[Show abstract][Hide abstract] ABSTRACT: Pancreatic cancer is one of the major malignancies and cause for mortality across the world, with recurrence and metastatic progression remaining the single largest cause of pancreatic cancer mortality. Hence it is imperative to develop novel biomarkers of pancreatic cancer prognosis. The E3 ubiquitin ligase ITCH has been previously reported to inhibit the tumor suppressive Hippo signaling by suppressing LATS1/2 in breast cancer and chronic lymphocytic leukemia. However, the role of ITCH in pancreatic cancer progression has not been described. Here we report that ITCH transcript and protein expression mimic metastatic trait in pancreatic cancer patients and cell lines. Loss-of-function studies of ITCH showed that the gene product is responsible for inducing metastasis in vivo. We furthermore show that hsa-miR-106b, which itself is down regulated in metastatic pancreatic cancer, directly interacts and inhibit ITCH expression. ITCH and hsa-miR-106b are thus potential biomarkers for pancreatic cancer prognosis.
[Show abstract][Hide abstract] ABSTRACT: Objectives:
Severe acute pancreatitis (SAP) is a fatal disease with natural course of early SAP (ESAP) and late SAP (LSAP) phases. Peripancreatic percutaneous catheter drainage (PCD) is effective in management of LSAP. Although our previous study indicates that intra-abdominal PCD ahead of peripancreatic PCD benefits ESAP patients with sterile fluid collections, the mechanism is still uncovered.
According to therapeutic results, 452 SAP patients who underwent PCD were divided into sterile group (248 cases), secondary infection group (145 cases), and primary infection group (59 cases).
The mortality was 4.1%, 10.9%, and 18.6%, respectively. Logistic-regression analysis indicated that multiorgan dysfunction syndrome (odds ratio [OR], 1.717; 95% confidence interval [95% CI], 1.098-2.685; P = 0.018), catheters located intra-abdominally (OR, 0.511; 95% CI, 0.296-0.884; P = 0.016), and intra-abdominal hypertension (OR, 1.534; 95% CI, 1.016-2.316; P = 0.042) were predictors for infection after PCD. Receiver operating characteristics curve delineated that decrease of intra-abdominal pressure (IAP) of more than 6.5 mm Hg after PCD had the ability to predict infection with sensitivity of 84.0% and specificity of 79.5%.
Intra-abdominal PCD for acute sterile fluid collections seems to be an effective option rather than peripancreatic PCD. Patients with a significant decrease of IAP had a lower incidence of infection and better alleviation of organ failure.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
This study aimed to investigate the therapeutic potential of hydrogen-rich saline on pancreatic ischemia/reperfusion (I/R) injury in rats.
Eighty heterotopic pancreas transplantations (HPT) were performed in syngenic rats. The receptors were randomized blindly into the following three groups: the HPT group and two groups that underwent transplantation and administration of hydrogen-rich saline (HS, >0.6 mM, 6 mL/kg) or normal saline (NS, 6 mL/kg) via the tail vein at the beginning of reperfusion (HPT + HS group, HPT + NS group). Samples from the pancreas and blood were taken at 12 hours after reperfusion. The protective effects of hydrogen-rich saline against I/R injury were evaluated by determining the changes in histopathology and measuring serological parameters, oxidative stress-associated molecules, and proinflammatory cytokines.
Administration of hydrogen-rich saline produced notable protection against pancreatic I/R injury in rats. Histopathological improvements and recovery of impaired pancreatic function were observed. In addition, TNF-α, IL-1β, and IL-6 were reduced markedly in the HPT + HS group. Additionally, there were noticeable inhibitory effects on the pancreatic malondialdehyde level and considerable recruitment of SOD and GPx, which are antioxidants.
Hydrogen-rich saline treatment significantly attenuated the severity of pancreatic I/R injury in rats, possibly by reducing oxidative stress and inflammation.
Preview · Article · Apr 2015 · Mediators of Inflammation
[Show abstract][Hide abstract] ABSTRACT: To investigate the clinical efficacy of gastric bypass surgery in non-obese patients with type 2 diabetes.
