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The military vocational education is facing the reform under the background of "Internet +" education. O2O teaching is a model that combines the online teaching resource platform with the offline traditional education, and it is consistent with the development trend of contemporary military vocational education. In this study, we analyze the comparative advantages of O2O teaching model in military vocational education, including the multi-dimensional teaching content, the interactive teaching method, and the autonomy of teaching design. In this model, students become the subject of learning, and the process of storing knowledge will be transformed into the application and creation of knowledge. This paper also elucidates the feasibility of O2O teaching in the military vocational education, and further discusses its design in application from the point of view of managers, teachers and learners.
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ObjectiveDepression is common in patients with primary biliary cholangitis （PBC）， but the role of depression in disease progression remains unclear. This study aims to investigate the association between depression and treatment response and the impact of depression on liver cirrhosis in PBC patients. MethodsA retrospective analysis was performed for the clinical data of 141 patients with PBC who attended the outpatient service of autoimmune liver diseases in General Hospital of Tianjin Medical University from January 2018 to December 2020 and received standard ursodeoxycholic acid （UDCA） monotherapy for 1 year， and 170 healthy controls， matched for age and sex， who underwent physical examination in Physical Examination Center were enrolled as healthy control group. Patient Health Questionnaire-9 （PHQ-9） was used to evaluate depressive state in the patients with PBC and the healthy controls. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups； the chi-square test was used for comparison of categorical data between two groups. The binary logistic regression model and the decision tree model were used to analyze the influencing factors for liver cirrhosis in patients with PBC， as well as the influence of depression and the HLA-DRB1 gene on liver cirrhosis. The receiver operating characteristic （ROC） curve， the area under the ROC curve （AUC）， and goodness of fit were used to evaluate model performance. All 13 variables were used to establish a classification and regression tree （CART） model， i.e.， age， sex， PHQ-9 score， the DRB1*03∶01 gene， and the serum levels of alanine aminotransferase， aspartate aminotransferase， alkaline phosphatase （ALP）， gamma-glutamyl transpeptidase （GGT）， total bilirubin， immunoglobulin G， immunoglobulin M （IgM）， C3， and C4. The indications including AUC， sensitivity， and specificity were used to evaluate the performance of CART model in the model cohort. ResultsCompared with the normal control group， the PBC group had a significantly higher proportion of the patients with depression （53.9% vs 15.3%， χ2=57.836， P<0.001）. Compared with the PBC patients without depression， the PBC patients with depression had a significantly poorer response to UDCA treatment （χ2=7.549， P=0.006） and significant increases in the serum levels of ALP （Z=-2.157， P=0.031）， GGT （Z=-2.180， P=0.029）， and IgM （Z=-2.000， P=0.046）. Compared with the PBC patients without depression， the PBC patients carrying the HLA-DRB1*03∶01 allele had a significant increase in the risk of liver cirrhosis （P<0.001）. The binary logistic regression model analysis showed that PHQ-9 score （OR=1.148， 95%CI： 1.050 — 1.255， P=0.002）， the HLA-DRB1*03∶01 gene （OR=5.150， 95%CI： 1.362 — 19.478， P=0.016）， age （OR=1.057， 95%CI： 1.009 — 1.106， P=0.018）， and serum ALP level （OR=1.009， 95%CI： 1.001 — 1.017， P=0.020） were independent risk factors for liver cirrhosis in patients with PBC. The decision tree analysis showed that PHQ-9 score ≥3.5 was also a risk factor for liver cirrhosis in PBC patients. ConclusionDepression is associated with poor treatment response in patients with PBC， and it is an independent risk factor for liver cirrhosis in patients with PBC. This study highlights the important clinical significance of the identification and early management of depressive state in patients with PBC.
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Hepatolenticular degeneration (HLD) is an autosomal recessive liver disease associated with copper metabolism disorders. Mutations in the ATP7B gene on chromosome 13 result in impaired transmembrane transport of copper ions, which in turn leads to excessive deposition of copper in the liver, brain, cornea, kidney, and bone joints (mainly in the liver and the brain). Early diagnosis and treatment can significantly reduce tissue damage and improve the prognosis of patients. American Association for the Study of Liver Diseases issued the guidelines for the diagnosis and treatment of HLD in 2008, and the European Association for the Study of the Liver released such guidelines in 2012. This article summarizes the recent research advances in China and foreign countries to give an overview of the treatment of HLD.
