中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R

2016 No. 3

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Editorial
Metabolic syndrome and fatty liver
Fan JianGao, Yan ShiYan
2016, 32(3): 407-410. DOI: 10.3969/j.issn.1001-5256.2016.03.001
Abstract:
There is a close relationship of metabolic syndrome( MS) with chronic liver disease,especially fatty liver. There have been many studies on the clinical features,pathogenesis,diagnosis,and treatment of MS with fatty liver,but controversy still exists. This article reviews the latest progress and difficulties in the clinical studies of MS and related fatty liver,alcoholic liver disease,and chronic viral hepatitis,so as to help physicians improve the management of MS and fatty liver.
Therapeutic guidelines
Guideline for the diagnosis and treatment of gallbladder carcinoma(2015 edition)
Biliary Surgery Group of Surgery Branch of Chinese Medical Association
2016, 32(3): 411-419. DOI: 10.3969/j.issn.1001-5256.2016.03.002
Abstract(379) PDF (407KB)(2793)
Abstract:
An interpretation of recommendations for expert consensus on the diagnosis and treatment of primary sclerosing cholangitis(2015)
Han Ying, Zhu JiangYi
2016, 32(3): 420-422. DOI: 10.3969/j.issn.1001-5256.2016.03.003
Abstract:
Recommendations for APASL Clinical Practice Guidelines: management of hepatitis B (updated in 2015)
Zhu Peng, Tang Yi, Wang YuMing
2016, 32(3): 423-428. DOI: 10.3969/j.issn.1001-5256.2016.03.004
Abstract:
Recommendations for EASL clinical practice guidelines: liver transplantation(2015)
Shi YingHong, Tian MengXin, Fan Jia
2016, 32(3): 429-431. DOI: 10.3969/j.issn.1001-5256.2016.03.005
Abstract:
Discussions by experts
Nonalcoholic fatty liver disease and hepatocellular carcinoma
Li LiangPing
2016, 32(3): 432-436. DOI: 10.3969/j.issn.1001-5256.2016.03.006
Abstract:
As the etiology of hepatocellular carcinoma( HCC) has been changing,the incidence of HCC related to nonalcoholic fatty liver disease( NAFLD) is gradually increasing in developed countries in Europe and America and some countries in Asia. This article introduces the close association between NAFLD and HCC,risk factors,clinicopathological features,and prevention and screening,and points out that although the incidence of NAFLD is not as high as that of hepatitis B- or hepatitis C- related HCC,there are a large absolute number of NAFLD patients,especially the high- risk patients with diabetes and obesity,or liver fibrosis / cirrhosis,due to a huge base number of NAFLD patients. NAFLD- related HCC is commonly seen in the elderly with various comorbidities and a poor prognosis. This article also points out that the prevention should focus on the effective treatment of NAFLD. The strict screening of high- risk population is the strategy for the diagnosis of early- stage HCC. At present,the sensitivity of alpha- fetoprotein is relatively low,and imaging examinations including computed tomography are the main screening methods; however,there are no measures for early warning of NAFLD- related HCC.
Nonalcoholic fatty liver disease and serum uric acid
Xu BeiBei, Wang BingYuan
2016, 32(3): 437-441. DOI: 10.3969/j.issn.1001-5256.2016.03.007
Abstract:
Nonalcoholic fatty liver disease( NAFLD) is considered the manifestation of metabolic syndrome( MS) in the liver. Besides glucose and lipid metabolic disorders,the level of serum uric acid( SUA) is also associated with the progression of NAFLD. This article reviews the research achievements in the association between SUA and NAFLD and points out that SUA can independently predict the risks of MS,type 2 diabetes,and cardiovascular disease in both healthy people and patients. Its mechanism may be that SUA increases the expression of reactive oxygen species( ROS) / thioredoxin- interacting protein( TXNIP) through inducing ROS,and then it activates the NLR pyrin domain containing 3 inflammasome and induces the secretion of interleukin. Both basic and clinical research show that the drugs reducing SUA can inhibit the TXNIP pathway,reduce the blood glucose level,and alleviate liver ROS,inflammation,steatosis,and fibrosis. This article suggests that SUA may be a promising therapeutic method for NAFLD and needs further basic and clinical research.
Role of cell senescence in development and progression of nonalcoholic fatty liver disease
Zhang Jing, Wang BingYuan, Shi JunPing
2016, 32(3): 442-445. DOI: 10.3969/j.issn.1001-5256.2016.03.008
Abstract:
Nonalcoholic fatty liver disease( NAFLD) is a clinicopathological syndrome characterized by fatty degeneration of hepatocytes due to nonalcoholic reasons. Liver cirrhosis and hepatocellular carcinoma are two important outcomes of NAFLD. Cell senescence is a relatively stable state in which cells deviate from the normal cell cycle and experience an irreversible loss of proliferative capacity,which is an objective law in cell life. Research shows that cell senescence is closely associated with the progression of liver fibrosis and the development and progression of hepatocellular carcinoma in NAFLD,and provides a new perspective for the prevention and treatment of liver fibrosis and hepatocellular carcinoma.
Research advances in susceptibility genes and their role in the pathogenesis of nonalcoholic fatty liver disease
Xuan ShiYing, Yuan Chen, Lu LinLin, Xin YongNing
2016, 32(3): 446-452. DOI: 10.3969/j.issn.1001-5256.2016.03.009
Abstract(2272) PDF (1559KB)(1048)
Abstract:
Currently the incidence of nonalcoholic fatty liver disease( NAFLD) is increasing,and the age of onset is getting younger worldwide,resulting in a heavy economic burden for both individuals and the society. Since NAFLD is closely related to heredity,metabolism,and the environment,genetic factors play an important role in the development and progression of NAFLD. With the development and wide application of the techniques from the genome- wide association studies,new research advances have been achieved in the susceptibility genes of NAFLD. This review summarizes the related research findings at home and abroad,and investigates the pathogenic factors for NAFLD and related mechanisms with a focus on the polymorphisms of susceptibility genes.
Original articles_ Fatty liver and metabolic syndrome
Prevalence of nonalcoholic fatty liver disease and its prognostic factors
Ni ManMan, Zhang YingQiu, Chen YueXiang, Zhang PingPing, Ceng Xin
2016, 32(3): 453-458. DOI: 10.3969/j.issn.1001-5256.2016.03.010
Abstract:

Objective To investigate the prevalence,natural history,and causes of death of nonalcoholic fatty liver disease( NAFLD),as well as related influencing factors. Methods A total of 833 retired cadres and staff members who underwent physical examination in Shanghai Changzheng Hospital and Shanghai 85 Hospital of the PLA from January 1 to December 31,2011 and received follow- up visits in either hospital every year since 2011 were enrolled as study subjects,and were divided into NAFLD group( 459 patients who were diagnosed with NAFLD before December 31,2011) and control group( 374 patients without liver or biliary diseases). The patients' clinical data were collected,including body height,body weight,systolic pressure,diastolic pressure,blood biochemical parameters,presence or absence of diabetes,hyperlipidemia,cerebrovascular and cardiovascular diseases,and malignant tumor,and smoking and drinking,and the death time and causes of death were clarified for the patients who died. The prevalence and natural course of NAFLD and related risk factors and prognostic factors were analyzed in this population. The t- test was applied for comparison of continuous data between groups,the chi- square test was applied for comparison of categorical data between groups,the multivariate binary logistic regression was applied to analyze the risk factors for the pathogenesis of NAFLD,and the multinomial logistic regression was applied to analyze the influencing factors for aggravation or alleviation of NAFLD. Results The patients in NAFLD group accounted for 55. 1% of all subjects,and the proportion of male patients was higher than that of female patients( 58. 0% vs 46. 7%,χ2= 4. 962,P = 0. 026). Compared with the control group,the NAFLD group had significantly higher body mass index( BMI),systolic pressure,diastolic pressure,alanine aminotransferase( ALT),fasting blood glucose,serum uric acid,and triglyceride( TG),a significantly higher proportion of male patients,and significantly higher proportions of patients with hypertension,diabetes,metabolic syndrome,newly- onset diabetes,and newly- onset metabolic syndrome( all P < 0. 05),as well as a significantly lower high- density lipoprotein cholesterol level( t =- 9. 818,P < 0. 001). Of all 374 patients in the control group,64( 17. 1%) had newly- onset NAFLD,and the incidence rate of newly- onset NAFLD showed no significant difference between male and female patients( 18% vs 15%,χ2= 0. 349,P > 0. 05); BMI and TG were the independent risk factors for newly- onset NAFLD( OR =1. 304,95% CI: 1. 153- 1. 474,P < 0. 001; OR = 1. 509,95% CI: 1. 080- 2. 166,P = 0. 016). At the end of follow- up in NAFLD group,235 patients( 51. 2%) achieved a stable disease,40( 8. 7%) achieved improvement,144( 31. 4%) achieved remission,and 40( 8. 7%) experienced aggravation. The increase in BMI increased the risk of aggravation of NAFLD( OR = 1. 163,95% CI: 1. 028- 1. 316,P = 0. 016),while reductions in BMI and serum uric acid were the protective factors against NAFLD( OR = 0. 849,95% CI: 0. 781-0. 923,P < 0. 001; OR = 0. 997,95% CI: 0. 995- 1. 000,P = 0. 038). Ten patients in NAFLD group died( including 5 patients with malignant tumor and 2 patients with cerebrovascular and cardiovascular diseases),and 6 patients in the control group died( including 2 patients with malignant tumor,no patients with cerebrovascular and cardiovascular diseases),and the risk of death showed no significant difference between the two groups( P > 0. 05). Conclusion The prognosis of NAFLD is relatively good in people who underwent physical examination,and BMI,TG,and serum uric acid are the factors affecting the prognosis of such patients. The major causes of death in NAFLD patients are malignant tumor and cerebrovascular and cardiovascular diseases,rather than end- stage liver disease.

