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Altered blood-brain barrier permeability in rats with prehepatic portal hypertension turns to normal when portal pressure is lowered

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World Journal of Gastroenterology 2006年第9期12卷 1367-1372页

作者： Francisco Eizayaga Camila Scorticati Juan P Prestifilippo Salvador Romay Maria A Fernandez José L Castro Abraham Lemberg Juan C Perazzo laboratory of portal hypertension department of pathophysiology School of Pharmacy and BiochemistryUniversity of Buenos AiresBuenos AiresArgentina Catedra de Farmacología School of Pharmacy and Biochemistry University of Buenos Aires Buenos Aires Argentina laboratory of portal hypertension department of pathophysiology School of Pharmacy and Biochemistry University of Buenos Aires Buenos AiresArgentina

AIM： To study the blood-brain barrier integrity in prehepatic portal hypertensive rats induced by partial portal vein ligation, at 14 and 40 dafer ligation when portal pressure is spontaneously normalized. METHODS： Adult male Wistar rats were divided into four groups： Group Ⅰ： Sham14d, sham operated; Group Ⅱ： PHil, portal vein stenosis, （both groups were used 14 days after surgery）; Group Ⅲ： Sham4od, Sham operated and Group Ⅳ： PH4od portal vein stenosis （Groups Ⅱ and Ⅳ used 40 d afer surgery）. Plasma ammonia, plasma and cerebrospinal fluid protein and liver enzymes concentrations were determined. Trypan and Evans blue dyes, systemically injected, were investigated in hippocampus to study blood-brain barrier integrity. portal pressure was periodically recorded. RESULTS： Forty days afer stricture, portal pressure was normalized, plasma ammonia was moderately high, and both dyes were absent in central nervous system parenchyma. All other parameters were reestablished. When portal pressure was normalized and ammonia level was lowered, but not normal, the altered integrity of blood-brain barrier becomes reestablished. CONCLUSION： The impairment of blood-brain barrier and subsequent normalization could be a mechanism involved in hepatic encephalopathy reversibility. Hemodynamic changes and ammonia could trigger blood-brain barrier alterations and its reestablishment.

关键词： Blood-brain barrier Rats Prehepatic portal hypertension

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Endothelial phosphodiesterase 4B inactivation ameliorates endothelial-to-mesenchymal transition and pulmonary hypertension

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1726-1741页

作者： Yanjiang Xing Yangfeng Hou Tianfei Fan Ran Gao Xiaohang Feng Bolun Li Junling Pang Wenjun Guo Ting Shu Jinqiu Li Jie Yang Qilong Mao Ya Luo Xianmei Qi Peiran Yang Chaoyang Liang Hongmei Zhao Wenhui Chen Jing Wang Chen Wang State Key laboratory of Respiratory Health and Multimorbidity Institute of Basic Medical SciencesChinese Academy of Medical SciencesPeking Union Medical CollegeBeijing 100005China department of Lung Transplantation National Center for Respiratory MedicineNational Clinical Research Center for Respiratory DiseasesChina–Japan Friendship HospitalInstitute of Respiratory MedicineChinese Academy of Medical SciencesBeijing 100029China Haihe laboratory of Cell Ecosystem Chinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin 300051China The State Key laboratory of Complex Severeand Rare DiseasesInstitute of Basic Medical SciencesChinese Academy of Medical SciencesDepartment of PathophysiologyPeking Union Medical CollegeBeijing 100005China department of Pharmacy West China HospitalSichuan UniversityChengdu 610044China

Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PDE4A–D). Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH;however, this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes. Here, we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues. We also confirmed that PDE4B is mainly expressed in the lung endothelial cells (ECs). Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH. In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition (EndMT), and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA–CREB–BMPRII axis. Finally, treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH. Collectively, our findings indicate a critical role for PDE4B in EndMT and PH, prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH.

