Objective:To investigate the relationship between serum vascular endothelial growth factor (VEGF), peripheral blood microRNA-126 (miR-126) and the number and distribution of cerebral microbleeds (CMBs).Methods:Consecutive patients with non-acute ischemic cerebrovascular disease admitted to the Department of Neurology, the First Affiliated Hospital of Baotou Medical College from June 2019 to June 2020 were enrolled. The clinical data were collected, 3.0 T MRI examination was performed, and susceptibility-weighted imaging was used to detect CMBs. The serum VEGF concentration was detected by enzyme-linked immunosorbent assay, and miR-126 was detected by fluorescence quantitative polymerase chain reaction. Multivariate logistic regression analysis was used to determine the independent influencing factors of CMBs. Multiple linear regression analysis was used to determine the correlation between serum VEGF concentration, miR-126 in peripheral blood and the number of CBMs. Receiver operating characteristic (ROC) curve was used to evaluate the predictive value of serum VEGF concentration and relative expression of miR-126 in peripheral blood for CMBs. Results:A total of 193 patients with non-acute ischemic cerebrovascular disease were enrolled, including 110 patients (57.0%) in the non-CMBs group, 20 (10.4%) in the strictly lobar CMBs group and 63 patients (32.6%) in non-strictly lobar CMBs group. The comparison among the three groups showed that age might be a risk factor for strictly lobar CMBs, while higher VEGF, higher cystatin C level, lower relative expression of miR-126 in peripheral blood, hypertension and previous stroke or transient ischemic attack might be the risk factors for non-strictly lobar CMBs. Multivariate logistic regression analysis showed that higher serum VEGF concentration was an independent risk factor for non-strictly lobar CMBs (odds ratio 1.186, 95% confidence interval 1.035-1.358; P=0.014), while the higher relative expression of miR-126 was an independent protective factor for non-strictly lobar CMBs (odds ratio 0.154, 95% confidence interval 0-0.269; P=0.026). Multiple linear regression analysis showed that higher serum VEGF concentration ( r=0.848, P<0.001) and the lower relative expression of miR-126 ( r=-0.043, P=0.035) significantly increased the number of CMBs. ROC curve analysis showed that the area under the curve of serum VEGF for predicting non-strictly lobar CMBs was 0.803 (95% confidence interval 0.741-0.865), the optimal cut-off value was 120.55 ng/L, the sensitivity was 70.7%, and the specificity was 75.5%. Conclusions:In patients with non-acute ischemic cerebrovascular disease, there is a significant correlation between serum VEGF concentration and the relative expression of miR-126 in peripheral blood and the number and distribution of CMBs. Serum VEGF can be used as a biomarker for predicting the presence of non-strictly lobar CMBs.

Objective:To analyze the clinicopathological characteristics of patients with unknown etiology of portal hypertension and investigate the efficacy of endoscopic management of gastroesophageal varices in these patients.Methods:Patients with unknown etiology of portal hypertension and gastroesophageal varices who received liver biopsy between January, 2017 and January, 2020 in Zhongshan Hospital were included. The characteristics of pathology, portal computed tomography (CT) angiography, and endoscopy were recorded and follow-up for the occurrence of bleeding after treatment.Results:A total of 31 patients were included and divided into cirrhosis with unknown etiology group ( n=10) and non-cirrhotic portal hypertension group ( n=21). Patients in the non-cirrhotic group were younger [28.0(29.5-49.5) vs 58.5(43.5-65.8), P=0.004] and mostly male (71.4%), and fewer comorbidities including diabetes (4.8% vs 40.0%, P=0.027). The features of pathology finding including vasculopathy, cholestasis, and hepatic sinusoidal dilatation as well as the Sarin classification and bleeding rate of gastroesophageal varices, proportion of patients receiving endoscopic treatment were shown similar between the two groups ( P>0.05). The hepatic venous pressure gradient (HVPG) was significantly lower in the non-cirrhotic group [4.5(2.8-12.8)mmHg vs 12(8-18)mmHg, P=0.018]. Among them, 21 patients received endoscopic treatment, and the bleeding rate had no difference between these two groups after endoscopic treatment ( P=0.751). Conclusions:Non-cirrhotic portal hypertension in a predominantly young male population has similar clinicalpathological characteristics when compared to cirrhotic portal hypertension with unknown etiology. HVPG can not reflect the actual portal pressure in these patients. Endoscopic treatment is the effective treatment option for the prevention of variceal bleeding.