Clinical data of 58 non-obese patients with type 2 diabetes (body mass index range from 22.1-25.8 kg/m(2)) were collected one year after gastric bypass surgery. Collected parameters included fasting plasma glucose, 2-hour postprandial blood glucose, glycosylated hemoglobin, fasting plasma glucagon-like peptide-1 and 2-hour postprandial plasma glucagon-like peptide-1. The insulin resistance index (HOMA-IR = fasting plasma glucose × fasting serum insulin/22.5) and the body mass index were calculated.
Of the 58 patients, 48 had stopped taking all hypoglycemic drug treatments and had achieved complete remission (82.8%). Seven patients were unable to completely withdraw from hypoglycemic agents, although their intake of drugs was reduced at least 50% compared to pre-surgical values (12.0%). Three of the cases showed no significant change in blood glucose after surgery (5.2%). In addition, values for fasting plasma glucose, 2-hour postprandial blood glucose, glycosylated hemoglobin and HOMA-IR significantly decreased after surgery. Values for fasting plasma glucagon-like peptide-1 and 2-hour postprandial plasma glucagon-like peptide-1 significantly increased after surgery, and the body mass index at the sixth post-operative month were significantly lower than pre-operative.
For non-obese patients with type 2 diabetes, gastric bypass surgery has a significant clinical effect. Potential mechanisms include improvements in insulin resistance and/or increased endogenous intestinal glucagon-like peptide-1 secretion leading to improved insulin secretion.
No preview · Article · Mar 2015 · International Journal of Clinical and Experimental Medicine
[Show abstract][Hide abstract] ABSTRACT: Due to unsatisfying prognosis of AFP for hepatocellular carcinoma (HCC), we aim to evaluate the prognostic value of combination of exosomes and miRNAs in detecting HCC.
HCC was induced with diethylnitrosamine in rats and using a scoring system based on histological examination six different stages (normal liver, degeneration, fibrosis, cirrhosis, early HCC and late HCC) were identified in the development of HCC. The expression levels of AFP, exosomes and miRNAs (miRNA-10b, miRNA-21, miRNA-122 and miRNA-200a) were detected in both tissue and blood samples from those six stages. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the power of each parameter and their different combinations in diagnosing HCC or cirrhosis.
A change in the expression of both exosomes and miRNAs was observed during cirrhosis, which in contrast with AFP starts showing up until the early HCC stage. Interestingly, the expressions of exosomes and the selected four miRNAs at early HCC stage obtained more remarkably alterations than the level of AFP (P < 0.05). On correlation analysis, four selected miRNAs had a significant closer relationship with exosomes when compared with AFP. The different combinations of AFP, exosomes, serous miRNAs and exosomal miRNAs had stronger power in predicting HCC than AFP (area under the curve of ROC, 0.943 vs 0.826).
To conclude, the combination of circulating miRNAs and exosomes might serve as promising biomarkers for non-virus infected HCC screening and cirrhosis discrimination.
No preview · Article · Feb 2015 · Journal of Cancer Research and Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: Previously, other groups and our team consistently demonstrate that the possible origination of liver cancer stem cells (LCSCs) is malignant transformation from liver normal stem cells (LNSCs). However, this complex and multi-step process is far from clear due to the accumulation of various gene dysregulations. As noncoding RNAs (ncRNAs) could regulate multiple genes, family genes, and even whole chromosome, in the present study, we further investigated the effect of our found dysregulated short ncRNA microRNA-10b and long ncRNA HOTAIR between LNSCs and LCSCs on their phenotypes reversion. To clarify the role of ncRNA in LNSCs malignant transformation, using lentivirus transduction, the miR-10b and HAOAIR expression levels were enhanced in our previously isolated rat LNSCs. The malignant abilities of proliferation, invasiveness and tumorigenesis were observed and compared in cells before and after ncRNAs enhancement. After microRNA-10b and HOTAIR were separately enhanced, several cancer stem cell (CSC)-like traits appeared in these LNSCs, such as in vitro enhanced proliferative capacity, expression of putative LCSC markers, progressed obtainment of invasive ability, and even in vivo aggravation into and taking place of normal liver tissue. Furthermore, strengthened expression of these ncRNAs partially degraded the E-cadherin in LNSCs, which is the key moleculeone of the classic markers in epithelial-mesenchymal transitions (EMT). HOTAIR or miR-10b enhanced in LNSCs may drive the LNSCs to arise malignant transformation tendency. Collectively, this study partially uncovers the mechanism that miR-10b or HOTAIR promotes LNSCs malignant transformation through down-regulating E-cadherin and inducing EMT.