关键词： Phosphodiesterase 4B Pulmonary hypertension Endothelial-to-mesenchymal transition

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MEAN AND RANGE OF THE AMBULATORY PRESSUREIN NORMOTENSIVE SUBJECTS

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中华医学杂志(英文版) 1992年第4期105卷 328-333页

作者： J Staessen C Guo P De Cort R Fagard P Lijnen L Thijs R Van Hoof A Amery hypertension and Cardiovascular Rehabilitation Unit Department of Pathophysiology University of Leuven Belgium

To perform a meta-analysis of published reportsin an attempt to determine the mean and range ofnormal ambulatory blood pressure(BP),23 studies in-cluding a total of 3 476 normal subjects *** studies were compatible with a mean24-h BP in the range of 115-120/70-75mmHg,amean day time BP of 120-125/75-80mmHg,and amean night time BP of 105 to 110/60 to 65 *** weighting for the number of subjects included inthe individual studies,the 24-h BP averaged 118/72mmHg,the day time BP 123/76 mmHg,and thenight time BP 106/64 *** night/day pres-sure ratio averaged 0.87 for systolic and 0.83 fordiastolic BP,with ranges across the individual studiesfrom 0.79 to 0.92 and from 0.75 to 0.90,*** the mean ± 2 standard deviation interval in the va-rious studies was considered normal,the range ofnormality was on average 97 to 139/57 to 87 mmHgfor the 24-h BP,101 to 146/61 to 91 mmHg for theday time BP,and 86 to 127/48 to 79 mmHg for thenight time *** the results of prospective studieson the relation between the ambulatory BP and the in-cidence of cardiovascular morbidity and mortality be-come available,the aforementioned intervals,whichsummarize the experience of 23 investigators,couldserve as a temporary reference for clinical practice.

关键词： BLOOD-PRESSURE hypertension VALUES AGE

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TRIALS IN ELDERLY PATIENTS WITH ISOLATED SYSTOLIC hypertension

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中华医学杂志(英文版) 1992年第5期105卷 364-368页

作者： J Staessen C Guo H Celis R Fagard L Thijs A Amery hypertension and Cardiovascular Rehabilitation Unit Department of Pathophysiology University of Leuven Belgium

The hypothesis that antihypertensive drugs shouldbe prescribed to elderly patients with isolated systolichypertension is being addressed in at least 3 trials:theSystolic hypertension in the Elderly Program(SHEP)in the United States,a trial in China,and theSyst-Eur study in *** SHEP trial has recent-ly reported its final morbidity and mortality *** article summarizes the protocol of the Europeanstudy. To be eligible for the Syst-Eur trial,patientsmust be at least 60 years old and have a systolic bloodpressure averaging 160-219 mmHg with a diastolicpressure less than 95 *** must give theirinformed consent and be free of major cardiovascularand non-cardiovascular diseases at *** patientsare randomized into active treatment or ***-tive treatment consists of nitrendipine(10-40 mg/d),combined with enalapril(5-20 mg/d)andhydrochlorothiazide(12.5-25 mg/d),as *** control group received matching ***(or matching placebos)are stepwise titrated andcombined in order to reduce systolic blood pressure by20 mmHg at least to a level below 150 *** and mortality are monitored to enable anintention-to-treat and per protocol comparison of theoutcome in the two treatment groups.

关键词： BLOOD-PRESSURE

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Recent advances in promising drugs for primary prevention of gastroesophageal variceal bleeding with cirrhotic portal hypertension

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Hepatobiliary & Pancreatic Diseases International 2024年第1期23卷 4-13页

作者： Ji-Yao Sheng Zi-Fan Meng Qiao Li Yong-Sheng Yang department of Hepatobiliary and Pancreatic Surgery the Second Hospital of Jilin UniversityChangchun 130041China Jilin Engineering laboratory for Translational Medicine of Hepatobiliary and Pancreatic Diseases the Second Hospital of Jilin UniversityChangchun 130041China