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Objective@#To observe and analyze the role of intestinal barrier in the pathognesis of autoimmune hepatitis (AIH), to explain the pathogenesis of AIH and to explore the intestinal based new treatment strategies.@*Methods@#A total of 14 AIH patients from January to December 2017 at Tianjin Medical University General Hospital (six patients without liver cirrhosis, and eight patients with liver cirrhosis) and 10 healthy controls were enrolled. The serum levels of D-lactic acid (D-Lac) and diamine oxidase (DAO) were detected by enzyme-linked immunosorbent assay. Real time fluorescence quantitative polymerase chain reaction was used to detect the relative expression levels of connexin (zonula occluden-1 (ZO-1), occludin), cytokines (interleukin(IL)-2, interferon(IFN)-γ, IL-4, IL-10) and Toll-like receptor 4 (TLR4) in terminal ileal tissues of each group. The relative expression of secretory immunoglobulin A (sIgA) in the terminal ileum was determined by Western blotting. Thirty BALB/c mice were selected and divided into blank control group, dextran sulfate sodium (DSS) group, concanavalin A (ConA) group, DSS+ ConA group, and DSS+ bacterium+ ConA group, with six mice in each group. The relative expression levels of ZO-1, occludin in mouse colonic tissues, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and inflammatory activity degree of liver tissues (Knodell score) of each group were measured. T-test and one-way analysis of variance were performed for statistical analysis.@*Results@#The serum D-Lac and DAO levels of AIH with liver cirrhosis group and AIH without liver cirrhosis group were both higher than those of healthy control group ((1 768.2±147.1) μg/L, (436.2±197.0) μg/L vs. (100.2±10.9) μg/L, and (11.5±2.5) U/L, (5.4±0.9) U/mL vs. (3.5±0.9) U/mL), and the levels of D-Lac and DAO of AIH with liver cirrhosis group were the highest; and the differences were statistically significant (t=5.512, 36.010, 4.088 and 9.443, F=396.958 and 46.640, all P<0.01). The relative expression levels of ZO-1 and occludin in the terminal ileal mucosa of AIH with liver cirrhosis group were lower than those of healthy control group (0.20±0.14 vs. 1.67±0.51, 0.12±0.09 vs. 0.90±0.21), and the relative expression of ZO-1 in AIH without liver cirrhosis group was lower than that in healthy control group (0.99±0.37 vs. 1.67±0.51); and the differences were statistically significant (t=8.641, 7.407 and 2.295, all P<0.05). The relative expression levels of IL-2 and IFN-γ in terminal ileal tissues of AIH with liver cirrhosis group were higher than those of healthy control group (1.11±0.43 vs. 0.24 ±0.16, and 3.50 ± 1.90 vs. 0.32±0.30), however the relative expression of sIgA in terminal ileal tissues was lower than that of healthy control group (0.506±0.024 vs. 1.081±0.102); and the differences were statistically significant (t=4.679, 3.981 and 5.493, all P<0.05). While the relative expression levels of IL-10 in AIH with liver cirrhosis group and AIH without liver cirrhosis group were lower than that in healthy control group (0.30±0.20, 0.42±0.24 vs. 0.84± 0.23), and the relative expression levels of TLR4 in ileum mucosa of the both groups were higher than that of healthy control group (8.74 ±5.13, 6.74 ±3.65 vs. 0.89 ± 0.70); and the differences were statistically significant (t=3.095, 4.816, 3.856 and 3.685, all P<0.05). The relative expression levels of ZO-1 and occludin of DSS+ ConA group were lower than those of ConA group (0.14±0.08 vs. 0.98±0.13, and 0.09±0.02 vs. 0.98±0.16), however serum ALT, AST levels and the Knodell score were all higher than those of ConA group ((5 496.67±618.83) U/L vs. (3 325.00±1 030.06) U/L, (8 825.00±1 165.35) U/L vs. (5 433.33±1 691.14) U/L, and 18.00±2.00 vs. 9.33±3.01); and the differences were statistically significant (t=13.480, 13.520, 4.227, 4.045 and -2.892, all P<0.05). The relative expression levels of ZO-1 and occludin in DSS+ bacterium+ ConA group were higher than those in DSS+ ConA group (0.46±0.08 vs. 0.14±0.08, and 0.53±0.15 vs. 0.09±0.02), while serum ALT and AST levels were lower than those of DSS+ ConA group ((4 343.33±252.16) U/L vs. (5 496.67±618.83) U/L, and (6 123.33±1 086.60) U/L vs. (8 825.00±1 165.35) U/L); and the differences were statistically significant (t=6.928, 7.122, 4.228 and 4.153, all P<0.01).@*Conclusions@#AIH patients have increased intestinal permeability and impaired intestinal barrier which is more serious in patients with liver cirrhosis than in patients without cirrhosis. The intestinal barrier injury can aggravate ConA-induced immune-mediated liver injury. While the protection and repair of intestinal barrier can alleviate immune-mediated liver injury induced by ConA.