Clinical significance of Fibro Touch,ultrasound,and computed tomography in diagnosis of fatty liver disease: a comparative analysis
Li JingBo, Liu Shu, Wen Bo, Gao Nan, Wang BingYuan
2016, 32(3): 459-462. DOI: 10.3969/j.issn.1001-5256.2016.03.011
Abstract:

Objective To investigate the clinical significance of image- guided transient elastography Fibro Touch with fat attenuation parameter( FAP) in the diagnosis of fatty liver disease. Methods A total of 1080 persons who underwent physical examination in The First Affiliated Hospital of China Medical University from January to December,2014 were enrolled,and liver FAP,the results of color Doppler ultrasound for the liver,and liver / spleen CT ratio on computed tomography( CT) scan for the liver were collected and analyzed. The Kruskal- Wallis H test was applied for comparison of continuous data between groups,and the Kappa consistency coefficient and receiver operating characteristic curve were used to investigate the consistency between FAP and the results of color Doppler ultrasound for the liver or liver / spleen CT ratio on CT scan for the liver in the diagnosis of fatty liver disease and their diagnostic values. Results Liver ultrasound found 336 patients( 31. 11%) without fatty liver disease and 744 patients( 68. 89%) with fatty liver disease; with reference to the results of ultrasound,the sensitivity and specificity of Fibro Touch were 80. 5% and 75. 3%,respectively. Liver CT found 821 patients( 76. 02%)without fatty liver disease( grade 0) and 259 patients with fatty liver disease,among whom 216 had mild fatty liver disease( grade 1),34 had moderate fatty liver disease( grade 2),and 9 had severe fatty liver disease( grade 3); with reference to the results of liver CT,the sensitivity and specificity of Fibro Touch were 95. 4% and 47. 0%,respectively,and the sensitivity and specificity of ultrasound were 93. 1%and 36. 8%,respectively. As for the diagnosis of fatty liver disease,the results of Fibro Touch had a higher consistency with ultrasound results( Kappa coefficient = 0. 597,P < 0. 0001),and a lower consistency with CT results( Kappa coefficient = 0. 113,P < 0. 0001). Conclusion Fibro Touch has the advantages of high accuracy,easy operation,noninvasiveness,and low cost,and therefore it is a promising imaging method for the diagnosis of fatty liver disease.

Current status of nonalcoholic fatty liver disease and related risk factors: an analysis of an enterprise in Xi'an
Zhou Juan, Niu ChunYan, Wang Dan, Zhao HongXin, Yan YingLi, Yan Rong
2016, 32(3): 463-466. DOI: 10.3969/j.issn.1001-5256.2016.03.012
Abstract:

Objective To investigate the current status of nonalcoholic fatty liver disease( NAFLD) in an enterprise in Xi'an,China,and to provide a scientific basis for further studies on NAFLD in Shanxi. Methods A total of 415 employees who underwent health examination in The First Affiliated Hospital of Xi'an Medical University from June to July,2014 were enrolled. All the patients underwent physical examination,abdominal ultrasound,and serological examination,and completed related questionnaires. The t- test was applied for comparison of continuous data,and the Pearson correlation analysis was applied for correlation analysis. Results Of all the 415 patients,86( 20. 7%)had NAFLD,consisting of 70 patients( 16. 9%) with mild NAFLD and 16 patients( 3. 8%) with moderate NAFLD. The population with an age of 50- 58 years had the highest prevalence rate( 30. 8%,16 /52). Of all the 86 patients with NAFLD,57( 66. 3%) had obesity,and76( 88. 4%) had abdominal obesity. The employees with moderate NAFLD had a significantly higher alanine aminotransferase( ALT) level,a significantly higher aspartate aminotransferase( AST) level,a significantly larger abdominal circumference,and a significantly higher body mass index( BMI) than those with mild NAFLD( t =- 4. 140,- 3. 512,- 4. 405,and- 5. 051,respectively,all P < 0. 05). In the employees with NAFLD,BMI and abdominal circumference were correlated with AST level( r = 0. 283 and 0. 271,both P < 0. 05) and ALT level( r = 0. 325 and 0. 316,both P < 0. 05). Most employees in this enterprise had a bad eating habit,a sedentary lifestyle,and a lack of physical exercise. Conclusion This enterprise has a high prevalence rate of NAFLD. BMI and abdominal circumference of patients with NAFLD have certain clinical values in predicting the degree of fat deposition in the liver,and are correlated with AST and ALT levels.

