016, and the average annual concentration of PM2.5 tended to slow down after the year between 2014-2016. The annual average concentration of PM10 decreased in the year between 2014-2016, but continued to rise in the year between 2014-2016. The annual mean concentration of O3 showed a trend of continuous increase from the year between 2014-2016. The age of pneumonia group was generally higher than that of non-pneumonia group, most of them were male, and had higher expected mortality and acute physiology and chronic health evaluation II (APACHE II) score. The average air temperature in the pneumonia group was lower than that in the non-pneumonia group on the day of entering the group, and the air pollutants such as PM2.5 and PM10 were significantly higher than those in the non-pneumonia group. The analysis of multiple regression models showed that PM2.5 and air temperature were significantly related to patients with ICU pneumonia on the day of entry (PM2.5: OR = 1.02, 95%CI = 1.00-1.03, P < 0.05; air temperature: OR = 0.96, 95%CI = 0.92-0.98, P < 0.05), and the effect of PM2.5 on patients with ICU pneumonia could last for at least 5 days (OR = 1.04, 95%CI = 1.00-1.09, P < 0.05), and the effect disappeared until the 7th day. According to the analysis of the influence of different concentrations of PM2.5 on ICU pneumonia patients, when the PM2.5 concentration reached 200 µg/m3, its effect on ICU pneumonia patients would last for 5 days (OR = 1.45, 95%CI = 1.07-1.76, P < 0.01). CONCLUSIONS: PM2.5 and air temperature are significantly related to the condition of ICU patients with pneumonia, and the influence of high concentration of PM2.5 on ICU patients with pneumonia has a lag effect.

[VEGF165 transfected endothelial progenitor cells mediated by lentivirus alleviated ALI in rats].

OBJECTIVE: To investigate the protective effects of vascular endothelial growth factor-165 (VEGF165) transfected the endothelial progenitor cells (EPCs) mediated by lentivirus on acute lung injury (ALI) in rats. METHODS: The mononuclear cells from the male Sprague-Dawley (SD) rats were isolated and cultured to get the EPCs for study. The lentivirus vector carrying the human VEGF165 gene was constructed. According to the random number table method, 90 male SD rats were divided into ALI model group, phosphate buffer solution (PBS) group, EPCs treatment group, none transfected EPCs treatment group and VEGF165 transfected EPCs treatment group, and the rats in each group were subdivided into 4, 12 and 48 hours subgroups, with 6 rats in each subgroup. The rat model of ALI was reproduced by intravenous injection of oleic acid (0.15 µL/g). Then each treatment group was given PBS, EPCs, none transfected EPCs and VEGF165 transfected EPCs respectively with the same volume of 0.2 mL. For the groups with cells, about 1×106 cells were contained. Abdominal aortic blood and lung tissue were harvested at 4, 12 and 48 hours. Arterial blood gas analysis was performed. The lung wet/dry weight ratio (W/D) was calculated. The expressions of induced nitric oxide synthase (iNOS), endothelin-1 (ET-1) and VEGF165 were determined by enzyme-linked immunosorbent assay (ELISA). After dyed with hematoxylin-eosin (HE), the lung tissue pathology was observed and the lung injury score was performed. RESULTS: Compared with the ALI model group, the arterial partial pressure of oxygen (PaO2) in EPCs, none transfected EPCs and VEGF165 transfected EPCs treatment groups was significantly increased from 4 hours, and lung W/D, expressions of iNOS and ET-1 were significantly decreased, and VEGF165 expression was significantly increased. Compared with the EPCs treatment group, the increase in PaO2, the decrease in lung W/D and expressions of iNOS and ET-1, and the increase in VEGF165 expression in VEGF165 transfected EPCs treatment group were more significant [4 hours: PaO2 (mmHg, 1 mmHg = 0.133 kPa) was 82.84±10.69 vs. 72.34±9.36, lung W/D ratio was 4.83±0.23 vs. 5.55±0.37, iNOS (ng/mg) was 8.77±1.10 vs. 14.84±1.34, ET-1 (ng/mg) was 103.41±5.66 vs. 153.08±5.12, VEGF165 (ng/mg) was 130.56±12.16 vs. 83.03±5.95; 12 hours: PaO2 (mmHg) was 91.67±6.81 vs. 78.5±8.81, lung W/D ratio was 4.44±0.35 vs. 5.32±0.25, iNOS (ng/mg) was 7.23±0.24 vs. 14.04±1.18, ET-1 (ng/mg) was 91.98±3.52 vs. 125.99±7.55, VEGF165 (ng/mg) was 164.49±5.71 vs. 96.61±6.12]; individual parameters reached valley value or peak value at 48 hours [lung W/D ratio was 4.26±0.30 vs. 4.89±0.15, iNOS (ng/mg) was 5.79±0.85 vs. 12.72±1.10, ET-1 (ng/mg) was 74.53±7.10 vs. 108.33±5.84, VEGF165 (ng/mg) was 237.43±10.79 vs. 134.24±11.99, all P < 0.05]. Over time, lung tissue injury in each group was gradually increased, and the lung injury score was gradually increased. The lung injury score at 48 hours in the EPCs, none transfected EPCs and VEGF165 transfected EPCs treatment groups were lower than that in the ALI model group. Compared with the EPCs treatment group, the VEGF165 transfected EPCs treatment group had a lower score at 48 hours (8.50±1.05 vs. 10.50±1.05, P < 0.05). CONCLUSIONS: The transplantation of EPCs which were transfected with VEGF165 mediated by lentivirus could obviously improve the oxygen pressure, reduce the lung water seepage, decrease the iNOS and ET-1 expressions in lung tissue, and had obvious protective effects on ALI.