Background:Gastroesophageal variceal bleeding is one of the most severe complications of patients with *** primary prevention drugs,including non-selectiveβ-blockers,have effectively reduced the incidence of bleeding,their efficacy is limited due to side effects and related *** recent advances in precision medicine,precise drug treatment provides better treatment *** sources:Literature search was conducted in PubMed,MEDLINE and Web of Science for relevant articles published up to May *** on clinical trials was obtained from https://***/and http://***/.Results:The in-depth understanding of the pathogenesis and advances of portal hypertension has enabled the discovery of multiple molecular targets for promising *** to the site of action,these drugs could be classified into four classes:intrahepatic,extrahepatic,both intrahepatic and extrahepatic targets and *** these classes of drugs offer advantages over traditional treatments in prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal ***:This review classified and summarized the promising drugs,which prevent gastroesophageal variceal bleeding by targeting specific markers of pathogenesis of portal hypertension,demonstrating the significance of using the precision medicine strategy to discover and develop promising drugs for the primary prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal hypertension.

关键词： Cirrhotic portal hypertension Target drug Primary prevention Bleeding

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Antioxidant role of heme oxygenase-1 in prehepatic portal hypertensive rats

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World Journal of Gastroenterology 2006年第26期12卷 4149-4155页

作者： Soledad Gonzales María Julia Pérez Juan C Perazzo María Luján Tomaro department of Biological Chemistry School of Pharmacy and Biochemistry University of Buenos AiresBuenos Aires 1113Argentina laboratory of portal hypertension department of Biological Science School of Pharmacy and BiochemistryUniversity of Buenos AiresBuenos Aires 1113Argentina

AIM： To study the effect of bilirubin on the oxidative liver status and the activity and expression of heine oxygenase-1 （HO-1） in rat liver injury induced by prehepatic portal hypertension. METHODS： Wistar male rats, weighing 200-250 g, were divided at random into two groups： one group with prehepatic portal hypertension （PH） induced by regulated prehepatic portal vein ligation （PPVL） and the other group corresponded to sham operated rats. portal pressure, oxidative stress parameters, antioxidant enzymes, HO-1 activity and expression and hepatic sinusoidal vasodilatation were measured. RESULTS： In PPVL rats oxidative stress was evidenced by a marked increase in thiobarbituric acid reactive substances （TBARS） content and a decrease in reduced glutathione （GSH） levels. The activities of liver antioxidant enzymes, superoxide dismutase （SOD）, catalase （CAT） and glutathione peroxidase （GSH-Px） were also diminished while activity and expression of HO-1 were enhanced. Administration of bilirubin （5μmol/kg body weight） 24 h before the end of the experiment entirely prevented all these effects. Pretreatment with Sn-protoporphyrin IX （Sn-PPIX）（100 μg/kg body weight, i.p.）, a potent inhibitor of HO, completely abolished the oxidative stress and provoked a slight decrease in liver GSH levels as well as an increase in lipid peroxidation. Besides, carbon monoxide, another heme catabolic product, induced a significant increase in sinusoidal hepatic areas in PPVL group. Pretreatment of PPVL rats with Sn-PPIX totally prevented this effect CONCLUSION： These results suggest a beneficial role of HO-1 overexpression in prehepatic portal hypertensive rats.

关键词： Heme oxygenase-1 portal hypertensive rats Liver oxidative stress

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Dual neovascular targets of vascular endothelial growth factor receptors and platelet-derived growth factor receptor ameliorate thioacetamide induced liver fibrosis in rats

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portal hypertension & Cirrhosis 2024年第1期3卷 1-13页

作者： Bin Xiong Yaowei Bai Jiacheng Liu Tongqiang Li Yingliang Wang Chen Zhou department of Interventional Radiology The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdongChina department of Radiology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina Hubei Province Key laboratory of Molecular Imaging WuhanHubeiChina