No preview · Article · Feb 2015 · Rejuvenation Research
[Show abstract][Hide abstract] ABSTRACT: Although we previously demonstrated abdominal paracentesis drainage (APD) preceding percutaneous catheter drainage (PCD) as the central step for treating patients with moderately severe (MSAP) or severe acute pancreatitis (SAP), the predictors leading to PCD after APD have not been studied.
Consecutive patients with MSAP or SAP were recruited between June 2011 and June 2013. As a step-up approach, all patients initially received medical management, later underwent ultrasound-guided APD before PCD, if necessary, followed by endoscopic necrosectomy through the path formed by PCD. APD primarily targeted fluid in the abdominal or pelvic cavities, whereas PCD aimed at (peri)pancreatic fluid.
Of the 92 enrolled patients, 40 were managed with APD alone and 52 received PCD after APD (14 required necrosectomy after initial PCD). The overall mortality was 6.5%. Univariate analysis showed that among the 20 selected parameters, 13 factors significantly affected PCD intervention after APD. Multivariate analysis revealed that infected (peri)pancreatic collections (P = -0.001), maximum extent of necrosis of more than 30% of the pancreas (P = -0.024), size of the largest necrotic peri(pancreatic) collection (P = -0.007), and reduction of (peri)pancreatic fluid collections by <50% after APD (P = -0.008) were all independent predictors of PCD.
Infected (peri)pancreatic collections, a largest necrotic peri(pancreatic) collection of more than 100 ml, and reduction of (peri)pancreatic fluid collections by <50% after APD could effectively predict the need for PCD in the early course of the disease.
[Show abstract][Hide abstract] ABSTRACT: Objective:
This study investigated the effect of percutaneous catheter drainage (PCD) on pancreatic injury in severe acute pancreatitis (SAP) rats.
Sixty Wistar rats were equally randomized into three groups: a sham operated control group, an SAP control group, and a PCD group. The levels of inflammatory cytokines, the activity of group II phospholipase A2 (PLA2) in blood and ascitic fluid, and the pancreas level of group II PLA2 and trypsin activity were measured 24 h after the operation. The apoptosis of the pancreatic cells, the expression of cycloxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), active caspase-3, Bcl-2 and Bax in the pancreas was detected. Pancreatic pathological changes were observed.
The levels of proinflammatory cytokines, the activity of group II PLA2 and trypsin activity in pancreas in the SAP group were higher than those in the PCD group. The histopathological results revealed that the pancreatic injury was alleviated in the PCD group. The expression of COX-2 and iNOS in the pancreatic tissue in the SAP control rats was higher than that in the PCD rats. The expression of Bcl-2 was decreased and the expression of active caspase-3 and Bax was increased in the pancreas of PCD rats. The apoptosis index of the pancreatic cells in the PCD rats was higher than that in the SAP control rats.
PCD can relieve SAP-induced pancreatic injury by inhibiting inflammatory reactions, and promoting apoptosis of pancreatic cells.
[Show abstract][Hide abstract] ABSTRACT: The efficacy and safety of ultrasound-guided abdominal paracentesis drainage ahead of percutaneous catheter drainage as the new second step of a step-up approach are evaluated.
No preview · Article · Sep 2014 · Critical Care Medicine
[Show abstract][Hide abstract] ABSTRACT: Background
Electroacupuncture (EA) is one of the techniques of acupuncture and is believed to be an effective alternative and complementary treatment in many disorders. The aims of this study were to investigate the effects and mechanisms of EA at acupoint Zusanli (ST36) on the plasticity of interstitial cells of Cajal (ICCs) in partial bowel obstruction.
A Sprague Dawley rat model of partial bowel obstruction was established and EA was conducted at Zusanli (ST36) and Yinglingquan (SP9) in test and control groups, respectively. Experiments were performed to study the effects and mechanisms of EA at Zusanli on intestinal myoelectric activity, distribution and alteration of ICCs, expression of inflammatory mediators, and c-Kit expression.