[The impacts of low-dose corticosteroids infusion given in different manners on refractory septic shock patients].

OBJECTIVE: To discuss the influence of different ways of low-dose corticosteroids infusion on hemodynamics, changes in blood glucose level and prognosis in patients with refractory septic shock. METHODS: A prospective single-blind randomized controlled trial was conducted. Refractory septic shock patients admitted to the Department of Critical Care Medicine of Jiangxi Provincial People's Hospital from April 1st, 2013 to October 31st, 2014 were enrolled for the study. The patients were divided into control group and research group by random number table. Besides conventional treatment for septic shock, patients in control group were given 200 mg/d hydrocortisone intravenous infusion lasting for 2 hours, while those of research group were given 8.33 mg/h hydrocortisone per hour with an intravenous pump. Treatment lasted for 5 continuous days for both groups. The changes in heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP) and arterial blood lactic acid in both groups were observed at the time of enroldment and 6 hours, 24 hours, 48 hours, and 5 days after the treatment. With a dynamic blood glucose monitor, mean blood glucose (MBG) level, largest amplitude of glycemic excursions (LAGE), glucose variability (GV), and the ratio of hyperglycaemia time were recorded. The duration of shock, length of intensive care unit (ICU) stay, total length of hospital stay, and 28-day mortality of both groups were recorded. RESULTS: Seventy-nine septic shock patients were assigned to the treatment, with 41 in control group, and 38 in research group. Compared with control group, 6-hour MAP in research group was obviously lowered [mmHg (1 mmHg=0.133 kPa): 66.31±4.38 vs. 68.58±4.86, t=1.062, P=0.033], but there were no significant differences in HR, MAP, CVP, lactic acid clearance and norepinephrine (NE) utilization rates at other time points between two groups. No significant difference in MBG was found between research group and control group (mmol/L: 8.69±2.14 vs. 9.95±3.87, t=1.771, P=0.080), but LAGE, GV, the ratio of hyperglycemia time in research group were significantly lower than those of the control group [LAGE (mmol/L): 17.18±8.97 vs. 22.71±11.80, t=2.331, P=0.022; GV (mmol/L): 2.57±1.05 vs. 3.16±1.37, t=2.136, P=0.036; the ratio of hyperglycemia time: (43.1±11.7)% vs. (49.4±15.3)%, t=2.044, P=0.044]. There was no statistical difference in the following features between research group and control group, such as the duration of shock (days: 3.47±0.98 vs. 3.61±1.07, t=0.605, P=0.547), length of ICU stay (days: 8.74±3.12 vs. 9.97±3.37, t=1.543, P=0.120), total length of hospital stay (days: 18.34±9.27 vs. 19.58±9.83, t=0.576, P=0.566) and 28-day mortality rate (23.68% vs. 26.83%, χ2=0.103, P=0.748). CONCLUSIONS: Compared with slow intravenous infusion, a continuous intravenous supplementation of small amount of hydrocortisone to patients with refractory septic shock could stabilize blood glucose levels and maintain metabolic balance efficiently. However, in both groups there was no significant difference in the efficiency in stabilizing hemodynamics, shortening shock duration, reducing ICU or hospital days and decreasing 28-day mortality.