Aims:Neovascularization plays a crucial role in liver fibrosis(LF),and blocking vascular endothelial growth factor receptors(VEGFR)has been shown to improve *** aim of our study was to investigate the role of dual neovascularization targets,VEGFR,and platelet-derived growth factor receptor(PDGFR),in ameliorating ***:In vitro,we observed the effects of apatinib(APA)(a VEGFR inhibitor)and donafenib(DON)(a VEGFR and PDGFR inhibitor)on the activation,proliferation,and apoptosis of hepatic stellate cells(HSCs)from rats and *** vivo,we established a thioacetamide(TAA)-induced liver fibrosis rat model to explore the antifibrosis effect of APA and *** used the method of random table to randomly divide the rats into 4 *** detected the expression of angiogenesis-related proteins using Western blot and ***:APA and DON inhibited the proliferation and activation of HSCs,promoted apoptosis of HSCs,and arrested the S phase of the cell cycle in *** also found that DON had a stronger inhibitory effect on *** vivo,APA and DON ameliorated liver fibrosis,reduced collagen deposition andα-SMA expression in rats,and DON had a stronger improvement *** and DON downregulated the expression of VEGFR2 while inhibiting the phosphorylation of Akt and ERK1/*** can act through both VEGF and PDGF pathways,whereas APA can only act through the VEGF ***:Antiangiogenesis is a promising approach for the treatment of *** with a single-target drug(APA),the dual-target drug(DON)can achieve better therapeutic effects.

关键词： antiangiogenesis apatinib donafenib fibrosis

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One-year status of hepatic venous pressure gradient measurement from 85 hospitals in China

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portal hypertension & Cirrhosis 2024年第2期3卷 116-123页

作者： Jitao Wang Ting Cui Linpeng Zhang Zhiping Yan Lei Li Jinjun Chen Junhui Sun Hua Xiang He Zhu Hao Wu Jiancuo Gengzang Feng Zhang Wei Wu Guohong Cao Wuhua Guo Haibin Shi Hui Xue Guangjun Huang Qiang Yu Meng Niu Huiling Xiang Derun Kong Wei Gou Xuefeng Luo Fuliang He Min Yuan Wei Liu Yong Wang Hongjie Hu Xiaoli Zhu Tao Yu Qinxue Sun Wei Qu Ting Lu Deqiang Ma Li Zhang Jun Ma Jun Yang Ketao Mu Xiaoliang Zhu Kai Xiong Huiguo Ding Shengjuan Yao Mingsheng Huang Fang Wang Zexin Wang Yong Huang Jianan Li Hongfeng Yi Birun Huang Zhongwei Zhao Duiping Feng Yanming Lei Changlong Hou Wenbo Guo Shirong Liu Gaojun Teng Kangshun Zhu Fan Wu Xiaogang Hu Wenfeng Zhang Shaoqi Yang Zhouchao Hu Pengfei Pang Shaowu Zhuang Weidong Wang Qingliang Zhu Kunpeng Zhang Chengyu Liu Dongliang Li Chao Ma Hong Jiang Xingong Zhao Weixin Ren Zhiwei Wang Lei Yu Fuhuang Lin Chaoguang Yan Feng Wang Lei Yu Hui Huan Wenyong Shen Shaofei He Chengda Zhang Jinlun Bao Jiangtao Liu Jun Wu Jianbo Zhao Jian Zhang Xiaolong Qi Hebei Provincial Key laboratory of Cirrhosis&portal hypertension Xingtai People's HospitalXingtaiHebeiChina Center of portal hypertension Department of RadiologyZhongda HospitalSchool of MedicineSoutheast UniversityNanjingJiangsuChina department of Interventional Therapy Beijing Shijitan Hospital Affiliated to Capital Medical UniversityBeijingChina department of Intervention Taiyuan Third People's HospitalTaiyuanShanxiChina department of Intervention Zhongshan Hospital Affiliated to Fudan UniversityShanghaiChina department of Interventional Medicine The First Hospital of Lanzhou UniversityLanzhouGansuChina department of Infectious Diseases Nanfang Hospital of Southern Medical UniversityGuangzhouGuangdongChina Hepatobiliary and Pancreatic Intervention Center The First Affiliated Hospital of Zhejiang University School of MedicineHangzhouZhejiangChina Interventional Vascular Surgery Hunan Provincial People's HospitalChangshaHunanChina department of Intervention Sixth People's Hospital of ShenyangShenyangLiaoningChina department of Gastroenterology West China Hospital of Sichuan UniversityChengduSichuanChina department of Intervention The Fourth People's Hospital of Qinghai ProvinceXiningQinghaiChina department of Gastroenterology Nanjing Drum Tower HospitalNanjingJiangsuChina department of Gastroenterology The First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina department of Radiology Shulan(Hangzhou)HospitalHangzhouZhejiangChina department of Intervention Mengchao Hepatobiliary Hospital of Fujian Medical UniversityFuzhouFujianChina department of Interventional Radiology The First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsuChina department of Gastroenterology The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina department of Gastroenterology Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinanShandongChina department of Interventional Radiology Fifth Medical Center