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Objective:To explore the clinical characteristics of liver function of patients with autoimmune liver disease (AILD) complicated with gallbladder stone (GS), so as to guide clinical practice.Methods:From November 2009 to October 2018, at General Hospital of Tianjin Medical University, the clinical data of 386 patients with AILD were retrospectively analyzed. According to the relevant diagnostic criteria, 208 cases of autoimmune hepatitis (AIH), 129 cases of primary biliary cholangitis (PBC) and 49 cases of PBC-AIH overlap syndrome were screened out. The incidence, clinical characteristics and the changes of laboratory indicators including albumin, alkaline phosphatase (ALP) and γ-glutamyl transferase (GGT) of AILD patients complicated with GS were analyzed. Chi-square test, t test and rank sum test were performed for statistical analysis. Results:There was no significant difference in the incidence between AILD, AIH, PBC and PBC-AIH overlap syndrome patients complicated with GS (32.9%, 127/386; 28.8%, 60/208; 36.4%, 47/129 and 40.8%, 20/49; respectively; P>0.05). Gallstones of AILD patients complicated with GS mostly were multiple and small stones with maximum diameter <1 cm (45.7%, 58/127 and 57.7%, 60/104, respectively). The age of initial diagnosis, the proportion of liver cirrhosis at inital diagnosis and the levels of ALP and GGT were higher in AILD patients complicated with GS than those of AILD patients without GS ((60.5±11.5) years vs. (57.6±11.5) years; 53.5%, 68/127 vs. 42.1%, 109/259; 154.00 U/L (89.00 U/L, 257.00 U/L) vs. 125.00 U/L (86.00 U/L, 212.00 U/L); 169.00 U/L (79.00 U/L, 343.00 U/L) vs. 128.60 U/L (48.00 U/L, 284.00 U/L); respectively); however the albumin level was lower than that of AILD patients without GS ((36.46±7.30) g/L vs. (38.34±7.58) g/L), and the differences were statistically significant ( t=-2.361, χ2=4.506, Z=-2.192, -2.443, t=2.322; all P<0.05). The incidence of GS in AILD patients≥60 years old was higher than that AILD patients<60 years old (37.6%, 73/194 vs. 28.1%, 54/192), and the difference was statistically significant ( χ2=3.948, P=0.047). The incidence of GS in AILD patients and AIH patients complicated with liver cirrhosis was higher than that in patients without liver cirrhosis (38.4%, 68/177 vs. 28.2%, 59/209; 35.7%, 35/98 vs. 22.7%, 25/110; respectively), and the differences were statistically significant ( χ2=4.506 and 4.259, P=0.034 and 0.039). Conclusions:AILD patients complicated with GS are common, most are multiple and small stones. When complicated with GS, the initial diagnosis may be delayed and the rate of liver cirrhosis at initial diagnosis may increase. The incidence of GS is high in AILD patients with older age and liver cirrhosis.