[The influence of positive end-expiratory pressure on cerebral blood flow and cerebrovascular autoregulation in patients with acute respiratory distress syndrome].

OBJECTIVE: To explore the influence of different positive end-expiratory pressure (PEEP) levels on cerebral blood flow (CBF) and cerebrovascular autoregulation in patients with acute respiratory distress syndrome(ARDS). METHODS: A prospective study was conducted. Moderate or severe ARDS patients admitted to Department of Critical Care Medicine of Jiangxi Provincial People's Hospital from January 1st, 2013 to October 1st, 2013 were enrolled. The changes in hemodynamics, respiratory mechanics and gas exchange under different levels of PEEP were observed. CBF velocity of middle cerebral artery (MCA) was measured using transcranial Doppler (TCD), and breath-holding index (BHI) was also calculated. RESULTS: 35 patients with ARDS were included. The oxygenation index (OI), peak inspiratory pressure (PIP), plat pressure (Pplat) and central venous pressure (CVP) were markedly elevated (OI: 324.7±117.2 mmHg vs. 173.4±95.8 mmHg, t=5.913, P=0.000; PIP: 34.7±9.1 cmH2O vs. 26.1±7.9 cmH2O,t=4.222, P=0.000; Pplat: 30.5±8.4 cmH2O vs. 22.2±7.1 cmH2O, t=4.465, P=0.000; CVP: 12.1±3.5 mmHg vs. 8.8±2.2 mmHg, t=4.723, P=0.000) when PEEP was increased from (6.4±1.0) cmH2O to (14.5±2.0) cmH2O (1 cmH2O=0.098 kPa). But no significant difference in the heart rate (85.5±19.1 beats/min vs. 82.7±17.3 beats/min, t=0.643, P=0.523), mean arterial pressure (73.5±12.4 mmHg vs. 76.4±15.1 mmHg, t=0.878, P=0.383) and CBF velocity of MCA [peak systolic flow velocity (Vmax): 91.26±17.57 cm/s vs. 96.64±18.71 cm/s, t=1.240, P=0.219; diastolic flow velocity (Vmin): 31.54±7.71 cm/s vs. 33.87±8.53 cm/s, t=1.199, P=0.235; mean velocity (Vmean): 51.19±12.05 cm/s vs. 54.27±13.36 cm/s, t=1.013, P=0.315] was found. 18 patients with BHI<0.1 at baseline demonstrated that cerebral vasomotor reactivity was poor. BHI was slightly decreased with increase in PEEP (0.78±0.16 vs. 0.86±0.19, t=1.905, P=0.061). CONCLUSIONS: Some of moderate or severe ARDS patients without central nervous system disease have independent of preexisting cerebral autoregulation impairment. However, independent of preexisting cerebral autoregulation may not further be impaired when a high PEEP was chosen.