Aims:Surveys and research on the applications of the hepatic venous pressure gradient(HVPG)are important for understanding the current status and future development of this technology in *** article aimed to investigate the status of hepatic venous pressure gradient measurement in China in ***:We investigated the overall status of HVPG technology in China-including hospital distribution,hospital level,annual number of cases,catheters used,average cost,indications,and current challenges by using online *** counting the number and percentages of cases of these results,we hope to clarify the current status of HVPG measurements in ***:According to the survey,85 hospitals in China used HVPG technology in 2022 distributed across 29 provinces.A total of 4989 HVPG measurements were performed in all of the surveyed hospitals in 2022,of which 2813 cases(56.4%)were measured *** average cost of HVPG measurement was 5646.8±2327.9 *** the clinical teams who performed the measurements(sometimes multiple per hospital),94.3%(82/87)used the balloon method,and the majority of the teams(72.4%,63/87)used embolectomy ***:This survey clarified the clinical application status of HVPG in China and confirmed that some medical institutions in China have established a foundation for this *** is still necessary to continue promoting and popularizing this technology in the future.

关键词： application status hepatic vein pressure gradient questionnaire survey

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CILP-2 is a novel secreted protein and associated with insulin resistance

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Journal of Molecular Cell Biology 2019年第12期11卷 1083-1094页

作者： Tong Wu Qin Zhang Shaobo Wu Wenjing Hu Tingting Zhou Ke Li Dongfang Liu Harvest FGu Hongting Zheng Zhiming Zhu Ling Li and Gangyi Yang department of Endocrinology The Second Affiliated HospitalChongqing Medical UniversityChongqing Clinical Research Center for GeriatricsChongqingChina Key laboratory of Diagnostic Medicine(Ministry of Education)and department of Clinical Biochemistry College of Laboratory MedicineChongqing Medical UniversityChongqingChina Center for pathophysiology School of Basic Medicine and Clinical PharmacyChina Pharmaceutical UniversityNanjingChina department of Endocrinology Xinqiao HospitalThird Military Medical UniversityChongqingChina department of hypertension and Endocrinology Daping HospitalThird Military Medical UniversityChongqing Institute of HypertensionChongqingChina

Genetic association studies have implicated that cartilage intermediate layer protein 2 (CILP-2) confers the risk susceptibility for type 2 diabetes (T2DM). However, it is still unknown whether CILP-2 is involved in the regulation of glucose homeostasis and insulin resistance (IR). In the current study, we initially observed that CILP-2 as a secreted protein was detected in both conditioned medium and lysates of cells transfected with an overexpressed vector. We then found that circulating CILP-2 levels had a progressive increase from normal to impaired glucose tolerance (a pre-diabetic status) and then to diabetes, which was correlated positively with waist-to-hip ratio, triglyceride, fasting blood glucose, 2-h blood glucose after glucose overload, HbA1c, fasting insulin, 2-h plasma insulin after glucose overload, and homeostasis model assessment of insulin resistance but negatively with HDL-C. CILP-2 expression was increased in the liver and muscle but decreased in adipose tissues of obese mice or T2DM patients. Furthermore, we demonstrated that CILP-2 circulating levels were affected by OGTT and Exenatide. CILP-2 overexpression resulted in impaired glucose tolerance and hepatic IR in vivo and increased PEPCK expression whereas suppressed phosphorylation of insulin receptor and Akt kinase in vitro. Based on these findings, we have identified a direct interaction between CILP-2 and PEPCK and suggested that CILP-2 plays an important role in the regulation of hepatic glucose production.