Original articles_Viral hepatitis
Effects of serum levels of chemokines on sustained virological response in patients with HBeAg-positive chronic hep-atitis B after treatment with pegylated interferon α-2b
Li Yan, Wang Xia, Cheng LiWei, Pan XiuCheng, Dan Ben, Geng Jian, Liu RuiXia, Fu JuanJuan, Li Li
2016, 32(3): 467-471. DOI: 10.3969/j.issn.1001-5256.2016.03.013
Abstract:
Objective To investigate the changes in serum levels of interferon( IFN)- γ- inducible protein 10( IP- 10),monokine induced by IFN- γ( Mig),and chemokine regulated upon activation,normal T cell expressed and secreted( RANTES) in patients with HBe Ag- positive chronic hepatitis B( CHB) undergoing pegylated interferon( PEG- IFN) therapy,and to explore their predictive values for the efficacy of PEG- IFN therapy. Methods Fifty- three patients with HBe Ag- positive CHB who received PEG- IFN α- 2b therapy in our hospital from February 2012 to December 2013 were enrolled as subjects. Forty- six out of the fifty- three patients were followed up for 24 weeks after 48 weeks of treatment. According to the incidence of sustained virological response( SVR),these patients were divided into A group( SVR,n = 17) and B group( NO SVR,n = 29). Serum levels of IP- 10,Mig,RANTES,hepatitis B virus( HBV) DNA,HBs Ag,and alanine aminotransferase( ALT) in peripheral venous blood were measured at baseline,after 12,24,and 48 weeks of treatment,and at 24 weeks after treatment. Comparison of continuous data between two groups and within the groups was made by t test and paired t test,respectively. Correlation was analyzed using the Pearson correlation coefficient. Between- group comparison of categorical data was made by χ2test. Results Compared with the B group,the A group had significantly higher baseline serum levels of IP- 10 and Mig and a significantly lower level of HBs Ag( t = 2. 696,P < 0. 05; t = 2. 963,P < 0. 05; t = 2. 401,P < 0. 05). The baseline levels of IP- 10 and Mig were positively correlated with the baseline level of ALT( r = 0. 570,P < 0. 05; r = 0. 317,P < 0. 05). Compared with the baseline levels,patients had significantly reduced serum levels of HBV DNA,HBs Ag,ALT,and Mig after 12 weeks of treatment( t = 2. 126,P <0. 05; t = 2. 217,P < 0. 05; t = 2. 376,P < 0. 05; t = 2. 776,P < 0. 05) and 24 weeks of treatment( t = 2. 635,P < 0. 05; t = 2. 453,P <0. 05; t = 2. 627,P < 0. 05; t = 2. 803,P < 0. 05). There were significant differences in levels of IP- 10 and Mig between the SVR group and non- SVR group before and after 12 and 24 weeks of treatment( all P < 0. 05). In the A group,the levels of Mig after 12 and 24 weeks of treatment were significantly lower than the baseline level( t = 3. 061,P < 0. 01; t = 3. 105,P < 0. 01). In the B group,the serum level of Mig after 24 weeks of treatment was significantly lower than the baseline level( t = 2. 632,P < 0. 01). The baseline serum levels of IP-10,Mig,and HBs Ag had predictive values for SVR( all P < 0. 05). In the 46 patients,the incidence of SVR in patients with baseline levels of Mig higher than 80 pg / ml( 12 /20) was significantly higher than that in patients with baseline levels of Mig lower than 80 pg / ml( 5 /26)( 60. 0% vs 19. 2%,χ2= 8. 06,P < 0. 01); the incidence of SVR in patients with baseline levels of IP- 10 higher than 120 pg / ml( 12 /25) was significantly higher than that in patients with baseline levels of IP- 10 lower than 120 pg/ml( 5 /21)( 48. 0% vs 23. 8%,χ2= 3. 86,P < 0. 05). Conclusion The baseline serum levels of IP- 10 and Mig are both predictors of the incidence of SVR in patients with HBe Ag- positive CHB undergoing PEG- IFN therapy,and Mig provides superior prediction.
Correlation of HBV DNA load with liver pathology,liver function,and serological markers of liver fibrosis in children with chronic hepatitis B
Qin XiaoMei, Fan ChenYing, Li ShuangJie, Peng HuiYun
2016, 32(3): 472-475. DOI: 10.3969/j.issn.1001-5256.2016.03.014
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Objective To investigate the correlation of HBV DNA load with liver pathology,liver function,and serological markers of liver fibrosis in children with chronic hepatitis B( CHB). Methods A total of 79 children with a confirmed diagnosis of CHB who were admitted to Liver Research Center of Children's Hospital of Hunan Province from July 2010 to June 2015 were selected,and according to the serum HBV DNA load,they were divided into low load group( 103< HBV DNA load≤105copies / ml,n = 8),medium load group( 105< HBV DNA load ≤107copies / ml,n = 54),and high load group( HBV DNA load > 107 copies / ml,n = 17). The degree of liver pathological changes and serum levels of alanine aminotransferase( ALT),aspartate aminotransferase( AST),procollagen type Ⅲ( PC Ⅲ),laminin( LN),hyaluronic acid( HA),and type Ⅳ collagen( Ⅳ- C) were compared between the groups. The Kruskal- Wallis rank sum test was applied for comparison of continuous data between groups,and Kendall's tau- b rank correlation analysis was applied for correlation analysis. Results The three groups mainly had a liver inflammation grade of G1,which accounted for 75%,74. 1%,and 64. 7%,respectively,and the high load group had an increased proportion of G2 patients( 35. 5%). The three groups mainly had a fibrosis stage of S1,which accounted for 75. 0%,72. 2%,and 70. 6%,respectively,and there were S4 patients in the low load group( 12. 5%). HBV DNA load was not correlated with liver inflammation grade or fibrosis stage( r = 0. 069 and- 0. 047,both P > 0. 05). The medium load group had higher serum levels of ALT and AST than the low load group,and the high load group had higher serum levels of ALT and AST than the medium load group; serum ALT level showed a significant difference between the three groups( χ2= 5. 37,P = 0. 048). The medium load group had lower serum levels of HA,LN,PCⅢ,and Ⅳ- C than the low load group,and the high load group had lower serum levels of HA,LN,PCⅢ,and Ⅳ- C than the medium group; serum PCⅢ level showed a significant difference between the three groups( χ2= 6. 26,P = 0. 044).Conclusion In children with CHB,HBV DNA load is not significantly correlated with liver pathology. A comprehensive analysis of HBV DNA load,liver function,and serological markers of liver fibrosis in clinical practice in combination with liver biopsy can achieve an objective and accurate evaluation of the conditions of children with CHB.
Classification tree model analysis of influencing factors for hepatocyte steatosis in patients with chronic hepatitis B
Wang Peng, Zhang ZhiQiao, Kang KaiFu, Wu GuoBiao
2016, 32(3): 476-479. DOI: 10.3969/j.issn.1001-5256.2016.03.015
Abstract:
Objective To investigate the influencing factors for hepatocyte steatosis in patients with chronic hepatitis B( CHB) and the high- risk population by classification tree model analysis,and to establish a simple method to assess the risk of hepatocyte steatosis in CHB patients. Methods The clinical data and pathological results of the CHB patients who underwent liver biopsy in Department of Infectious Diseases,The First People's Hospital of Shunde,from January 2006 and December 2014 were collected. The classification tree model was applied to analyze the influencing factors for hepatocyte steatosis,and index value curve,misclassification matrix,and error of estimation were applied for overall evaluation of classification results of the classification tree model. Results The influencing factors for hepatocyte steatosis in CHB patients were body mass index( BMI),total cholesterol,and low- density lipoprotein,and the most important factor was BMI. This classification tree model had a sensitivity of 84. 3%,a specificity of 81. 5%,an accuracy of 82. 9%,and an error of estimation of 0. 171,suggesting that this model was well fitted. Conclusion Classification tree model analysis shows that the pathogenesis of hepatocyte steatosis in CHB patients is closely related to the influencing factors BMI,total cholesterol,and low- density lipoprotein. A simple classification method is established based on these factors to evaluate the risk of hepatocyte steatosis in CHB patients. It is necessary to conduct further clinical studies to investigate the clinical value of this method.
Genotypes and resistance loci in patients with chronic hepatitis B achieving virologic breakthrough in treatment with lamivudine combined with adefovir after developing drug resistance in treatment with lamivudine alone
Yang DongQiang, Chen Fang, Kang Yi, Ding GangQiang, Xiao ErHui, Peng Zhen, Shang Jia
2016, 32(3): 480-483. DOI: 10.3969/j.issn.1001-5256.2016.03.016
Abstract:
Objective To investigate the genotypes and resistance loci in patients with chronic hepatitis B( CHB) achieving virologic breakthrough in the treatment with lamivudine( LAM) combined with adefovir( ADV) after developing drug resistance in the treatment with LAM alone. Methods A total of 89 CHB patients who were admitted to Henan Provincial People's Hospital and treated with LAM and ADV as the antiviral therapy after developing drug resistance in the treatment with LAM alone from June 2010 to June 2013 were enrolled,and their serum samples were collected. Quantitative real- time PCR was used for hepatitis B virus( HBV) detection,and sequencing was applied to determine the genotype and detect the resistance loci rt N236 T,rt A181 V,rt M204 V,and rt L180 M. The t- test was applied for comparison of continuous data between groups,and the chi- square test was applied for comparison of categorical data between groups. Results LAM rt M204 V mutation was detected in all the 89 patients after treatment with LAM alone. After the combination therapy with LAM and ADV,ADV rt N236 T mutation was detected in 9 patients,ADV rt A181 V mutation in 5 patients,and rt N236 T + rt A181 V mutation in 8 patients,with an overall ADV resistance rate of 24. 7%( 22 /89). As for HBV genotyping,82 patients had genotype C,and rt A181 V + rt N236 T mutation was detected in 8 patients; 7 patients had genotype B. Conclusion Compared with the patients with HBV genotype B,the patients with genotype C are more susceptible to rt A181 V + rt N236 T mutation during the combination therapy with LAM and ADV after developing drug resistance in the treatment with LAM alone.
Effects of HBV X protein on expression and promoter methylation of p16 tumor suppressor gene
Kang YanHong, Li Wei, Zhan WeiLi, Shang Jia, Yang Lin
2016, 32(3): 484-487. DOI: 10.3969/j.issn.1001-5256.2016.03.017
Abstract:
Objective To explore the effects of hepatitis B virus X protein( HBx) on the expression and promoter methylation of the p16 tumor suppressor gene,and to investigate the epigenetic role of HBx in the development and progression of hepatitis B virus( HBV)- associated hepatocellular carcinomas( HCC). Methods Experiments were performed in the human hepatoblastoma cell line Hep G2,Hep G2 cells expressing green fluorescent protein( Hep G2 / GFP),and Hep G2 cells stably expressing GFP- HBx fusion protein( Hep G2 / GFP- HBx).Western blot was used to determine the expression levels of the p16 protein in Hep G2 cells,Hep G2 / GFP cells,and Hep G2 / GFP- HBx cells. Hep G2 / GFP- HBx cells were treated with a universal inhibitor of DNA methyltransferase( DNMT),5- aza- 2'- deoxycytidine( 5-aza- 2'- d C). Methylation- specific polymerase chain reaction( MSP) was used to determine the promoter methylation of the p16 tumor suppressor gene in Hep G2 cells,Hep G2 / GFP cells,and Hep G2 / GFP- HBx cells treated with or without 5- aza- 2'- d C. Multiple- group comparison was made by analysis of variance. Results According to the results of Western blot,Hep G2 / GFP- HBx cells had a significantly lower expression level of the p16 protein than Hep G2 cells and Hep G2 / GFP cells( P = 0. 0007; P = 0. 0014); there was no significant difference in the expression level of the p16 protein between Hep G2 / GFP and Hep G2 cells( P > 0. 05). The MSP assay revealed partial Cp G methylation in the p16 promoter region in Hep G2 / GFP- HBx cells. No promoter methylation was detected in Hep G2 cells or Hep G2 / GFP cells. Non- methylation in the p16 promoter region was restored in Hep G2 / GFP- HBx cells treated with 5- aza- 2'- d C. Conclusion In the hepatoblastoma cell line,HBx down- regulates the expression of the p16 tumor suppressor gene by inducing methylation in its promoter region. The DNMT inhibitor,5- aza- 2'- d C,restores non- methylation in the p16 promoter region. The reversible modification provides new insights for the treatment and prevention of HBV- associated HCC.
Original articles_Liver fibrosis and liver cirrhosis
Clinical manifestations and pathological features of congenital hepatic fibrosis: an analysis of 13 patients
Wu Jian, Yin Fang, Xia Lin, Luo GuanHong, Li Hong, Zhu ShaoHua, Zhang Jing, Zheng YangYang, Sun Han, Zhou XinMin
2016, 32(3): 488-490. DOI: 10.3969/j.issn.1001-5256.2016.03.018
Abstract:
Objective To summarize the clinical manifestations and pathological features of congenital hepatic fibrosis( CHF),and to improve the experience in the diagnosis and treatment of this disease. Methods A total of 13 patients with a confirmed diagnosis of CHF based on histopathological examinations who were hospitalized and treated in Xijing Hospital,Fourth Military Medical University,from January2011 to June 2015 were analyzed retrospectively. The clinical data including age,clinical manifestations,laboratory markers,and imaging findings were summarized and analyzed. Results Of all the patients,there were 8 cases of portal hypertension type,1 case of cholangitis type,1 case of mixed type,and 1 case of latent type. The imaging findings suggested that 8 patients had liver and kidney cysts,and 4 patients had cavernous transformation of the portal vein. Conclusion CHF patients often have portal hypertension and normal liver function as prominent manifestations,with concurrent liver and kidney cysts and Caroli disease. Liver biopsy should be performed for unexplained liver cirrhosis,especially for patients with inconsistency between reduction in liver function and portal hypertension.
Clinical value of apparent diffusion coefficient in classification of liver fibrosis in chronic liver diseases
Zhang Jing, Zhao Hong, Zhang JiHong, Huang Rui, Lin XiaoRui, Liu RuJun, Li AnLian, Bei JinLing
2016, 32(3): 491-494. DOI: 10.3969/j.issn.1001-5256.2016.03.019
Abstract:
Objective To investigate the clinical value of apparent diffusion coefficient( ADC) in classification of liver fibrosis in chronic liver diseases. Methods A total of 63 chronic liver disease patients with liver fibrosis who were admitted to The Second People's Hospital of Zhuhai from December 2012 to June 2015 were analyzed retrospectively and divided into S0 group( 24 patients),S1 group( 18 patients),S2 group( 10 patients),S3 group( 6 patients),and S4 group( 5 patients) according to the fibrosis stage. All the patients received conventional magnetic resonance imaging scan and diffusion- weighted imaging,and ADC values were obtained. The Kruskal- Wallis H test was applied for comparison between multiple groups,and the Mann- Whitney U test was applied for further comparison between each two groups; the Spearman rank correlation analysis was applied for correlation analysis. Results Classification of liver fibrosis in chronic hepatitis was negatively correlated with ADC( r =- 0. 389,P < 0. 001); ADC showed significant differences between the five groups( H =19. 904,P < 0. 001); ADC value in the S0 group was significantly different from those in the S1,S2,S3,and S4 groups( U = 18. 5,3. 0,0 and 0,respectively,all P < 0. 05); ADC value in the S1 group was significantly different from those in the S2,S3,and S4 groups( U =129. 5,16. 5,and 70. 0,respectively,all P < 0. 05); the areas under the receiver operating characteristic curve for ADC value in quantitative evaluation of no liver fibrosis( S≥1) and moderate- to- severe liver fibrosis( S≥2) were 0. 950 and 0. 799,respectively,with sensitivities of 100% and 77. 8% and specificities of 89. 7% and 85. 7%. Conclusion ADC has a certain clinical value in classification of liver fibrosis in chronic liver diseases.
Correlation between serum levels of complement C5a and liver fibrosis markers in patients with obstructive jaundice
Li ZhangZheng, Liu QuanDa, Yu HuiJie, Hu WenWei, Li Xue, Liu MingHao
2016, 32(3): 495-498. DOI: 10.3969/j.issn.1001-5256.2016.03.020
Abstract:
Objective To investigate the change in the serum level of complement C5 a after obstruction removal and its correlation with the serum levels of liver fibrosis markers in patients with obstructive jaundice. Methods A total of 164 patients with obstructive jaundice who underwent endoscopic retrograde cholangiopancreatography and obstruction removal in our hospital from June 2012 to June 2014 were enrolled,and 20 healthy adults were enrolled as the control group. The serum levels of complement C5 a and four liver fibrosis markers,type Ⅳcollagen( ⅣP),pre- type Ⅲ collagen( PⅢP),laminin( LN),and hyaluronic acid( HA),were measured. The t- test was applied for comparison between groups,and linear correlation analysis was applied for correlation analysis. Results Compared with the healthy controls,the patients with obstructive jaundice had a significantly higher serum level of complement C5a( 89. 7 ± 30. 2 vs 62. 2 ± 21. 1 ng / L;t = 2. 213,P = 0. 016),and the serum level of complement C5 a was closely related to the course of obstruction( r = 0. 954,P = 0. 003).The serum level of complement C5 a decreased significantly after obstruction removal( 66. 2 ± 26. 3 ng / L; t = 1. 998,P = 0. 021). Before obstruction removal,the serum level of complement C5 a increased synchronously with those of ⅣP( r = 0. 976,P < 0. 001),PⅢP( r =0. 972,P < 0. 001),LN( r = 0. 915,P = 0. 039),and HA( r = 0. 962,P = 0. 002); after obstruction removal,the serum level of complement C5 a decreased synchronously with those of ⅣP( r = 0. 965,P = 0. 001),PⅢP( r = 0. 912,P = 0. 003),and HA( r = 0. 875,P =0. 023). Conclusion Complement C5 a may be involved in the development of liver fibrosis induced by obstructive jaundice.
Relationship of hyponatremia with degree of liver injury and prognosis in patients with decompensated liver cirrhosis
Li Ying, Xu JiZhe, Liang LiNa, Liu LiNa
2016, 32(3): 499-502. DOI: 10.3969/j.issn.1001-5256.2016.03.021
Abstract:
Objective To investigate the relationship between hyponatremia and degree of liver injury,complications and survival time,and the prognostic value of hyponatremia in patients with decompensated liver cirrhosis. Methods A total of 218 patients who were diagnosed with decompensated liver cirrhosis for the first time in The First Affiliated Hospital of Dalian Medical University from January 2000 to March2005 were enrolled in this study,and according to the serum sodium concentration,these patients were divided into group Ⅰ with a serum sodium concentration of ≥130 mmol / L( n = 51),group Ⅱ with a serum sodium concentration of ≥120 and < 130 mmol / L( n = 97),group Ⅲ with a serum sodium concentration of < 120 mmol / L( n = 70). The patients' sex,age,serum sodium concentration,Child- Pugh class,and complications were analyzed,and the survival time was calculated. The one- way analysis of variance was applied for comparison of continuous data between groups,and the least significant difference t- test was applied for comparison between any two patients; the chi- square test was applied for comparison of categorical data between groups; the Kaplan- Meier method was applied for survival analysis,and the Cox regression model was applied for regression analysis. Results Compared with groups Ⅰ and Ⅱ,group Ⅲ had the highest proportion of patients with Child- Pugh C cirrhosis. With the increasing Child- Pugh score,the serum sodium concentration decreased; the serum sodium concentration showed significant differences across the patients with Child- Pugh A,B,and C cirrhosis( F = 17. 336,P <0. 001),and differed significantly between any two groups of these patients( all P < 0. 05). Compared with groups Ⅰ and Ⅱ,group Ⅲ had the highest incidence rate of complications,and the incidence rates of hepatic encephalopathy and hepatorenal syndrome showed significant differences across the three groups( χ2= 17. 718 and 6. 277,both P < 0. 05). Group Ⅲ had a significantly shorter survival time than groupsⅠ and Ⅱ( both P < 0. 05). Conclusion In patients with decompensated liver cirrhosis,the severity and incidence rate of hyponatremia increase significantly as liver injury becomes more severe,which suggests that hyponatremia can be used as a prognostic indicator in patients with decompensated liver cirrhosis.
Antifibrotic mechanism of Fuzheng Huayu prescription by regulation of the differential expression of microRNAs in mouse liver
Wang QingLan, Tao YanYan, Lu: Jing, Liu Ping, Liu ChengHai
2016, 32(3): 503-508. DOI: 10.3969/j.issn.1001-5256.2016.03.022
Abstract:
Objective To identify microRNAs( miRNAs) regulated by Fuzheng Huayu prescription( FZHY) and analyze their biological functions,and to partially reveal the antifibrotic mechanism of FZHY in liver fibrosis. Methods The mouse model of liver fibrosis was developed by subcutaneous injection of CCl4. The mice were divided into normal group,model group,and FZHY group. The mice received FZHY once a day at 3 days before model establishment,and the treatment lasted for 8 weeks. Collagen deposition in liver tissue was evaluated by Sirius Red staining and determination of hydroxyproline( Hyp) content. The expression profile of miRNAs in mouse liver was determined by miRNA microarray. According to the expression profile,miRNAs regulated by FZHY were identified by looking for miRNAs showing the same trends in the normal group and the FZHY group compared with the model group. The results were confirmed by quantitative real- time PCR. The miRNA targets were predicted using Target Scan program and PITA database. The DAVID database was used to analyze and identify the substantial functions and signaling pathways of those miRNA targets. Comparison between multiple groups was made by analysis of variance. Results FZHY substantially reduced Hyp content and inhibited collagen deposition in the fibrotic liver tissue. The miRNA microarray identified mmu- miR- 322,mmu- miR- 342- 3p,and mmu- miR- 296- 5p as miRNAs regulated by FZHY. According to the analysis of signaling pathway,the three miRNAs might regulate 32 signaling pathways,including chemokine signaling pathway,focal adhesion,MAPK signaling pathway,regulation of actin cytoskeleton,gap junction,ECM- receptor interaction,Wnt signaling pathway,and Jak- STAT signaling pathway,which were closely related to liver fibrosis; the functional enrichment analysis predicted 32 substantial functions of the three miRNAs,including GTPase regulator,cell junction,regulation of apoptosis,regulation of Ras signal transduction,and small GTPase regulator,which were closely related to liver fibrosis. Conclusion The antifibrotic effect of FZHY in the liver might be achieved by down- regulation of the expression of miR- 322,miR- 342- 3p,and miR- 296- 5p,which regulates their specific functions,such as MAPK signaling pathway,Wnt signaling pathway,regulation of apoptosis,and regulation of Ras signal transduction. The conclusion deserves further investigation.
Original articles_Liver neoplasms
Tumor features and correlation between lymphocyte count and biochemical parameters in patients with hepatitis B vi-rus- associated primary liver cancer with Yin deficiency
Yang ZhiYun, Du LinLin, He LingLing, Zhao YaLin, Jiang YuYong, Li XiuLan
2016, 32(3): 509-513. DOI: 10.3969/j.issn.1001-5256.2016.03.023
Abstract:

Objective To investigate the tumor features and the correlation between lymphocyte count and biochemical parameters in patients with hepatitis B virus- associated primary liver cancer( PLC) with yin deficiency. Methods A total of 148 PLC patients who were treated in Beijing Ditan Hospital,Capital Medical University,from July 2013 to February 2015 were enrolled and divided into yin- deficiency PLC group( 52 patients) and non- yin- deficiency PLC group( 96 patients). The patients' general information and laboratory markers were collected,including oncological parameters( alpha- fetoprotein,carcinoembryonic antigen( CEA),and carbohydrate antigen 199( CA19- 9)),virological parameter( HBs Ag),gross type( nodular type,massive type,bulky type,and diffuse type),radiological features( main portal vein diameter,portal vein tumor thrombus,and extrahepatic metastasis),biochemical parameters( Model for End- Stage Liver Disease( MELD) score,white blood cell,red blood cell,platelet( PLT),alanine aminotransferase,aspartate aminotransferase,total bilirubin( TBil),gamma- glutamyl transpeptidase,alkaline phosphatase,albumin,cholinesterase,prothrombin time( PT),and prothrombin time activity( PTA)),and lymphocyte count. The t- test was applied for comparison of normally distributed continuous data between groups,and the Pearson correlation analysis was applied for correlation analysis. The Mann- Whitney U test was applied for comparison of non- normally distributed continuous data between groups,and the Spearman correlation analysis was applied for correlation analysis. The chi- square test was applied for comparison of categorical data between groups. Results HBs Ag showed a significant difference between the two groups( χ2= 5. 658,P = 0. 017). Compared with the non- yin- deficiency PLC group,the yin- deficiency PLC group had significantly increased CEA and CA19- 9( U =- 2. 200 and- 2. 194,both P < 0. 05),significantly increased MELD score,TBil,and PT( t = 2. 2,U=- 2. 0,U =- 2. 0,all P < 0. 05),and significantly reduced PLT and PTA( U =- 3. 1,t =- 2. 5,both P < 0. 05),as well as significantly reduced lymphocyte,T lymphocyte,CD8+T lymphocyte,and CD4+T lymphocyte( t =- 2. 7,U =- 2. 6,t =- 2. 2,U =- 2. 9,all P < 0. 05). In the PLC patients with yin deficiency,CD4+T lymphocyte count was positively correlated with PLT and PTA( r = 0. 360 and 0. 295,both P < 0. 05); CD8+T lymphocyte count was positively correlated with PLT and PTA( r = 0. 352 and 0. 464,both P < 0. 05)and was negatively correlated with MELD score,TBil,and PT( r =- 0. 358,- 0. 378,and- 0. 520,all P < 0. 05). Conclusion Compared with the liver cancer patients with other syndrome types,PLC patients with yin deficiency have a worse liver synthetic function,more significant cholestatic symptoms,and a lower immune function,and coagulation function tends to become worse when CD4+T lymphocyte count decreases. With the decreasing CD8+T lymphocyte count,coagulation function and liver reserve function become worse.