Diagnostic and prognostic value of minor elevated cardiac troponin levels for percutaneous coronary intervention-related myocardial injury: a prospective, single-center and double-blind study.

Cardiac troponin-I (cTnI) and -T (cTnT) are sensitive and specific markers of myocardial injury. However, the role of increased cTnI and cTnT in percutaneous coronary intervention (PCI)-related myocardial injury remains controversial. In this prospective, single-center and double-blind study, we aimed to determine the diagnostic and prognostic value of cTnI as well as cTnT (cTns) in PCI-related myocardial injury in a Chinese population. A total of 1,008 patients with stable angina pectoris and non-ST-segment elevation acute coronary syndrome were recruited. The levels of cTnI and cTnT were examined before and after PCI. All patients were followed up for 26±9 months to observe the incidence of major adverse cardiac events (MACEs). Our results showed that post-PCI cTnI and/or cTnT levels were increased to more than the 99(th) percentile upper reference limit (URL) in 133 (13.2%) patients, among which 22 (2.2%) were more than 5 × 99(th) percentile URL. By univariate analysis, an elevation in cTns after PCI was not an independent predictor of increased MACEs, HR 1.35 (P  =  0.33, 95%CI: 0.74-2.46). In conclusion, our data demonstrate that the incidence of PCI-related myocardial injury is not common in a Chinese population and minor elevated cTns levels may not be a sensitive prognostic marker for MACEs.

Variants in neuronal nitric oxide synthase gene may contribute to increased ischemic stroke susceptibility in a Han Chinese population.

Variants in neuronal NOS (nNOS) gene were associated with atherosclerosis and stroke susceptibility. We aimed to investigate the association between nNOS gene polymorphism and risk of ischemic stroke caused by small-artery occlusion (SAO) and large-artery atherosclerosis (LAA) in a Chinese population. We conducted a case-control study involving 381 ischemic stroke patients and 366 healthy subjects. Selected SNPs (rs1483757, rs2293050, and rs2139733) were genotyped and assessed; the association with the risk of ischemic stroke was analyzed. Furthermore, gender- and etiologic subtype-stratified analyses were also carried out to evaluate the association between nNOS polymorphisms and risk of ischemic stroke. No significant difference was observed between selected nNOS loci and risk of ischemic stroke in alleles or any genetic models in total study population, males or females, adjusted with age, drinking and smoking status. Rs2293050 and rs2139733 genotypes were associated with total cholesterol (rs2293050, P = 0.026; rs2139733, P = 0.040) and LDL (rs2293050, P = 0.031; rs2139733, P = 0.046) in females. A significant difference in allele distribution of rs2293050 (P = 0.040) and a marginally significant difference of rs2139733 (P = 0.061) in LAA-caused ischemic stroke cases and controls were observed in total population. No association between rs1483757 and ischemic stroke was found in this study. T allele of rs2293050 and A allele of rs2139733 in nNOS gene may contribute to increased susceptibility of LAA-caused ischemic stroke in Han Chinese.

The angiotensinogen gene polymorphism is associated with heart failure among Asians.

The angiotensinogen (AGT) gene M235T polymorphism has been suggested to be linked to risk of heart failure (HF). However, association studies on the M235T polymorphism and HF risk have shown conflicting results. PubMed and China Biology Medicine (CBM) databases were systematically searched to identify relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association. A total of 1,281 HF cases and 1,376 controls were included in the analysis. The pooled data showed that there was no significant associations between the AGT M235T polymorphism and HF risk for TT vs. MM (OR = 1.17, 95%CI = 0.62-2.19, P = 0.635), MT vs. MM (OR = 0.97, 95%CI = 0.77-1.22, P = 0.776), MT/TT vs. MM (OR = 1.07, 95%CI = 0.67-1.69, P = 0.781), and TT vs. MM/MT (OR = 1.23, 95%CI = 0.86-1.76, P = 0.259). In contrast, in the HF subgroup analysis by ethnicity, the AGT M235T polymorphism had a decreased risk of HF among Asians (MT vs. MM, OR = 0.39, 95%CI = 0.17-0.92, P = 0.032). Our results suggest that the AGT M235T polymorphism is a low-penetrant risk factor for the development of HF among Asians.