关键词： CILP-2 secreted protein insulin resistance type 2 diabetes

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Spleen volume is associated with overt hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in patients with portal hypertension

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World Journal of Gastrointestinal Surgery 2024年第7期16卷 2054-2064页

作者： Chun-Juan Zhao Chao Ren Zhen Yuan Guo-Hui Bai Jin-Yu Li Long Gao Jin-Hui Li Ze-Qi Duan Dui-Ping Feng Hui Zhang College of Medical Imaging Shanxi Medical UniversityTaiyuan 030001Shanxi ProvinceChina department of Radiology The First Hospital of Shanxi Medical UniversityTaiyuan 030001Shanxi ProvinceChina department of Occupational Health School of Public HealthShanxi Key Laboratory of Environmental Health Impairment and PreventionNHC Key Laboratory of PneumoconiosisMOE Key Laboratory of Coal Environmental Pathogenicity and PreventionShanxi Medical UniversityTaiyuan 030001Shanxi ProvinceChina department of Oncological and Vascular Intervention The First Hospital of Shanxi Medical UniversityTaiyuan 030001Shanxi ProvinceChina Shanxi Provincial Clinical Research Center for Interventional Medicine The First Hospital of Shanxi Medical UniversityTaiyuan 030001Shanxi ProvinceChina First Clinical Medical College Shanxi Medical UniversityTaiyuan 030001Shanxi ProvinceChina Shanxi Key laboratory of Intelligent Imaging and Nanomedicine The First Hospital of Shanxi Medical UniversityTaiyuan 030001Shanxi ProvinceChina Intelligent Imaging Big Data and Functional Nano-imaging Engineering Research Center of Shanxi Province The First Hospital of Shanxi Medical UniversityTaiyuan 030001Shanxi ProvinceChina

BACKGROUND portal shunt and immune status related to the spleen are related to the occurrence of hepatic encephalopathy(HE).It is unknown whether spleen volume before transjugular intrahepatic portosystemic shunt(TIPS)is related to postoperative *** To investigate the relationship between spleen volume and the occurrence of *** This study included 135 patients with liver cirrhosis who underwent TIPS,and liver and spleen volumes were elevated upon computed tomography *** Kaplan-Meier curve was used to compare the difference in the incidence rate of HE among patients with different spleen *** and multivariate Cox regression analyses were performed to identify the factors affecting overt HE(OHE).Restricted cubic spline was used to examine the shapes of the dose-response association between spleen volumes and OHE *** The results showed that 37(27.2%)of 135 patients experienced OHE during a 1-year follow-up *** with preoperative spleen volume(901.30±471.90 cm3),there was a significant decrease in spleen volume after TIPS(697.60±281.0 cm^(3))in OHE *** the severity of OHE increased,the spleen volume significantly decreased(P<0.05).Compared with patients with a spleen volume≥782.4 cm^(3),those with a spleen volume<782.4 cm^(3) had a higher incidence of HE(P<0.05).Cox regression analysis showed that spleen volume was an independent risk factor for post-TIPS OHE(hazard ratio=0.494,P<0.05).Restricted cubic spline model showed that with an increasing spleen volume,OHE risk showed an initial increase and then decrease(P<0.05).CONCLUSION Spleen volume is related to the occurrence of OHE after *** spleen volume is an independent risk factor for post-TIPS OHE.

关键词： Hepatic encephalopathy Transjugular intrahepatic portosystemic shunt Spleen volume portal hypertension Cirrhosis

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