Clinical features of non- B non- C hepatocellular carcinoma and virus-associated hepatocellular carcinoma and re-lated prognostic factors
Huang Yu, Huang Di, Liu Shuo, Weng JieFeng, Zhang Shuai, Zhang Qiang, Mai ZhenHao, Gu WeiLi
2016, 32(3): 514-517. DOI: 10.3969/j.issn.1001-5256.2016.03.024
Abstract:
Objective To investigate the differences in the clinical features of non- B,non- C hepatocellular carcinoma( NBNC- HCC)and virus- associated hepatocellular carcinoma( BC- HCC) and related prognostic factors. Methods A total of 231 patients with primary liver cancer who underwent partial hepatectomy in Guangzhou First People's Hospital from January 1,1999 to July 1,2014 were selected,and those who were lost to follow- up and unwilling to cooperate were excluded; 146 patients were finally enrolled,and were divided into NBNC- HCC group( 35 patients) and BC- HCC group( 111 patients). The patients' clinical data were collected,and the patients were followed up to record their survival,time to recurrence,and death time. The chi- square test was applied for comparison of categorical data between groups,and the t- test was applied for comparison of continuous data between groups. The log- rank test was applied for comparison of survival rates,the Kaplan- Meier method was applied for univariate analysis and survival analysis,and the Cox proportional hazards regression model was applied for multivariate analysis. Results Compared with the BC- HCC group,the NBNC- HCC group had a significantly higher mean age and a significantly higher proportion of patients in TNM stage Ⅰ- Ⅱ( t = 3. 878,P < 0. 05; χ2= 4. 357,P < 0. 05),as well as a significantly lower preoperative level of alpha- fetoprotein( AFP)( t = 7. 848,P < 0. 05). The mean survival time for the NBNC- HCC group and the BC- HCC group was 35. 5 ± 27. 9 months and 26. 8 ± 21. 7 months,respectively,and there were significant differences in the 3- and 5- year survival rates between the NBNC- HCC group and the BC- HCC group( 61. 6% vs 26. 6%,39. 2% vs14. 1%,both P < 0. 05). Multivariate analysis showed that albumin( Alb) level was the independent prognostic factor for the NBNC- HCC group( RR = 0. 919,95% CI: 0. 851- 0. 994; P = 0. 036); the diameter of tumor was the independent prognostic factor for the BC- HCC group( RR = 1. 082,95% CI: 1. 027- 1. 141; P = 0. 003). Conclusion NBNC- HCC and BC- HCC have differences in age,AFP level,and TNM stage. Alb level is the independent prognostic factor for NBNC- HCC,and the diameter of tumor is the independent prognostic factor for BCV- HCC.
Clinical effect of precise sequential interventional therapy in patients with unresectable hepatic metastasis after surgery for colorectal cancer
Wang Xin, Zhang Hui, He XiaoJun, Li XinHui, Liu Yang, Zhang HongYi
2016, 32(3): 518-521. DOI: 10.3969/j.issn.1001-5256.2016.03.025
Abstract:
Objective To investigate the clinical effect of precise sequential interventional therapy in patients with unresectable hepatic metastasis after surgery for colorectal cancer. Methods The clinical data of 63 patients with unresectable hepatic metastasis after surgery for colorectal cancer,who were admitted to Air Force General Hospital,PLA from January 2005 to September 2012,were collected. According to therapeutic methods,these patients were divided into precise sequential interventional therapy group( group A,33 patients) and systemic chemotherapy group( group B,30 patients). The patients in group A underwent transcatheter arterial chemoembolization and radiofrequency ablation,and those in group B underwent systemic chemotherapy. The percentages of peripheral blood CD3+,CD4+,and CD8+T cells and CD4+/ CD8+ratio were measured before and after the initial treatment. The level of carcinoembryonic antigen( CEA) was measured and compared before the initial treatment and after the final treatment,and follow- up was conducted to observe tumor progression and survival.The t- test was applied for comparison of continuous data between groups; the chi- square test was applied for comparison of categorical data between groups; the Wilcoxon rank sum test was applied for comparison of clinical effect; the Log- Rank test was applied for comparison of survival rate. Results In group A,the percentages of CD3+,CD4+,and CD8+T cells and CD4+/ CD8+ratio changed significantly after the initial treatment( t = 4. 52,- 3. 27,2. 95,and 4. 54,all P < 0. 05); serum CEA level also changed significantly after treatment( 38. 76 ± 9. 57) μg/ml vs( 10. 53 ± 8. 62) μg/ml,t = 2. 13,P = 0. 03). The serum level of CEA after the final treatment showed a significant difference between group A and group B( 10. 53 ± 8. 62) ug / L vs( 35. 21 ± 10. 22) μg / L; t = 5. 23,P < 0. 01). Group A had a significantly higher objective response rate than group B( 66. 7% vs 43. 3%; Z =- 2. 042,P = 0. 041). Group A had a significantly longer survival time than group B,and group A had a significantly higher surrival rate than group B( 45. 5% vs 23. 3%,χ2= 3. 97,P = 0. 046).Conclusion In patients with unresectable hepatic metastasis after surgery for colorectal cancer,precise sequential interventional therapy can improve their immune function,increase clinical outcome,and prolong survival time.
Original articles_Biliary diseases
Effect of ursodeoxycholic acid on bile secretion after endoscopic nasobiliary drainage in patients with cholestatic liver disease of various causes
Li Lei, Li Bing, Ding HuiGuo
2016, 32(3): 522-525. DOI: 10.3969/j.issn.1001-5256.2016.03.026
Abstract:

Objective To observe the effect of ursodeoxycholic acid( UDCA) on bile secretion in patients with cholestatic liver disease of various causes. Methods A total of 48 patients who underwent endoscopic nasobiliary drainage( ENBD) in Beijing You'an Hospital Affiliated to Capital Medical University from July 2013 to May 2014 were enrolled and divided into UDCA treatment group( n = 36) and control group( n = 12). The patients in the UDCA group were further divided into common bile duct stone group( n = 9),cholangiocarcinoma group( n = 7),sclerosing cholangitis group( n = 7),and post- liver transplantation group( n = 13). The patients in the UDCA treatment group received oral UDCA capsules( 250 mg,3 times / day) since the second day after surgery,and the daily volume of bile drainage was recorded for 7 days after surgery. Serum levels of total bilirubin( TBil),total bile acid( TBA),gamma- glutamyl transpeptidase( GGT),and alkaline phosphatase( ALP) were measured on the day before surgery and the 7th day after surgery,and the effects of UDCA on volume of bile drainage,TBil,TBA,GGT,and ALP were compared between groups. The t- test was applied for comparison between groups,comparison of continuous data between these groups was made by analysis of variance; the chi- square test was applied for comparison of categorical data between groups. Results Compared with the control group,the UDCA treatment group had a significantly increased volume of bile drainage on the 3rd,4th,and 5th days after surgery( t = 2. 461,3. 896,and 2.760; P = 0. 048,0. 021,and 0. 034),and the increase in volume of bile drainage was more significant in the common bile duct stone group,the cholangiocarcinoma group,and the post- liver transplantation group,with peak values appearing on the 4th day after surgery. The patients in the common bile duct stone group and the post- liver transplantation group had significantly lower serum levels of TBil,GGT,and ALP on the 7th day after surgery( t = 3. 340,2. 503,and 2. 158,P = 0. 016,0. 038,and 0. 045; t = 2. 951,2. 805,and 2. 461,P = 0. 014,0. 029,and 0. 034). Conclusion UDCA can increase bile secretion and improve liver function in patients with cholestatic liver disease of various causes.