Objective:In this study, a simple and easy diagnostic index of sarcopenia based on computed tomography (CT) images, linear skeletal muscle index (LSMI), was proposed and its diagnostic efficiency was verified.Methods:From April 2013 to September 2017, patients with cirrhotic gastroesophageal varices were selected from the Department of Gastroenterology, Zhongshan Hospital, Fudan University. The SMI of the third lumbar lower than 50 cm 2/m 2 in male and 39 cm 2/m 2 in female was defined as sarcopenia. The sensitivity, specificity, positive predictive value, negative predictive value, Youden index and receiver operating characteristic (ROC) curve were used to evaluate the diagnostic efficacy of LSMI in patients with cirrhotic gastroesophageal varices. Results:A total of 115 patients with cirrhotic gastroesophageal varices were finally recruited. All participants were randomly divided into modeling group ( n=58) and validation group ( n=57). In the modeling group, the area under the ROC curve of LSMI was 0.913(95% CI:0.84-0.986, P<0.001) in total population, 0.895(95% CI:0.793-0.997, P<0.001) in male and 0.917(95% CI:0.782-1.000, P<0.008) in female. The cut-off value of LSMI was 24.114 cm 2/m 2 in male and 22.54 cm 2/m 2 in female. According to the diagnostic cut-off value of the modeling group, the area under the ROC curve of LSMI was 0.846(95% CI:0.737-0.954, P<0.001) in the validation group. The sensitivity, specificity, positive predictive value, negative predictive value and Youden index were 88.5%, 80.6%, 79.3%, 89.3% and 0.691, respectively. Conclusions:48.7% of patients with cirrhosis of esophageal and gastric varices have sarcopenia. LSMI is a simple and convenient method for diagnosis of sarcopenia in patients with liver cirrhosis.

Objective To investigate the role of nuclear transcription factor kappa B (NF-κB) -matrix metalloproteinase-9 (MMP-9) signaling pathway in delayed encephalopathy after acute carbon monoxide poisoning (DEACMP). Methods 150 male SD rats were randomly assigned to air control group (AC group) , CO poisoning group (CO group) , pyrrolidine thiocarbamate (PDTC) + CO poisoning group (PC group). DEACMP model was reconstructed by modified intraperitoneal injections. The 1, 3, 7, 14, and 21 d after intraperitoneal injection were observed here by different approaches. Morris water maze test was used to test the learning and memory ability of rats.HE staining was used to observe the morphology of hippocampal CA3 cells. Immunofluorescence and Western Blot methods were used to detect the expression of NF-κB and MMP-9. RT-PCR was used to measure the expression of MMP-9 mRN A. Transmission electron microscopy was used to observe the ultrastructure of synapses. Results After14 days, the average intubation period of CO group was longer than that of AC group (P < 0.05) , and that of PC group was shorter than that of CO group (P < 0.05). However, average intubation period of PC group was longer than that of AC group (P< 0.05). In CO group, the expression of NF-κB in hippocampus increased (day 1). At day 3, the expression of NF-κB rapidly increased. The expression of MMP-9 gene and protein increased in the first three days and then decreased thereafter. The expression of NF-κB and MMP-9 in PC group was lower than that in CO group (P < 0.05) , while it was higher than AC group (P < 0.05). The peak value of apoptosis in CO group was delayed to 7-14 d after exposure, the apoptotic cells in PC group decreased significantly, and it was obvious on the 14 th day.Electron microscopy showed that the damage of synapses ultrastructure in CO group was significantly heavier than that in PC group on the 14 th day. Conclusions NF-κB-MMP-9 signal pathway leads to DEACMP, and PDTC could alleviate the impairment of learning and memory ability in rats with acute CO poisoning.