1) EA at Zusanli somewhat improved slow wave amplitude and frequency in the partial obstruction rats. 2) EA at Zusanli significantly stimulated the recovery of ICC networks and numbers. 3) the pro-inflammatory mediator TNF-α and NO activity were significantly reduced after EA at Zusanli, However, no significant changes were observed in the anti-inflammatory mediator IL-10 activity. 4) EA at Zusanli re-expressed c-Kit protein. However, EA at the control acupoint, SP9, significantly improved slow wave frequency and amplitude, but had no effect on ICC or inflammatory mediators.
We concluded that EA at Zusanli might have a therapeutic effect on ICC plasticity, and that this effect might be mediated via a decrease in pro-inflammatory mediators and through the c-Kit signaling pathway, but that the relationship between EA at different acupoints and myoelectric activity needs further study.
Preview · Article · Jun 2014 · BMC Complementary and Alternative Medicine
[Show abstract][Hide abstract] ABSTRACT: In a previous study, the Notch pathway inhibited with N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (also called DAPT) was shown to promote the differentiation of fetal liver stem/progenitor cells (FLSPCs) into hepatocytes and to impair cholangiocyte differentiation. The precise mechanism for this, however, was not elucidated. Two mechanisms are possible: Notch inhibition might directly up-regulate hepatocyte differentiation via HGF (hepatocyte growth factor) and HNF (hepatocyte nuclear factor)-4α or might impair cholangiocyte differentiation thereby indirectly rendering hepatocyte differentiation as the dominant state. In this study, HGF and HNF expression was detected after the Notch pathway was inhibited. Although our initial investigation indicated that the inhibition of Notch induced hepatocyte differentiation with an efficiency similar to the induction via HGF, the results of this study demonstrate that Notch inhibition does not induce significant up-regulation of HGF or HNF-4α in FLSPCs. This suggests that Notch inhibition induces hepatocyte differentiation without the influence of HGF or HNF-4α. Moreover, significant down-regulation of HNF-1β was observed, presumably dependent on an impairment of cholangiocyte differentiation. To confirm this presumption, HNF-1β was blocked in FLSPCs and was followed by hepatocyte differentiation. The expression of markers of mature cholangiocyte was impaired and hepatocyte markers were elevated significantly. The data thus demonstrate that the inhibition of cholangiocyte differentiation spontaneously induces hepatocyte differentiation and further suggest that hepatocyte differentiation from FLSPCs occurs at the expense of the impairment of cholangiocyte differentiation, probably being enhanced partially via HNF-1β down-regulation or Notch inhibition.
No preview · Article · Apr 2014 · Cell and Tissue Research
[Show abstract][Hide abstract] ABSTRACT: Berberine is a traditional drug used to treat gastrointestinal disorders in China and has been demonstrated to attenuate intestinal barrier dysfunction in certain animal models. However, the effects of berberine on pancreatitis‑induced intestinal barrier dysfunction are yet to be fully elucidated. This study aimed to investigate the effect of berberine pretreatment on the attenuation of intestinal barrier dysfunction induced by severe acute pancreatitis (SAP). A total of 36 rats were randomly divided into Sham, SAP and SAP plus berberine groups. Pancreatitis was induced using retrograde injection of 3% Na‑taurocholate into the pancreatic duct. Histological examinations of the pancreas were performed and intestinal barrier dysfunction was characterized by histological measurements and the assessment of serum diamine oxidase activity and endotoxin levels. Zonula occludens‑1 and occludin mRNA and protein expression, as well as myosin light chain (MLC) phosphorylation, were assessed. SAP rat models were successfully established. Berberine treatment was found to have no significant effect on the histological changes in the pancreas, but was observed to ameliorate the intestinal mucosal barrier damage and membrane permeability associated with SAP. Although berberine exerted minimal effects on tight junction proteins in the ilea of SAP rats, it was observed to significantly inhibit SAP‑induced MLC phosphorylation. To the best of our knowledge, this is the first study to demonstrate that berberine attenuates SAP‑induced intestinal barrier dysfunction in vivo. In addition, this study shows that the effect of berberine on intestinal barrier function may be associated with the inhibition of SAP‑induced upregulation of MLC phosphorylation.