Effect of laparoscopic cholecystectomy on aminotransferase levels in patients with hyperlipidemia
Liu Yang, Zhang HongYi, Zhao Gang
2016, 32(3): 526-529. DOI: 10.3969/j.issn.1001-5256.2016.03.027
Abstract:

Objective To investigate the effect of laparoscopic cholecystectomy( LC) on postoperative levels of alanine aminotransferase( ALT) and aspartate aminotransferase( AST) in patients with different types of hyperlipidemia( HLP). Methods A total of 213 HLP patients who underwent LC in Department of Hepatobiliary Surgery in Air Force General Hospital,PLA from January 2012 to December 2014 were analyzed retrospectively,and according to the serum levels of total cholesterol( TC),triglyceride( TG),and high- density lipoprotein cholesterol( HDL),they were divided into high TC group( n = 63),high TG group( n = 53),and mixed group( n = 48),low HDL group( n = 49). The patients with normal blood lipid who underwent LC during the same period of time were enrolled as non- HLP group( n =204). Enzyme- linked immunosorbent assay was performed before surgery and on days 1,3,and 7 after surgery to measure the levels of ALT and AST. Analysis of variance was used for comparison of continuous data between several groups,and q- test was used for comparison of such data between each two groups; the chi- square test was applied for comparison of categorical data between groups. Results All the HLP groups had significantly higher levels of aminotransferases before surgery than the normal control group( all P < 0. 05),and the high TC group had significantly greater increases in ALT and AST levels compared with the other HLP groups( all P < 0. 05). Compared with the control group,all the HLP groups had varying degrees of increase in ALT and AST levels on days 1 and 3 after LC,and the high TC group had significantly greater increases in ALT and AST levels compared with the other HLP groups( all P < 0. 05). In all the groups,the levels of aminotransferases on day 7 after surgery returned to normal,with no occurrence of severe abnormal liver function. Conclusion LC has a little influence on the liver in HLP patients. Clinical observation should be performed,and the treatment to protect the liver and reduce the levels of aminotransferases should be given when necessary.

Original articles_Pancreatic diseases
Efficacy of incision and drainage versus percutaneous catheter drainage in treatment of severe acute pancreatitis com-plicated by pancreatic abscess
Yang Feng, Xu Jing, Luo XuJuan, Peng Yan
2016, 32(3): 530-532. DOI: 10.3969/j.issn.1001-5256.2016.03.028
Abstract:
Objective To investigate the clinical features and treatment of severe acute pancreatitis( SAP) complicated by pancreatic abscess( PA). Methods The clinical data of 17 SAP patients with PA who were admitted to Affiliated Hospital of Luzhou Medical College from January 1,2005 to August 25,2015 were analyzed retrospectively. The clinical manifestations,therapeutic methods,and outcome were summarized. Results Of all the 17 patients,12 patients underwent surgical operation,among whom 9 were cured,1 experienced postoperative intestinal fistula,and 2 experienced recurrence of abscess and underwent the surgery again( 1 died of multiple organ failure),and the mean hospital stay was( 108. 29 ± 52. 37) d; 5 patients underwent percutaneous catheter drainage,among whom 4 were cured,and 1 underwent surgical treatment due to inadequate drainage,and the mean hospital stay was( 53. 03 ± 6. 71) d. Conclusion Adequate drainage should be performed once a confirmed diagnosis of PA is made,and appropriate drainage methods should be selected based on the patient's actual condition. Minimally invasive treatment has a good effect,a short length of hospital stay,and few complications,and holds promise for clinical application.
Effect and prognosis of peri- pancreatic stepwise minimally invasive treatment in patients with severe acute pancreatitis
Xiong Yong, Wang HeBin, Liu DeQin, Chen JianXun, Liu JianPing, Sun ChangQin
2016, 32(3): 533-536. DOI: 10.3969/j.issn.1001-5256.2016.03.029
Abstract:
Objective To investigate the clinical effect and prognosis of peri- pancreatic stepwise minimally invasive treatment in patients with severe acute pancreatitis( SAP). Methods The clinical data of 110 patients with SAP who were treated in Panzhihua Central Hospital from January 2013 to December 2014 were analyzed retrospectively,and these patients were divided into two groups( 55 patients in each group) according to the treatment regimen. The patients in the control group were treated with laparotomy,and those in the study group received peri- pancreatic stepwise minimally invasive treatment. The postoperative short- term treatment outcome,Acute Physiology and Chronic Health Evaluation Ⅱ( APACHE Ⅱ) score,laboratory markers [serum amylase( AMS),white blood cell( WBC),and C- reactive protein( CRP) ],time to intestinal recovery,incidence of complications,and mortality were compared between the two groups. The t- test was applied for comparison of continuous data between the two groups,and the chi- square test was applied for comparison of categorical data between the two groups. Results Compared with the control group,the study group had significantly higher short- term marked response rate,response rate,and overall response rate( χ2= 5. 1665,4. 9865 and 5. 6357,all P < 0. 05). There were significant differences in AMS,WBC,pulse oxygen saturation( Sp O2),CRP,and APACHE Ⅱ score between the two groups at 1 week after surgery and at discharge( t =13. 6585,13. 4698,12. 0566,14. 6856,and 13. 8869 for 1 week after surgery,t = 12. 8946,14. 2683,13. 8963,14. 8989,and 13. 0986 for discharge,all P < 0. 05); there was a significant difference in WBC count on day 1 after surgery between the two groups( χ2= 12. 6984,P < 0. 05); both groups showed significant improvements in AMS,WBC,Sp O2,CRP,and APACHE Ⅱ score at 1 week after surgery and at discharge compared with the values on day 1 after surgery,and there were significant changes in these values within each group( all P <0. 05); compared with the control group,the study group had a significantly shorter time to intestinal recovery,a significantly lower mortality rate,and a significantly lower incidence of complications( pleural effusion,dyspnea,false- positive cysts,and wound infection)( t = 13. 6985,P = 0. 042,χ2= 8. 3968,5. 6357,4. 0673,4. 0371,and 4. 4071,all P < 0. 05). Conclusion Peri- pancreatic stepwise minimally invasive treatment has a significant effect in the treatment of SAP and can improve the prognosis of patients. Therefore,it holds promise for clinical application.
Therapeutic effect of gemcitabine hydrochloride combined with stereotactic radiotherapy for locally advanced pancre-atic cancer
Ji HongBing, Chen ZhongHua
2016, 32(3): 537-540. DOI: 10.3969/j.issn.1001-5256.2016.03.030
Abstract:
Objective To investigate the clinical therapeutic effect of gemcitabine hydrochloride combined with stereotactic radiotherapy for locally advanced pancreatic cancer. Methods A total of 122 previously untreated patients with locally advanced pancreatic cancer who were not able to undergo surgical resection and were admitted to Fuzhou General Hospital from June 2008 to June 2013 were selected,and according to the therapies,they were divided into the group with a combination of gemcitabine hydrochloride and stereotactic radiotherapy( group A,n = 56) and the group with gemcitabine therapy alone( group B,n = 66). The changes in condition,toxic and side effects,and death time were recorded. The chi- square test was applied for comparison between groups,and the Kaplan- Meier method was applied for plotting survival curves. Results There was a significant difference in response rate between group A and group B [67. 8%( 38 /56) vs22. 7%( 15 /66),χ2= 25. 11,P < 0. 01]; the effective pain- relieving rate showed a significant difference between group A and group B( 95. 8% vs 77. 2%,χ2= 7. 39,P < 0. 01); there were significant differences in 1- year survival rate,2- year survival rate,and median survival time between the two groups [58. 9%( 33 /56) vs 31. 8%( 21 /66),χ2= 9. 03,P < 0. 01; 28. 6%( 16 /56) vs 10. 6%( 7 /66),χ2= 6. 39,P < 0. 01; 12. 8 months vs 7. 9 months; χ2= 15. 51,P < 0. 01]. Conclusion Gemcitabine hydrochloride combined with stereotactic radiotherapy has good short- and long- term efficacy,and toxic and side effects are tolerable.
Original articles_Others
Liver injury in children with severe sepsis: a clinical study of 58 patients
Peng HuiYun, Li Miao, Zhou LiFang, Tan XiaoMei, Fan ChenYing, Li ShuangJie
2016, 32(3): 541-544. DOI: 10.3969/j.issn.1001-5256.2016.03.031
Abstract:

Objective To investigate the clinical characteristics and prognostic value of liver injury in children with severe sepsis. Methods Children with severe sepsis who were admitted to our hospital and had complete clinical data from November 2013 to May 2015 were enrolled as subjects. Clinical characteristics and parameters of liver function were evaluated within 24 hours after admission to the hospital. The relationship of the parameters of liver function with the level and prognosis of severe sepsis was analyzed. Continuous data of the two groups were compared using the Mann- Whiteny U test and categorical data were copared using the χ2test. Results A total of 110 patients were enrolled as subjects. In these patients,52. 7%( 58 /110) had liver injury. According to the level of alanine aminotransferase( ALT),patients were divided into four groups that had ATL levels of < 80 IU / L,80- 200 IU / L,200- 400 IU / L,and > 400 IU / L,respectively. There were significant differences in mortality rate between the four groups( 40. 7%,47. 6%,64. 3%,and 81. 3%; χ2= 9. 458,P < 0. 05). Patients were divided into jaundice group and non- jaundice group based on the total bilirubin level. The jaundice group had a significantly higher mortality rate than the non- jaundice group( 75. 0% vs 44. 2%,χ2= 7. 129,P < 0. 01). According to the level of serum albumin,patients were divided into four groups that had levels of serum albumin of > 35 g / L,30- 35 g / L,25- 30 g / L,and < 25 g / L,respectively. There were significant differences in mortality rate between the four groups( 35. 9%,44. 1%,59. 1%,and 93. 3%; χ2= 15. 536,P <0. 01). According to the International Normalized Ratio,patients were divided into coagulopathy group and non- coagulopathy group. The mortality rate was significantly higher in the coagulopathy group than in the non- coagulopathy group( 80. 8% vs 41. 7%,χ2= 12. 147,P <0. 01). The survival group had significantly higher incidence rates of increased ALT level,jaundice,hypoproteinemia,and coagulopathy than the dead group( all P < 0. 05). Conclusion The incidence of liver injury is high in children with severe sepsis. The mortality rate in patients is significantly correlated with the increase in the ALT level,jaundice,hypoproteinemia,and coagulopathy,which play an important role in the prognosis of severe sepsis.

Protective effect of magnesium isoglycyrrhizinate in rats with acute liver failure induced by D- galactosamine
Li XiaoPeng, Li Ming, Lei Wan, Zhang LunLi
2016, 32(3): 545-548. DOI: 10.3969/j.issn.1001-5256.2016.03.032
Abstract:

Objective To investigate the protective effect of magnesium isoglycyrrhizinate( Mg IG) in rats with acute liver failure induced by D- galactosamine( D- Gal N) and related mechanisms. Methods A total of 90 Sprague- Dawley rats were randomly divided into normal group( group A,n = 10),model group( group B,n = 20),low- dose Mg IG group( group C,n = 20),medium- dose Mg IG group( group D,n = 20),and high- dose Mg IG group( group E,n = 20). The rats in group A received intraperitoneal injection of the same volume of normal saline,and those in the other groups received single intraperitoneal injection of 10% D- Gal N. At 30 minutes after establishment of the model,the rats in groups C,D,and E received tail vein injection of Mg IG injection( 25,50,and 100 mg / kg). At 24 and 48 hours after establishment of the model,HE staining was performed to observe the pathological changes in the liver,and serum was collected to measure the levels of liver function parameters [alanine aminotransferase( ALT),aspartate aminotransferase( AST),total bilirubin( TBil),and albumin( Alb) ],proinflammatory factors [tumor necrosis factor- α( TNFα),interleukin- 1β( IL- 1β),and interferon-γ( IFNγ) ],and anti- inflammatory factors [interleukin 4( IL- 4),interleukin- 10( IL- 10),and transforming growth factor β( TGFβ) ]in rats. The one- way analysis of variance was applied for comparison between multiple groups,and the Student- Newman-Keuls test was applied for comparison between any two groups. Results The serum levels of ALT,AST,TBil,and Alb showed significant differences across the five groups( F = 74. 6,108. 9,25. 1,and 58. 4,all P < 0. 05); compared with group A,group B had significant increases in the serum levels of ALT,AST,and TBil and a significant reduction in the serum level of Alb( all P < 0. 05); compared with group B,groups C,D,and E had significant reductions in the serum levels of ALT,AST,and TBil and a significant increase in the serum level of Alb,and these parameters showed the most significant changes in group E( all P < 0. 05). The serum levels of TNFα,IL- lβ,IFNγ,IL-4,IL- 10,and TGFβ showed significant differences across the five groups( F = 75. 1,58. 9,25. 4,43. 6,66. 4,and 86. 8,all P <0. 05); compared with group A,group B had significant increases in the serum levels of TNFα,IL- lβ,IFNγ,IL- 4,IL- 10,and TGFβ( all P < 0. 05); compared with group B,groups C,D,and E had significant reductions in the serum levels of TNFα,IL- lβ,and IFNγand significant increases in the serum levels of IL- 4,IL- 10,and TGFβ,and these parameters showed the most significant changes in group E( all P < 0. 05). Conclusion Mg IG can reduce inflammatory response through reducing proinflammatory factors and increasing anti- inflammatory factors,and thus exert protective effect on rats with ALF.

Case reports
Tang ShanHong, Ceng WeiZheng, Wu XiaoLing, Wang HaiQiong, Chen YiHua, Wang Zhao, Yang JianKun, Zhang Ming, Jiang MingDe
2016, 32(3): 549-551. DOI: 10.3969/j.issn.1001-5256.2016.03.033
Abstract:
Reviews
Current status of research on nonalcoholic fatty liver disease in China
Hu ZhongJie, Zhang Jing
2016, 32(3): 552-556. DOI: 10.3969/j.issn.1001-5256.2016.03.034
Abstract:
With the increasing prevalence rate of nonalcoholic fatty liver disease( NAFLD),this disease has been taken more seriously,more and more studies have been carried out in this field,and some important progress has been made. This article introduces the important research findings in the epidemiology,risk factors,pathogenesis,noninvasive diagnosis,and treatment of NAFLD,as well as related liver cirrhosis and hepatocellular carcinoma in China within the past five years,in order to know the current status of related research. This article points out that there still exists a certain gap between related clinical and basic research in China and the rest of the world,especially in the public's perception and the medical workers' emphasis on NAFLD. In the future,the research on epidemiology,pathogenesis,patient management,and drug therapies should be enhanced.
Research advances in natural drugs for prevention and treatment of nonalcoholic fatty liver disease
Liu BaoQing, Xu XiuQin, Men SiYe, Yu Wen, Yang ChengCheng, De Ji, Suo LangPingCuo, Chen Jing, Ni MaZhaBa, Dun ZhuCiRen, Wu Wei
2016, 32(3): 557-560. DOI: 10.3969/j.issn.1001-5256.2016.03.035
Abstract:

At present,nonalcoholic fatty liver disease( NAFLD) is the most common liver disease,and is often regarded as the manifestation of metabolic syndrome in the liver. There are no specific drugs for this disease at the moment,and the only therapeutic method proved effective is guiding life style to reduce body weight. Insulin resistance,oxidative stress response,inflammatory response,and apoptosis are involved in the pathogenesis of NAFLD. Animal experiments and human studies have proved that various natural drugs have antioxidant,anti- inflammatory,or insulin- sensitizing effects and thus have significant efficacy in the treatment of NAFLD. This article summarizes the research advances in 10 natural drugs commonly used for the prevention and treatment of NAFLD in recent years and treatment of NAFLD in recent years and concludes that more studies are needed to confirm the efficacy of natural drugs in NAFLD patients.

Role of dietary intervention in nonalcoholic fatty liver disease
Hong Ze, Chen SiYing, Yang WenJuan, Ding QiLong
2016, 32(3): 561-564. DOI: 10.3969/j.issn.1001-5256.2016.03.036
Abstract:
Nonalcoholic fatty liver disease( NAFLD) is the most common chronic liver disease. However,at present,there are still no effective therapeutic methods for NAFLD in clinical practice. Lifestyle changes,especially changes in eating habits,play an important role in the treatment of NAFLD. This review summarizes the role of fatty acids,carbohydrates,proteins,and vitamins in the development and progression of NAFLD,and points out that a proper diet can help improve the condition of patients with NAFLD.
Association between nonalcoholic fatty liver disease and malignant transformation of hepatocytes
Gu JuanJuan, Yao Min, Yao DengFu
2016, 32(3): 565-569. DOI: 10.3969/j.issn.1001-5256.2016.03.037
Abstract:

Nonalcoholic fatty liver disease( NAFLD) is a clinicopathological syndrome characterized by diffuse macrovesicular steatosis and excessive lipid accumulation in the liver due to nonalcoholic reasons and other specific factors for liver injury,including simple fatty liver,nonalcoholic steatohepatitis,and liver cirrhosis. With the increasing incidence of NAFLD,the risk of hepatocellular carcinoma( HCC) is also increasing,but the exact mechanism remains unknown. This paper summarizes the roles of lipid accumulation,related cells,proteins,hormones,and metabolites in malignant transformation of hepatocytes,as well as the relationship between NAFLD,HCC,and lipid metabolism,and provides a new perspective for the prevention of HCC in clinical practice.

Role of liver immunological inflammation in development and progression of nonalcoholic fatty liver disease
Zhu JuanJuan, Cheng MingLiang, Zhao XueKe
2016, 32(3): 570-573. DOI: 10.3969/j.issn.1001-5256.2016.03.038
Abstract:

Non- alcoholic fatty liver disease( NAFLD) is a common liver disease in clinical practice and has a complex pathogenesis. At present,the " two- or three- hit" theory is still widely acknowledged as the major pathogenesis of NAFLD. However,in recent years,the role of liver immunological inflammation in the development and progression of NAFLD has been taken more and more seriously. This article elaborates on the mechanism of liver immunological inflammation in the development and progression of NAFLD from the perspective of liver immunological inflammation.