Viral-encoded microRNAs (miRNAs) have vital roles in the regulation of virus replications and host immune responses. The results of previous studies have indicated that miRNA clusters are involved in the replication and virulence of the pseudorabies virus (PRV), which may potentially lead to immune escape or facilitation of PRV replication. This study's previous research revealed that prv-miR-LLT11a was differentially expressed during PRV infection. The present study's results have demonstrated that prv-miR-LLT11a could significantly inhibit PRV replication. It was further determined that SLA-1 was the target gene of prv-miR-LLT11a, and simultaneously, that overexpression of prv-miR-LLT11a could downregulate the mRNA and protein levels of SLA-1 in a dose-independent manner. Furthermore, the present study also observed that prv-miR-LLT11a can downregulate TAP1 expression. Our findings provide a better understanding of the molecular mechanism involved in the effects of prv-miR-LLT11a on SLA-1 and TAP1 as well as its involvement in immune system evasion of PRV.
Herpesvirus 1, Suid ; Immune System ; MicroRNAs ; Pseudorabies ; RNA, Messenger ; United Nations ; Virulence ; Virus Replication

Objective:To explore the pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) from imaging perspective by analyzing voxel-based morphology (VBM) and functional connectivity (FC) in resting state functional magnetic resonance imaging (rs-fMRI).Methods:Thirty-five patients with NPSLE and 30 patients with non-NPSLE admitted to Department of Rheumatology and Immunology, Taizhou People's Hospital Affiliated to Nanjing Medical University from June 2020 to March 2023 were enrolled; 31 healthy subjects were included as healthy control group during the same period. All subjects completed routine MRI and rs-fMRI, laboratory tests (C3, C4, IgA, IgM and IgG levels), mini-mental state examination (MMSE), hospital anxiety and depression scale (HADS), and fatigue scale for motor and cognitive functions (FSMC). Whole brain gray matter volume in subjects of the 3 groups was analyzed by VBM method, and the brain regions enjoying significant differences in gray matter volume between the NPSLE group and non-NPSLE group were selected as regions of interest (ROIs) for whole brain FC analysis. Partial correlation method was used to analyze the correlations of imaging indexes in brain regions enjoying significant differences with clinical indexes and imaging scores between NPSLE group and non-NPSLE group. Efficacy of imaging indexes in brain regions enjoying significant difference in differentiating NPSLE from non-NPSLE was analyzed by receiver operating characteristic (ROC) curve.Results:(1) Covariance analysis among the 3 groups showed that the gray matter volume in the left inferior frontal gyrus of orbit, left superior frontal gyrus, right rectus gyrus, right transverse temporal gyrus, and right superior frontal gyrus was significantly different among the 3 groups ( P<0.001, FDR corrected); compared with the healthy control group, the NPSLE group had significantly reduced gray matter volume in the left inferior frontal gyrus of orbit, left superior frontal gyrus of orbit, right rectus gyrus, right transverse temporal gyrus, and right superior frontal gyrus ( P<0.001, FDR corrected); compared with the non-NPSLE group, the NPSLE group had significantly decreased gray matter volume in the left inferior frontal gyrus of orbit, right rectus gyrus, and right transverse temporal gyrus ( P<0.001, FDR corrected). (2) Whole brain FC analysis with brain regions enjoying significant differences as seed points showed that Fisher z-transformed FC (zFC) in the right transverse temporal gyrus and bilateral postcentral gyrus of the NPSLE group were significantly decreased ( P<0.001, FDR corrected). (3) Partial correlation analysis showed that, in the NPSLE group, zFC from the right transverse temporal gyrus to left posterior central gyrus was negatively correlated with disease course ( r=-0.390, P=0.027); gray matter volume in the right orbital superior frontal gyrus was negatively correlated with FSMC-cognitive ( r=-0.401, P=0.023); the gray matter volume in the right orbital superior frontal gyrus was negatively correlated with FSMC-motor ( r=-0.374, P=0.035). (4) ROC curve found that gray matter volume in the right rectus gyrus and zFC from the right transverse temporal gyrus to the right posterior central gyrus had relatively high efficacy in differentiating NPSLE from non-NPSLE, with AUC of 0.771 (95% CI: 0.658-0.885, P<0.001) and 0.794 (95% CI: 0.685-0.904, P<0.001), respectively. Conclusion:NPSLE patients have reduced gray matter volume in multiple brain regions (concentrating in the prefrontal limbic system); and reduced FC with some brain regions is noted; multiple indexes are correlated with clinical indexes.