No preview · Article · Feb 2014 · Molecular Medicine Reports
[Show abstract][Hide abstract] ABSTRACT: Cholecystolithiasis is the most common disease treated by general surgery, with an incidence of about 0.15-0.22 %. The most common therapies are open cholecystectomy (OC) or laparoscopic cholecystectomy (LC). However, with a greater understanding of the function of the cholecyst, more and more patients and surgeons are aware that preserving the functional cholecyst is important for young patients, as well as patients who would not tolerate anesthesia associated with either OC or LC. Based on these considerations, we have introduced a notable, minimally invasive treatment for cholecystolithotomy.
We performed a retrospective review of patients with cholecystolithiasis who were unable to tolerate surgery or who insisted on preserving the functional cholecyst. Our particular approach can be simply described as ultrasound-guided percutaneous cholecystostomy combined with a choledochoscope for performing a cholecystolithotomy under local anesthesia.
Ten patients with cholecystolithiasis were treated via this approach. All except one patient had their gallbladder stones totally removed under local anesthesia, without the aggressive procedures associated with OC or LC. The maximum number of gallbladder stones removed was 16, and the maximum diameter was 13 mm without lithotripsy. After the minimally invasive surgery, the cholecyst contractile functions of all patients were normal, confirmed via ultrasound after a high-fat diet. Complications such as bile duct injury, biliary fistula, and bleeding occurred significantly less often than with OC and LC. The recurrence rates for each of 2 post-operative years were about 11.11 % (1/9, excluding a failure case) with uncertainty surrounding recurrence or residue, and 22.22 % (2/9, including one non-recurrence patient with follow-up time of 22 months), respectively.
Ultrasound-guided percutaneous cholecystostomy combined with choledochoscope is a safe, efficient, and minimally invasive cholecystolithotomy method. We recommend this technique for the management of small stones (less than 15 mm) in high-risk surgical patients.
No preview · Article · Feb 2014 · Surgical Endoscopy
[Show abstract][Hide abstract] ABSTRACT: The aim of the present study was to identify key genes associated with atopic dermatitis (AD) using microarray data and bioinformatic analyses. The dataset GSE6012, downloaded from the Gene Expression Omnibus (GEO) database, contains gene expression data from 10 AD skin samples and 10 healthy skin samples. Following data preprocessing, differentially expressed genes (DEGs) were identified using the limma package of the R project. Interaction networks were constructed comprising DEGs that showed a degree of node of >3, >5 and >10, using the Osprey software. Functional enrichment and pathway enrichment analysis of the network comprising all DEGs and of the network comprising DEGs with a high degree of node, were performed with the DAVID and WebGestalt toolkits, respectively. A total of 337 DEGs were identified. The functional enrichment analysis revealed that the list of DEGs was significantly enriched for proteins related to epidermis development (P=2.95E-07), including loricrin (LOR), keratin 17 (KRT17), small proline-rich repeat proteins (SPRRs) and involucrin (IVL). The chemokine signaling pathway was the most significantly enriched pathway (P=0.0490978) in the network of all DEGs and in the network consisting of high degree‑node DEGs (>10), which comprised the genes coding for chemokine receptor 7 (CCR7), chemokine ligand (CCL19), signal transducer and activator of transcription 1 (STAT1), and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1). In conclusion, the list of AD-associated proteins identified in this study, including LOR, KRT17, SPRRs, IVL, CCR7, CCL19, PIK3R1 and STAT1 may prove useful for the development of methods to treat AD. From these proteins, PIK3R1 and KRT17 are novel and promising targets for AD therapy.
No preview · Article · Jan 2014 · Molecular Medicine Reports
[Show abstract][Hide abstract] ABSTRACT: Liver stem/progenitor cells (LSPCs) are able to duplicate themselves and differentiate into each type of cells in the liver, including mature hepatocytes and cholangiocytes. Understanding how to accurately control the hepatic differentiation of LSPCs is a challenge in many fields from preclinical to clinical treatments. This review summarizes the recent advances made to control the hepatic differentiation of LSPCs over the last few decades. The hepatic differentiation of LSPCs is a gradual process consisting of three main steps: initiation, progression and accomplishment. The unbalanced distribution of the affecting materials in each step results in the hepatic maturation of LSPCs. As the innovative and creative works for generating hepatocytes with full functions from LSPCs are gradually accumulated, LSPC therapies will soon be a new choice for treating liver diseases.