Role of inflammatory factors in development and progression of alcoholic liver disease
Qiu YuanYuan, Wang WeiHeng, Zhu Liang
2016, 32(3): 574-578. DOI: 10.3969/j.issn.1001-5256.2016.03.039
Abstract:
Alcohol liver disease( ALD) is the most common disease resulting in liver injury in the world. Inflammatory response is an important reason for liver injury in ALD. After being absorbed into the intestines,alcohol can increase the amount of intestinal endotoxin which enters the bloodstream through enterohepatic circulation and activates Toll- like receptor 4 in liver Kupffer cells to release inflammatory factors. The inflammatory factors including tumor necrosis factor- α induce liver injury,while interleukin- 6( IL- 6) and interleukin- 10( IL- 10) protect the liver through regulating inflammatory response. IL- 6 can increase the expression of various anti- injury genes in hepatocytes through activating signal transducer and activator of transcription 3( STAT3),and IL- 10 can inhibit liver inflammatory response through activating STAT3 in Kupffer cells. The processes of imbalance and rebalance between proinflammatory factors and anti- inflammatory factors are the development and prognosis of ALD. This article systematically reviews the role of inflammatory factors in the development and progression of ALD from the perspective of inflammatory response.
Research advances in paternal- fetal vertical transmission during HBV infection
Zhang Kai, Lin ShuMei, Yang XueLiang, Kong Ying, Liu XiaoJing, Zhang Xi, Shi Lei, Chen YunRu, Ye Feng, Li Na
2016, 32(3): 579-583. DOI: 10.3969/j.issn.1001-5256.2016.03.040
Abstract:
Hepatitis B virus( HBV) infection is a global public health problem which greatly threatens human health. Paternal- fetal vertical transmission( P- FT) is one of the leading causes of persistent HBV infection,and has a transmission rate similar to that of mother- to- child vertical transmission. In recent years,P- FT has been attracting more and more attention and has become a hot research topic at home and abroad. It has been confirmed that P- FT occurs via sperm,but the mechanism remains unknown. Studies have shown that a high HBV DNA load in serum and semen and positive serum HBe Ag are the major risk factors for the occurrence of P- FT. Random integration of HBV DNA into sperm can affect sperm quality,cause male infertility,and even affect the maternal pregnancy outcome. Currently the most important measure to block P- FT is pre- pregnancy intervention,including antiviral therapy for the father and active immunization for the mother.
Research advances in association between Toll- like receptor 4 and hepatitis B
Fan WenHai, Chen QingFeng
2016, 32(3): 584-587. DOI: 10.3969/j.issn.1001-5256.2016.03.041
Abstract:

Toll- like receptor 4( TLR4) is an important pattern recognition receptor and plays an important role in the inhibition of hepatitis B virus( HBV) infection. It identifies the HBV- related proteins and produces inflammatory factors,such as tumor necrosis factor- α,interleukin- 6,and interleukin- 12,and type I interferon through the myeloid differentiation factor 88( My D88) and the non- My D88 pathway,and thus TLR4 exerts its antiviral effect. Meanwhile,it has been found that TLR4 regulates the balance between T helper 1 and T helper 2 cells,promotes the adhesion of CD8+T lymphocytes in the liver,induces the secretion of inducible nitric oxide synthase,and thus inhibits HBV. If overexpressed,TLR4 will aggravate liver inflammation by excessively activating the body's immune system,aggravating liver ischemia / reperfusion,and activating hepatic stellate cells. This article reviews related articles published at home and abroad in recent years,discusses the mechanisms of action of TLR4 in the pathogenesis of hepatitis B,and summarizes the association between TLR4 and hepatitis B,in order to find new therapies for hepatitis B and new protocols which delay the progression of hepatitis B to liver cirrhosis and liver cancer through the studies on the association between TLR4 and hepatitis B.

Application of magnetic resonance elastography as a non-invasive technique for diagnosis of liver fibrosis
Yang MingLei, Yao DingKang
2016, 32(3): 588-592. DOI: 10.3969/j.issn.1001-5256.2016.03.042
Abstract:
At present,liver biopsy is the gold standard for the diagnosis and grading of liver fibrosis,but its limitations have been widely acknowledged. The non- invasive detection methods are needed in clinical practice,and at present,magnetic resonance elastography( MRE)is a hot research topic. This article reviews the advances in the clinical application of MRE in related fields,and studies have shown that MRE has a high diagnostic value due to its high sensitivity and specificity in the diagnosis and grading of liver fibrosis and an area under the receiver operating characteristic curve as high as 0. 95. Compared with serological and other imaging diagnostic methods,MRE can determine fibrosis stage more accurately and has good reproducibility and objectivity. MRE can be widely applied in all patients except those with hemochromatosis,with special advantages in the diagnosis for patients with obesity and ascites,and can make up for the disadvantages of other methods. This article points out that MRE may become the best non- invasive method for the assessment of liver fibrosis,especially advanced fibrosis.
Research advances in electroencephalographic monitoring of minimal hepatic encephalopathy
An Shuang, Yang WenXuan, Zhang GuoShan, Zhang ZeTian, Zhou HongJie, Yang Kun, Wang ShouQing, Guo XiaoLin
2016, 32(3): 593-596. DOI: 10.3969/j.issn.1001-5256.2016.03.043
Abstract:
Hepatic encephalopathy( HE) is a serious neuropsychological complication in advanced liver disease,and is a major cause of death in patients with liver disease. The paper briefly introduces the advances in application of HE grading,examination methods,and electroencephalography( EEG) in the diagnosis of HE,and points out that EEG has been developed greatly in the field of HE,with huge potentials for the diagnosis,evaluation,prognosis,and guidance for treatment of HE. However,the clinical value of EEG monitoring in HE has not been widely acknowledged in the medical world,and further investigation is still needed in the future.
Research advances in mesenchymal stem cells from various sources in treatment of liver fibrosis
Wang DongDong, Chen Gang, Hu ZongQiang, Li Li
2016, 32(3): 597-600. DOI: 10.3969/j.issn.1001-5256.2016.03.044
Abstract:
Mesenchymal stem cells( MSC) are derived from the mesoderm,and exhibit multipotential differentiation. MSC can alleviate liver fibrosis and improve liver function through paracrine cytokines and cell- cell interactions,but their therapeutic mechanism remains unknown. MSC are derived from various tissues,such as bone marrow,umbilical cord tissue,umbilical cord blood,peripheral blood,and adipose tissue. However,there are different advances in MSC with various sources in experimental studies and clinical treatment of liver fibrosis. This paper summarizes the possible therapeutic mechanisms of MSC in alleviating liver fibrosis,as well as the advances in experimental studies and clinical application of MSC with various sources. MSC transplantation is a new therapeutic method for liver fibrosis and has a broad application prospect in this field.
Research advances in application of molecular- targeted therapy for hepatocellular carcinoma
Liang Yuan, Wang ShiMing, Shi ZhenMing
2016, 32(3): 601-604. DOI: 10.3969/j.issn.1001-5256.2016.02.03.045
Abstract:

Hepatocellular carcinoma( HCC) greatly threatens human health. In clinical treatment,the therapeutic strategies for HCC are attracting more attention. With the research advances in the pathogenesis of HCC and the rapid development of molecular biology techniques,the therapies with molecular- targeted antitumor drugs for advanced HCC have become a hot research topic,and significant efficacy has been achieved in clinical practice. This article summarizes the research advances in clinical application of molecular- targeted drugs for the treatment of HCC and related issues,discusses the future perspectives of therapeutic strategies,and provides a new direction and reference for the clinical treatment of HCC.

Research advances in renal replacement therapy for hepatorenal syndrome
Chen Li, Mei Yong, Yang YiBin, Cao MingYan
2016, 32(3): 605-608. DOI: 10.3969/j.issn.1001-5256.2016.03.046
Abstract:

Hepatorenal syndrome( HRS) is a serious complication of the end- stage liver disease. The overall treatment outcome of HRS is not satisfactory,with a short survival time and a poor prognosis. Currently,renal replacement therapy is one of the main non- transplantation therapeutic methods,but its clinical effect remains controversial. This review summarizes the research on HRS and advances in the clinical effect of renal replacement therapy for HRS,and points out that renal replacement therapy is not suitable as the conventional therapy for HRS,but it can be applied as the pre- transplantation transitional treatment for patients with a plan for liver transplantation,as well as the short- term treatment for non- transplantation patients who do not respond to vasoconstrictors.

Role of UGT1A1 gene polymorphism in the pathogenesis of Gilbert syndrome
Song JinYun, Sun Mei, Li JiaYan, Wang JianFang, Wu XuPing
2016, 32(3): 609-612. DOI: 10.3969/j.issn.1001-5256.2016.03.047
Abstract:
As a bilirubin metabolic disorder,Gilbert syndrome belongs to the category of congenital non- hemolytic jaundice. Deficiency or decrease in the activity of bilirubin- uridine diphosphate glucuronyltransferase( UGT) is an important reason for the pathogenesis of Gilbert syndrome. UGT1A1,an isoenzyme of UGT,is a key enzyme to direct bilirubin in the liver. Mutations in UGT1A1 gene lead to the structural abnormality of UGT,and thus result in the decrease or loss of the ability of UGT to bind bilirubin. This article summarizes the research advances in the role of UGTA1 and its polymorphism in the pathogenesis and diagnosis of Gilbert syndrome.