Publications (14)50.24 Total impact
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Article: The diminished expression of proangiogenic growth factors and their receptors in gastric ulcers of cirrhotic patients.
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ABSTRACT: The pathogenesis of the higher occurrence of peptic ulcer disease in cirrhotic patients is complex. Platelets can stimulate angiogenesis and promote gastric ulcer healing. We compared the expressions of proangiogenic growth factors and their receptors in the gastric ulcer margin between cirrhotic patients with thrombocytopenia and those of non-cirrhotic patients to elucidate possible mechanisms. Eligible cirrhotic patients (n = 55) and non-cirrhotic patients (n = 55) who had gastric ulcers were enrolled. Mucosa from the gastric ulcer margin and non-ulcer areas were sampled and the mRNA expressions of the proangiogenic growth factors (vascular endothelial growth factor [VEGF], platelet derived growth factor [PDGF], basic fibroblast growth factor [bFGF]) and their receptors (VEGFR1, VEGFR2, PDGFRA, PDGFRB, FGFR1, FGFR2) were measured and compared. Platelet count and the expressions of these growth factors and their receptors were correlated with each other. The two groups were comparable in terms of gender, ulcer size and infection rate of Helicobacter pylori. However, the cirrhotic group were younger in age, had a lower platelet count than those in the non-cirrhotic group (p<0.05). The cirrhotic patients had diminished mRNA expressions of PDGFB, VEGFR2, FGFR1, and FGFR2 in gastric ulcer margin when compared with those of the non-cirrhotic patients (p<0.05). Diminished expressions of PDGFB and VEGFR2, FGFR1, and FGFR2 were well correlated with the degree of thrombocytopenia in these cirrhotic patients (ρ>0.5, p<0.001). Our findings implied that diminished activity of proangiogenic factors and their receptors may contribute to the pathogenesis of gastric ulcers in cirrhotic patients.PLoS ONE 01/2013; 8(4):e61426. · 4.09 Impact Factor -
Article: Multiple effects of Honokiol on the life cycle of hepatitis C virus.
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ABSTRACT: Honokiol, a small active molecular compound extracted from magnolia, has recently been shown to inhibit hepatitis C virus (HCV) infection in vitro. This study further characterized aspects of the HCV lifecycle affected by the antiviral functions of honokiol. The influence of honokiol on HCV infection, entry, translation and replication was assessed in Huh-7.5.1 cells using cell culture-derived HCV (HCVcc), HCV pseudo-type (HCVpp) and sub-genomic replicons. Honokiol had strong antiviral effect against HCVcc infection at non-toxic concentrations. Combined with interferon-α, its inhibitory effect on HCVcc was more profound than that of ribavirin. Honokiol inhibited the cell entry of lentiviral particles pseudo-typed with glycoproteins from HCV genotypes 1a, 1b, and 2a, but not of the vesicular stomatitis virus. It had inefficient activity on HCV internal ribosome entry site (IRES)-translation at concentrations with significant anti-HCVcc effects. The expression levels of components of replication complex, NS3, NS5A and NS5B, were down-regulated by honokiol in a dose-dependent manner. It also inhibited HCV replication dose dependently in both genotypes 1b and 2a sub-genomic replicons. Honokiol inhibits HCV infection by targeting cell entry and replication and, only at a concentration >30 μM, IRES-mediated translation of HCV life cycle. Based on its high therapeutic index (LD(50) /EC(90) = 5.4), honokiol may be a promising drug for the treatment of HCV infection.Liver international: official journal of the International Association for the Study of the Liver 08/2011; 32(6):989-97. · 3.82 Impact Factor -
Article: Increased plasma malondialdehyde in patients with viral cirrhosis and its relationships to plasma nitric oxide, endotoxin, and portal pressure.
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ABSTRACT: Increased oxidative stress is involved in the development of portal hypertension in cirrhosis. Our study aimed to assess the relationship between oxidative stress and hemodynamic parameters in cirrhotic patients. Forty-two patients with viral cirrhosis and 24 normal controls were enrolled. Measurements of plasma levels of malondialdehyde (MDA), nitrite/nitrate (NOx), endotoxin, and activities of superoxide dismutase (SOD) were carried out in all subjects. Systemic and splanchnic hemodynamic measurements were carried out in cirrhotic patients. Plasma levels of MDA, endotoxin, and NOx were significantly higher in cirrhotic patients than in normal controls (900 +/- 751 versus 226 +/- 16 nM, P < 0.01; 62.0 +/- 26.0 versus 14.8 +/- 4.1 pg/mL, P < 0.01; 50.5 +/- 22.6 versus 15.0 +/- 9.2 nM, P < 0.01, respectively). Activities of SOD were significantly decreased in cirrhotic patients compared with in normal controls (2.62 +/- 0.7 versus 6.8 +/- 0.4 U/mL). Further, plasma levels of MDA in cirrhotic patients were significantly positively associated with hepatic venous pressure gradient (HVPG) (r = 0.35; P = 0.025), wedge hepatic venous pressure (WHVP) (r = 0.42; P = 0.007), and hepatic sinusoid resistance (HSR) (r = 0.33; P = 0.033). Plasma MDA levels also correlated positively with plasma endotoxin (r = 0.71, P < 0.001) and NOx (r = 0.55, P < 0.001) levels in the cirrhotic patients. Multiregression analysis showed that the independent and strongest factors to predict HVPG, WHVP, and HSR are plasma levels of NOx, MDA, and endotoxin, respectively. This study suggests a close interaction among MDA, endotoxin, and NOx and that these substances are also associated with hemodynamic derangement in cirrhosis.Digestive Diseases and Sciences 10/2009; 55(7):2077-85. · 2.12 Impact Factor -
Article: Gastropericardial fistula and Candida albicans pericarditis: a rare complication of gastric adenocarcinoma treated with radiation and chemotherapy.