Full-text · Article · Nov 2013 · Journal of Cellular and Molecular Medicine
[Show abstract][Hide abstract] ABSTRACT: Urinary function can be protected following open lateral node dissection (LND) with pelvic autonomic nerve preservation (PANP) for advanced rectal cancer. However data regarding urinary function after laparoscopic LND with PANP have not been reported. The goal of this study was to determine the effects of laparoscopic LND with PANP on urinary function in male patients with rectal cancer.
Urine flowmetry was performed using an Urodyn flowmeter. Patients were also asked to complete the standardized International Prostate Symptom Score (IPSS) questionnaire before surgery and 6 months after. In total, this study consisted of 60 males with advanced rectal cancer.
No significant differences were seen in maximal urinary flow rate, voided volume or residual volume before and after surgery. The total IPSS score increased significantly after surgery and at least 41 patients (68.3%) reported there was no change in one of the seven IPSS questions.
Laparoscopic LND with PANP was relatively safe in preserving urinary function.
[Show abstract][Hide abstract] ABSTRACT: Except for the most organized mature hepatocytes, liver stem/progenitor cells (LSPCs) can differentiate into many other types of cells in the liver including cholangiocytes. In addition, LSPCs are demonstrated to be able to give birth to other kinds of extra-hepatic cell types such as insulin-producing cells. Even more, under some bad conditions, these LSPCs could generate liver cancer stem like cells (LCSCs) through malignant transformation. In this review, we mainly concentrate on the molecular mechanisms for controlling cell fates of LSPCs, especially differentiation of cholangiocytes, insulin-producing cells and LCSCs. First of all, to certificate the cell fates of LSPCs, the following three features need to be taken into account to perform accurate phenotyping: (1) morphological properties; (2) specific markers; and (3) functional assessment including in vivo transplantation. Secondly, to promote LSPCs differentiation, systematical attention should be paid to inductive materials (such as growth factors and chemical stimulators), progressive materials including intracellular and extracellular signaling pathways, and implementary materials (such as liver enriched transcriptive factors). Accordingly, some recommendations were proposed to standardize, optimize, and enrich the effective production of cholangiocyte-like cells out of LSPCs. At the end, the potential regulating mechanisms for generation of cholangiocytes by LSPCs were carefully analyzed. The differentiation of LSPCs is a gradually progressing process, which consists of three main steps: initiation, progression and accomplishment. It's the unbalanced distribution of affecting materials in each step decides the cell fates of LSPCs.
No preview · Article · Nov 2013 · World Journal of Gastroenterology
[Show abstract][Hide abstract] ABSTRACT: Oxidative stress and inflammation play important roles in the progression from simple fatty liver to nonalcoholic steatohepatitis (NASH). The aim of this work was to investigate whether treatment with hydrogen sulfide (H2 S) prevented NASH in rats through abating oxidative stress and suppressing inflammation.
A methionine-choline-deficient (MCD) diet rat model was prepared. Rats were divided into three experimental groups and fed for 8 weeks as follows: (1) control rats; (2) MCD-diet-fed rats; (3) MCD-diet-fed rats treated with NaHS (intraperitoneal injection of 0.1 ml/kg/d of 0.28 mol/l NaHS, a donor of H2 S).
MCD diet impaired hepatic H2 S biosynthesis in rats. Treatment with H2 S prevented MCD-diet-induced NASH, as evidenced by hematoxylin and eosin staining, reduced apoptosis and activities of ALT and AST, and attenuated hepatic fat accumulation in rats. Treatment with H2 S abated MCD-diet-induced oxidative stress through reducing CYP2E1 expression, enhancing HO-1 expression and suppressing mitochondrial ROS formation, and suppressed MCD-diet-induced inflammation through suppressing activated NFκB signaling and reducing IL-6 and TNFα expression. In addition, Treatment of MCD-diet fed rats with H2 S had a beneficial modulation on expression profiles of fatty acid metabolism genes in livers.
Treatment with H2 S prevented NASH induced by MCD diet in rats possibly through abating oxidative stress and suppressing inflammation.
Preview · Article · Oct 2013 · Journal of Gastroenterology and Hepatology