BACKGROUND:Many clinical research observations have indicated a close association between rheumatoid arthritis and osteoporosis as well as bone mineral density(BMD).However,it remains unclear whether there is a causal genetic relationship between rheumatoid arthritis and the development of osteoporosis and alterations of BMD. OBJECTIVE:To assess the potential causal relationship between rheumatoid arthritis and osteoporosis as well as BMD using a two-sample Mendelian randomization approach,provide meaningful insights from a genetic perspective into the underlying mechanisms and offer a reference for early prevention of osteoporosis and improvement in the progression of the disease. METHODS:We conducted a study using data from publicly available genome-wide association studies databases to identify single nucleotide polymorphisms associated with rheumatoid arthritis as instrumental variables(P＜5×10-8).The main outcomes of the study included osteoporosis and BMD at five different sites,including total body BMD,lumbar spine BMD,femoral neck BMD,heel BMD,and forearm BMD.The inverse variance-weighted method was used as the primary analysis method to evaluate causal effects.Weighted median,simple median,weighted mode and MR-Egger regression were used as supplementary analyses.Causal relationships between rheumatoid arthritis and the risk of osteoporosis and BMD were assessed using odds ratios(OR)and 95%confidence intervals(CI).Heterogeneity was assessed using Cochran's Q test and horizontal pleiotropy was evaluated using MR-Egger intercept tests. RESULTS AND CONCLUSION:The inverse variance-weighted analysis demonstrated a positive association between genetically predicted rheumatoid arthritis and osteoporosis(OR=1.123,95%CI:1.077-1.171;P=4.02×10-8).Heterogeneity test(P=0.388)indicated no significant heterogeneity among the single nucleotide polymorphisms.MR-Egger intercept(P=0.571)tests did not detect horizontal pleiotropy,and sensitivity analysis showed no evidence of bias in the study results.There was no causal relationship between rheumatoid arthritis and BMD at the five different sites.The total body BMD(OR=1.000,95%CI:0.988-1.012;P=0.925),lumbar spine BMD(OR=0.999,95%CI:0.982-1.016;P=0.937),femoral neck BMD(OR=1.001,95%CI:0.986-1.016;P=0.866),heel BMD(OR=0.996,95%CI:0.989-1.004;P=0.419),and forearm BMD(OR=1.063,95%CI:0.970-1.031;P=0.996)indicated no significant association.MR-Egger intercept analysis did not detect potential horizontal pleiotropy(total body BMD:P=0.253;lumbar spine BMD:P=0.638;femoral neck BMD:P=0.553;heel BMD:P=0.444;forearm BMD:P=0.079).Rheumatoid arthritis may contribute to the development of osteoporosis through the interaction between chronic inflammation and bone formation,resorption,and absorption.Additionally,the use of glucocorticoids and the presence of autoantibodies(such as anti-citrullinated protein antibody)in patients with rheumatoid arthritis showed associations with osteoporosis.Future research should focus on monitoring systemic inflammatory markers,standardized use of glucocorticoids,and regular screening for osteoporosis risk in patients with rheumatoid arthritis.