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Objective:To observe and analyze the role of intestinal barrier in the pathognesis of autoimmune hepatitis (AIH), to explain the pathogenesis of AIH and to explore the intestinal based new treatment strategies.Methods:A total of 14 AIH patients from January to December 2017 at Tianjin Medical University General Hospital (six patients without liver cirrhosis, and eight patients with liver cirrhosis) and 10 healthy controls were enrolled. The serum levels of D-lactic acid (D-Lac) and diamine oxidase (DAO) were detected by enzyme-linked immunosorbent assay. Real time fluorescence quantitative polymerase chain reaction was used to detect the relative expression levels of connexin (zonula occluden-1 (ZO-1), occludin), cytokines (interleukin(IL)-2, interferon(IFN)-γ, IL-4, IL-10) and Toll-like receptor 4 (TLR4) in terminal ileal tissues of each group. The relative expression of secretory immunoglobulin A (sIgA) in the terminal ileum was determined by Western blotting. Thirty BALB/c mice were selected and divided into blank control group, dextran sulfate sodium (DSS) group, concanavalin A (ConA) group, DSS+ ConA group, and DSS+ bacterium+ ConA group, with six mice in each group. The relative expression levels of ZO-1, occludin in mouse colonic tissues, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and inflammatory activity degree of liver tissues (Knodell score) of each group were measured. T-test and one-way analysis of variance were performed for statistical analysis. Results:The serum D-Lac and DAO levels of AIH with liver cirrhosis group and AIH without liver cirrhosis group were both higher than those of healthy control group ((1 768.2±147.1) μg/L, (436.2±197.0) μg/L vs. (100.2±10.9) μg/L, and (11.5±2.5) U/L, (5.4±0.9) U/mL vs. (3.5±0.9) U/mL), and the levels of D-Lac and DAO of AIH with liver cirrhosis group were the highest; and the differences were statistically significant ( t=5.512, 36.010, 4.088 and 9.443, F=396.958 and 46.640, all P<0.01). The relative expression levels of ZO-1 and occludin in the terminal ileal mucosa of AIH with liver cirrhosis group were lower than those of healthy control group (0.20±0.14 vs. 1.67±0.51, 0.12±0.09 vs. 0.90±0.21), and the relative expression of ZO-1 in AIH without liver cirrhosis group was lower than that in healthy control group (0.99±0.37 vs. 1.67±0.51); and the differences were statistically significant ( t=8.641, 7.407 and 2.295, all P<0.05). The relative expression levels of IL-2 and IFN-γ in terminal ileal tissues of AIH with liver cirrhosis group were higher than those of healthy control group (1.11±0.43 vs. 0.24 ±0.16, and 3.50 ± 1.90 vs. 0.32±0.30), however the relative expression of sIgA in terminal ileal tissues was lower than that of healthy control group (0.506±0.024 vs. 1.081±0.102); and the differences were statistically significant ( t=4.679, 3.981 and 5.493, all P<0.05). While the relative expression levels of IL-10 in AIH with liver cirrhosis group and AIH without liver cirrhosis group were lower than that in healthy control group (0.30±0.20, 0.42±0.24 vs. 0.84± 0.23), and the relative expression levels of TLR4 in ileum mucosa of the both groups were higher than that of healthy control group (8.74 ±5.13, 6.74 ±3.65 vs. 0.89 ± 0.70); and the differences were statistically significant ( t=3.095, 4.816, 3.856 and 3.685, all P<0.05). The relative expression levels of ZO-1 and occludin of DSS+ ConA group were lower than those of ConA group (0.14±0.08 vs. 0.98±0.13, and 0.09±0.02 vs. 0.98±0.16), however serum ALT, AST levels and the Knodell score were all higher than those of ConA group ((5 496.67±618.83) U/L vs. (3 325.00±1 030.06) U/L, (8 825.00±1 165.35) U/L vs. (5 433.33±1 691.14) U/L, and 18.00±2.00 vs. 9.33±3.01); and the differences were statistically significant ( t=13.480, 13.520, 4.227, 4.045 and -2.892, all P<0.05). The relative expression levels of ZO-1 and occludin in DSS+ bacterium+ ConA group were higher than those in DSS+ ConA group (0.46±0.08 vs. 0.14±0.08, and 0.53±0.15 vs. 0.09±0.02), while serum ALT and AST levels were lower than those of DSS+ ConA group ((4 343.33±252.16) U/L vs. (5 496.67±618.83) U/L, and (6 123.33±1 086.60) U/L vs. (8 825.00±1 165.35) U/L); and the differences were statistically significant ( t=6.928, 7.122, 4.228 and 4.153, all P<0.01). Conclusions:AIH patients have increased intestinal permeability and impaired intestinal barrier which is more serious in patients with liver cirrhosis than in patients without cirrhosis. The intestinal barrier injury can aggravate ConA-induced immune-mediated liver injury. While the protection and repair of intestinal barrier can alleviate immune-mediated liver injury induced by ConA.