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ABSTRACT: Gastropericardial fistula is generally associated with benign gastric diseases and is an uncommon complication of gastric adenocarcinoma. Pericarditis and cardiac tamponade are the ultimate outcome, with extremely high mortality rates. We report a 47-year-old man with gastric adenocarcinoma who had completed radiotherapy and was on scheduled chemotherapy, who presented with fever and chest pain. Gastric adenocarcinoma complicated with gastropericardial fistula and Candida albicans pericarditis were diagnosed and treated successfully with conservative management. Initial chest radiography and computed tomography (CT) revealed no evident pericardial air or fluid. However, follow-up panendoscopy 2 weeks later revealed a malignant ulcer with a fistula opening over the lesser curvature of the high body of the stomach. Subsequent chest radiography and CT revealed pneumopericardium with fluid accumulation. Emergent CT-guided pericardial drainage was performed. The fluid was positive for Candida albicans. Total parenteral nutrition and antifungal therapy were administered. The patient refused surgical intervention and survived with medical management alone. This case demonstrates that first, panendoscopy may be safely performed in patients with gastropericardial fistula without significant risk of cardiac tamponade; second, although early diagnosis of gastropericardial fistula is generally important, delayed recognition may not lead to devastating outcomes even in the absence of surgical intervention.Journal of the Chinese Medical Association 08/2009; 72(7):374-8. · 0.79 Impact Factor -
Article: Effects of N-acetylcysteine administration in hepatic microcirculation of rats with biliary cirrhosis.
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ABSTRACT: Increased intrahepatic resistance (IHR) in cirrhosis is due to fibrosis and hepatic endothelial dysfunction (HED). Besides producing fibrosis, increased reactive oxygen species (ROS) promotes ROS-related nitration of anti-oxidative enzymes in cirrhotic livers. Tyrosine nitration (nitrotyrosilation)-related inactivation of anti-oxidative enzymes is increased in cirrhotic livers. This study investigates effects of N-acetylcysteine (NAC) administrations in bile-duct-ligation (BDL) rats. This study measured portal venous pressure (PVP), IHR, hepatic endothelial function, hepatic levels of anti-oxidants and oxidants, type III procollagen (PIIIP), proteins expression of thromboxane synthase (TXS), nitrotyrosine, manganese superoxide dismutase (MnSOD), and hepatic NOx and thromboxane A(2) (TXA(2)) production in perfusates. The improvement of HED was associated with decreased PVP and IHR, hepatic protein and mRNA levels of PIIIP, protein expression of TXS and nitrotyrosine, oxidants and production of TXA(2) in NAC-treated BDL rat livers. Conversely, hepatic NOx production, anti-oxidants, and protein expression of MnSOD were increased in NAC-treated BDL rat livers. In NAC-treated cirrhotic rats, the decrease in IHR was mainly caused by its anti-oxidative effect-related prevention of hepatic fibrogenesis associated with the decrease of oxidants-related nitrotyrosilation and improvement of HED.Journal of Hepatology 08/2008; 49(1):25-33. · 9.26 Impact Factor -
Article: Acute administration of sildenafil enhances hepatic cyclic guanosine monophosphate production and reduces hepatic sinusoid resistance in cirrhotic patients
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ABSTRACT: Aim: In liver cirrhosis, the increased production of nitric oxide (NO) contributes to increased systemic and splanchnic vasodilatation. The inhibition of phosphodiesterase-5 (PDE-5), an enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP), is widely used in the treatment of erectile dysfunction. The aim of our study is to evaluate the overall effects of PDE-5 inhibitor administration on splanchnic, pulmonary and systemic hemodynamics in cirrhotic patients.Methods: Sildenafil, a specific PDE-5 inhibitor, was administrated orally to cirrhotic patients (n = 7) to see the hemodynamic changes. A control group receiving a placebo was used as a point of comparison (n = 6).Results: Compared to the control group, the hepatic vein NO and cGMP levels were significantly increased after sildenafil administration in the sildenafil group (NO from 112.3 ± 43.5 to 325.3 ± 117.5 nM, P = 0.018; cGMP from 7.3 ± 0.4 to 19.2 ± 4.2 pmol, P = 0.018). The hepatic venous pressure gradient in the sildenafil group did not differ from that of the control group. However, a significantly decreased hepatic sinusoidal resistance in the sildenafil group (1999 ± 1243 vs. 1563 ± 1014 dyne/s/cm−5, P < 0.05) was noted. The study also found that the right arterial pressure, mean pulmonary arterial pressure and pulmonary capillary wedge pressure were reduced at 60 min after administration, compared with the basal parameters in cirrhotic patients receiving sildenafil (RAP1.3 ± 2.0 vs −0.6 ± 1.3 mmHg, MPAP 14.1 ± 11.3 vs 11.7 ± 9.5 mmHg, PCWP 4.6 ± 1.7 vs 2.9 ± 1.6 mmHg, P < 0.05 respectively).Conclusions: An oral administration of 50 mg of sildenafil significantly decreased the mean pulmonary arterial pressure and hepatic sinusoid resistance with a significant increase in hepatic NO and cGMP production, and did not worsen portal hypertension in cirrhotic patients.Hepatology Research 07/2008; 38(12):1186 - 1193. · 2.20 Impact Factor -
Article: Role of Ca2+-dependent potassium channels in in vitro anandamide-mediated mesenteric vasorelaxation in rats with biliary cirrhosis.