Objective:To explore whether portal vein thrombosis affects the efficacy of endoscopic treatment in preventing re-bleeding from ruptured gastroesophageal varices in hepatitis B-related liver cirrhosis.Methods:Hospitalized patients who received endoscopic therapy to prevent re-bleeding from ruptured gastroesophageal varices due to hepatitis B-related liver cirrhosis during 2013 to 2017 were selected, and followed up for 1 year after treatment for re-bleeding and survival status. Patients were divided into thrombotic and non-thrombotic group according to whether they were combined with portal vein thrombosis at the time of initial admission. The baseline data characteristics of the two groups were analyzed. The 1-year re-bleeding rate and survival rate of the two groups were compared by Kaplan-Meier survival analysis. The other risk factors for re-bleeding after endoscopic variceal therapy were evaluated by univariate and multivariate regression.Results:A total of 124 cases with re-bleeding from ruptured gastroesophageal varices due to hepatitis B-related liver cirrhosis were included. The average age was 50.7 years old. 81.5% (101 cases) were male, and 24.2% (30 cases) were combined with portal vein thrombosis. There were no statistically significant differences between the thrombotic and the non-thrombotic group in the average age, gender, liver function classification, transjugular portal pressure gradient, antiviral treatment, and non-selective β-blockers. Kaplan-Meier analysis of the re-bleeding rate after endoscopic treatment indicated that the incidence of non-bleeding in patients with thrombotic group at 60 days, 180 days and 1 year was significantly lower than that in the non-thrombotic group [86.7%, 80.0%, 56.7% vs. 95.7%, 93.6%, 87.2% ( P = 0.000 1)]. Analysis of the location of portal vein thrombosis showed that the bleeding rate in the main portal trunk, left and right branches and superior mesenteric vein had increased significantly after endoscopic treatment, while the splenic vein had no effect on the bleeding after endoscopic treatment. Univariate and multivariate regression analysis indicated that age (HR 1.05, 95% CI: 1.01-1.09, P = 0.02) and thrombosis in the main portal trunk, left and right branches (HR 4.95, 95% CI: 2.05-11.95, P < 0.01) were independent risk factors for re-bleeding at 1 year after endoscopic treatment. Conclusion:Portal vein thrombosis is an independent risk factor that affects the efficacy of endoscopic treatment in preventing re-bleeding from ruptured gastroesophageal varices in hepatitis B-related liver cirrhosis and the risk of re-bleeding increases significantly after endoscopic treatment in patients with thrombosis.

Objective:To analyze the fail mode of neoadjuvant therapy combined with surgery for locally advanced esophageal squamous cell carcinoma (ESCC) after long-term follow-up.Methods:Clinical data of consecutive 238 patients with locally advanced resectable ESCC who underwent neoadjuvant therapy combined with surgery in Zhejiang Cancer Hospital from September 2012 to October 2019 were retrospectively analyzed. The failure mode in the whole cohort was analyzed after long-term follow-up. The overall survival (OS) and disease free survival (DFS) rates were analyzed by Kaplan-Meier method. Survival differences were determined by log-rank test.Results:The pathological complete response (pCR) rate was 42.0% in 238 patients. After a median follow-up of 46.1 months, tumor progression occurred in 96 patients (40.3%), including 25 patients (10.5%) with local recurrence, 61 patients (25.6%) with distant metastases, and 10 patients (4.2%) with simultaneous local recurrence and distant metastases. The median OS and DFS were 64.7 months and 49.9 months. And the 3-, 5-, and 7-year OS and DFS rates were 70.0%, 52.8%, 36.4% and 63.5%, 42.5%, and 30.0%, respectively. The 3-, 5-, and 7-year locoregional recurrence-free survival rates and distant metastasis-free survival rates were 86.0%, 71.4%, 61.2% and 70.6%, 55.9%, 43.0%. Compared with non-pCR patients, the overall progression rate and distant metastasis rate of pCR patients were lower (26.0% vs. 50.7%, 16.0% vs. 32.6%, both P<0.05). And the 3-, 5-, and 7-year OS (83.0% vs. 60.2%, 69.7% vs. 41.7%, 50.4% vs. 27.7%, all P<0.001) and DFS rates (80.4% vs. 51.4%, 63.9% vs. 31.2%, 45.9% vs. 20.3%, all P<0.001) were significantly better in pCR patients. Conclusions:Distant metastasis is the main failure mode of patients with locally advanced ESCC after neoadjuvant therapy. Patients with postoperative pCR can achieve better long-term survival.