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Liver macrophages are in a dynamic equilibrium of immune tolerance and immune response after continuous antigen stimulation. The immune response of liver macrophages to external antigen is closely associated with the immune homeostasis of the liver. This article reviews the association between the programmed necrosis pathway and the apoptotic pathway and elaborates on the important role of the activity of IKK complex in the interactive regulation of the programmed necrosis and apoptotic pathways. Further studies are needed to clarify the role of programmed necrosis in the response of liver macrophages to extrahepatic antigens.
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Objective To provide clues for the study on the mechanism of autoimmune liver disease (AILD) by exploring the existence of specific bacteria in liver tissues of AILD patients.Methods From August 2017 to August 2018,at Department of Gastroenterology arnd Hepatology,Tianjin Medical University General Hospital,a total of 12 patients diagnosed as AILD (four autoimmune hepatitis (AIH),four primary biliary cirrhosis (PBC) and four PBC-AIH overlap syndrome (OS)) and four patients with hepatic cyst (control group) were enrolled and all the patients underwent liver biopsy.16S rRNA gene sequencing was carried out in the obtained aseptic liver tissues.Linear discriminant analysis effect size was used to find out the specific bacteria.Spearman correlation analysis was performed to analyze the correlation between the liver microbiota and the disease.The metabolic function of the 16S rRNA gene sequences was also predicted.Results Bacteria were detected in the liver tissues of all the 16 patients.At the species level,the abundance of Planococcus rifietoensis of AIH group was 0.100％,which was higher than those of other three groups (0),and the difference was statistically significant (linear discriminant analysis (LDA) =3.31,P =0.034).The abundance of Anoxybacillus flavithermus of PBC group was 0.200％,which was higher than those of other three groups (0.100％),and the difference was statistically significant (LDA =3.34,P =0.014).The abundance of Pseudomonas aeruginosa PAO1,Bacillus firmus,Brevibacillus agri,Acinetobacter baumannii,Sphingomonas zeae and Salmonella enterica were significantly negatively correlated with serum level of γ-glutamyl transferase (r=-0.68,-0.68,-0.67,-0.68,-0.68 and-0.66,all P ＜0.01).Compared with that of the hepatic cyst group,the lipid metabolism of AILD patients decreased.The levels of serum low density lipoprotein and total cholesterol were significantly negatively correlated with the biosynthesis of unsaturated fatty acids (r =-0.55 and-0.65,both P ＜ 0.05).Conclusions There exist specific bacteria in the liver tissues of AIH and PBC groups.The liver microbiota which is closely related with the pathogenesis of AILD might be a potential therapeutic target and diagnostic biomarker.
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Objective To explore the teaching effects of high altitude military hygiene protection, and to provide the basis for the reform of teaching methods. Methods A questionnaire survey was con-ducted among 55 students who had attended the training program of high altitude military hygiene protec-tion from 2015 to 2017. The survey included teaching effects, curriculum design, teaching methods and suggestions. The results of the survey were processed with SPSS 18.0, and the results were expressed in number and rate. Results 55 questionnaires were distributed and all of them were valid. 69.1％of the stu-dents considered that it was very rewarding to take part in the training class. 67.3％of the students believed that it was very helpful to improve post competence. 71.8％ of the students believed that the knowledge module was necessary. The teaching methods that students wanted to experience are:case teaching, practice teaching, discussion and communication, teacher lecturing, visiting teaching, equipment teaching and litera-ture studying. Conclusions The curriculum of the training program of high altitude military hygiene pro-tection is reasonable and helpful in improving post competence. Students recommended flexible teaching methods, which are suitable to try the reform of teaching methods.