[The clinical research of nystatin in prevention of invasive fungal infections in patients on mechanical ventilation in intensive care unit].

OBJECTIVE: To observe the effect of nystatin on incidence of invasive fungal infections (IFI) and the prognosis of mechanically ventilated critically ill patients. METHODS: A prospective study was conducted. Critical ill patients admitted to Department of Critical Care Medicine of Jiangxi Provincial People's Hospital from May 1st, 2012 to April 30th, 2013 needing mechanical ventilation were enrolled. The patients were randomly divided into two groups by envelope method. Patients in the nystatin group were administered nystatin 1000 kU three times a day via the gastric tube; and patients in the control group were given gastrointestinal prokinetic drug as placebo. The specimens were collected every 3 days throughout the ICU stay (T0, T3, T6, T9), the strain distribution was observed, and the corrected colonization index (CCI) of all patients were calculated. The incidence of candidemia and 28-day mortality as well as the duration of stay in ICU and hospital were also recorded. RESULTS: A total of 874 strains were isolated from 124 patients, of which Candida albicans accounted for 57.6% (503/874). The most frequently colonized body sites were oropharyngeal site,account for 35.6% (311/874). The CCI of the nystatin group were lower than those of the control group at T6 and T9 [T6: 0.19±0.10 vs. 0.39±0.15, T9: 0.00 (0.10) vs. 0.45 (0.30), all P<0.05]. The incidence of candidemia in the nystatin group was slightly lower than that in control group [0.5% (3/60) vs. 7.8% (5/64), P>0.05]. The mortality in the nystatin group was lower than that in control group [18.3% (11/60) vs. 34.4% (22/64), P<0.05]. ICU day in the nystatin group was shorter than that in the control group (days: 9.56±3.47 vs. 11.89±6.32, P<0.05). However,hospital day was similar in the two groups (days: 18.35±7.42 vs. 20.58±8.77, P>0.05). CONCLUSIONS: Nystatin might reduce the colonization of Candida albicans and was associated with shorter ICU day.

Plasma levels of lipometabolism-related miR-122 and miR-370 are increased in patients with hyperlipidemia and associated with coronary artery disease.

BACKGROUND: Hyperlipidemia plays a crucial role in the development and progression of coronary artery disease (CAD). Recent studies have identified that microRNAs (miRNAs) are important regulators of lipid metabolism, but little is known about the circulating levels of lipometabolism-related miRNAs and their relationship with the presence of CAD in patients with hyperlipidemia. METHODS: In the present study, we enrolled a total of 255 hyperlipidemia patients with or without CAD and 100 controls with normal blood lipids. The plasma levels of four known lipometabolism-related miRNAs, miR-122, miR-370, miR-33a, and miR-33b were quantified by real-time quantitative PCR. Blood levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol were determined. Furthermore, the severity of CAD was assessed with the Gensini score system based on the degree of luminal narrowing and its geographic importance. RESULTS: Our results revealed for the first time that plasma levels of miR-122 and miR-370 were significantly increased in hyperlipidemia patients compared with controls, and the levels of miR-122 and miR-370 were positively correlated with TC, TG, and LDL-C levels in both hyperlipidemia patients and controls. Multiple logistic regression analysis demonstrated that the increased levels of miR-122 and miR-370 were associated with CAD presence, even after adjustment for other cardiovascular risk factors. Furthermore, miR-122 and miR-370 levels were positively correlated with the severity of CAD quantified by the Gensini score. However, both miR-33a and miR-33b were undetectable in plasma. CONCLUSIONS: Our results suggest that increased plasma levels of miR-122 and miR-370 might be associated with the presence as well as the severity of CAD in hyperlipidemia patients.