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Objective To investigate the expression level of receptor-interacting protein serine threonine kinase (RIP) 3 in macrophages/monocytes activation in autoimmune hepatitis (AIH) and its regulation on inflammatory cytokines.Methods The degree of macrophage infiltration and the expression of RIP3 in liver tissues from patients with AIH or hepatic cysts by double-immunofluorescence.After 24 hours treated with different concentrations (0,1,3,6,10 μg/mL) of lipopolysaccharide (LPS),Necrostatin-1,the specific inhibitor of RIP3 signaling pathway,and 6-thioguanine,the active metabolite of azathioprine,the expression levels of RIP1 (RIP3 upstream signal molecule),RIP3 and mixed-lineage kinase domain-like protein (MLKL,RIP3 downstream substrate) in RAW264.7 macrophages were detected by Western blotting.The expression of macrophage-associated cytokine at mRNA level of each treatment group was determined by real time quantitative polymerase chain reaction (PCR).Student's t test and sum rank test were performed for statistical analysis.Spearman analysis was performed for the correlation analysis.Results Compared with hepatic cysts adjacent liver tissues,the infiltration of CD68 positive macrophages in liver tissue of AIH patients was significantly increased (4.75 ± 0.96 vs 28.86 ± 6.23),and the difference was statistically significant (t =7.80,P＜0.05),and the expression level of RIP3 also was significantly increased (15,11 to 22 vs 0,0 to 1),and the difference was statistically significant (Z=-2.66,P＜0.05).In vitro,compared with those of control group,the expression levels of RIP1,RIP3 and MLKL stimulated by LPS at 0,1,3,6,10 μg/mL were significantly increased,and the differences were statistically significant (t=4.00,4.90,6.40,10.30;3.80,9.30,9.80,9.00;4.90,9.90,9.30 and 7.70;all P＜0.05),and were dose-dependent (r=0.91,0.86 and 0.79,all P＜0.05).Furthermore,compared with those of LPS-stimulated group,the expressions of RIP1,RIP3,MLKL of LPS+Necrostatin-1 group were significantly decreased (0.73±0.11 vs 0.47±0.13,0.60±0.07 vs 0.37 ± 0.05,0.65 ± 0.22 vs 0.38 ± 0.04,respectively),and the differences were statistically significant (t=2.60,4.50 and 2.10,all P＜0.05).And the expressions of interleukin (IL)-1β,IL-6and IL-10 at mRNA levels were also decreased (810.3±200.8 vs 463.7±118.1,1 504.4±482.7 vs 290.4±106.9,1 358.6 ± 559.2 vs 677.8 ± 297.6,respectively),and the differences were statistically significant (t=5.40,12.52,5.70,all P＜0.05).However,the expressions of IL-4 and TGF-β at mRNA levels up-regulated (0.3±0.2 vs 0.6±0.3,0.4±0.1 vs 0.9±0.4,respectively),and the differences were statistically significant (t=4.60 and 6.10,both P＜0.05).Compared with those of the LPS-stimulated group,the expressions of IL-1β,IL-6 and IL-10 at mRNA levels of LPS and 6-thiopurine stimulated group significantly down-regulated (810.3±200.8 vs 283.4±65.5,1 504.4±482.7 vs 354.4±73.8,1 358.6± 559.2 vs 625.6±336.3),and the differences were statistically significant (t=4.30,10.60 and 3.50,all P＜0.05);however,the expressions of IL-4 and TGF-β at mRNA levels significantly up-regulated (0.3±0.2 vs 0.6±0.1 and 0.4±0.1 vs 0.5±0.1),and the differences were statistically significant (t=5.20and 12.50,P＜0.05).Conclusions The regulation effects of 6-thiopurine on RIP3 signaling pathway and related cytokines are similar to those of Necrostatin-1.And the expression of RIP3 signaling protein increasing in activated macrophages of liver tissues from AIH patients is closely related to the regulation of IL-6.The RIP3 mediated inflammatory signaling pathway in macrophage may be involved in the genesis and development of AIH and may be a potential therapeutic target.
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Liver macrophages are in a dynamic equilibrium of immune tolerance and immune response after continuous antigen stimulation. The immune response of liver macrophages to external antigen is closely associated with the immune homeostasis of the liver. This article reviews the association between the programmed necrosis pathway and the apoptotic pathway and elaborates on the important role of the activity of IKK complex in the interactive regulation of the programmed necrosis and apoptotic pathways. Further studies are needed to clarify the role of programmed necrosis in the response of liver macrophages to extrahepatic antigens.