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ABSTRACT: Background/Aim: Anandamide can activate potassium (K(+)) channels to induce an endothelium-dependent vasorelaxation in normal rat mesenteric arteries. Cannabinoids contribute partly to the splanchnic vasodilation in cirrhosis. This study investigated the roles of vascular K(+) channels in anandamide-induced mesenteric vasorelaxation in isolated rat cirrhotic vessels. Methods: The effects of the pretreatment of AM251, a specific CB(1) receptor antagonist, were assessed on the vascular reactivity to phenylephrine (PE), potassium chloride (KCl), acetylcholine (ACh) and sodium nitroprusside (SNP). Additionally, cannabinoid (CB(1) and CB(2)) receptors' protein expression and the effects of different K(+) channel blockers on vascular reactivity to anandamide were also studied. Results: Cirrhotic mesenteric arteries showed an overexpression of CB(1) receptor associated with hyporeactivity to PE and KCl, and hyper-response to ACh, SNP and anandamide. Pretreatment with AM251 significantly improved the hyporeactivity to KCl and ameliorated the hyper-response to ACh in cirrhotic vessels. Increased relaxation response to anandamide was suppressed by combinations of vascular Ca(2+)-dependent K(+) channel blockers (including apamin+charybdotoxin+iberiotoxin or apamin+TRAM-34+iberiotoxin) (TRAM-34, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole). Conclusions: In cirrhotic mesenteric arteries, vascular CB(1) receptor and anandamide contribute to the in vitro hyporeactivity to KCl. In addition, hyper-response to ACh may probably act through the modulation of vascular Ca(2+)-dependent K(+) channels.Liver international: official journal of the International Association for the Study of the Liver 11/2007; 27(8):1045-55. · 3.82 Impact Factor -
Article: Correlation and comparison of the model for end-stage liver disease, portal pressure, and serum sodium for outcome prediction in patients with liver cirrhosis.
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ABSTRACT: The model for end-stage liver disease (MELD), hepatic venous pressure gradient (HVPG), and serum sodium (SNa) are important prognostic markers for patients with liver cirrhosis. The correlation among these markers and their predictive accuracy for survival are unclear. A total of 213 cirrhotic patients undergoing hemodynamic measurement were analyzed. The correlations between MELD score, SNa, and hemodynamic parameters were investigated. There was a significant correlation between MELD and HVPG (r=0.255, P<0.001), between SNa and MELD (r=-0.483, P<0.001), and between HVPG and SNa (r=-0.213, P=0.002). Using mortality as the end-point, the area under receiver operating characteristic curve (AUC) for MELD was 0.789, compared with 0.659 for HVPG (P=0.165) and 0.860 for SNa (P=0.34) at 3 months; the difference between HVPG and SNa was significant (P=0.015). The AUC at 6 months was significantly higher for SNa and MELD compared with that of HVPG. Among 134 patients with low (<14) MELD scores, a high (>16 mm Hg) HVPG, and low SNa (<135 mEq/L) predicted early mortality. In the Cox multivariate model, MELD, HVPG, and Child-Turcotte-Pugh scores were consistently identified as independent poor prognostic predictors when they were treated either as dichotomous or continuous variables in the model. MELD score is closely associated with HVPG and SNa in cirrhotic patients. HVPG is not superior to MELD score or SNa for short-term outcome prediction. High HVPG and low SNa may identify high-risk patients with low MELD scores. High MELD, HVPG, and Child-Turcotte-Pugh scores are independent predictors of poor long-term survival.Journal of Clinical Gastroenterology 08/2007; 41(7):706-12. · 3.16 Impact Factor -
Article: Effect of chronic CB1 cannabinoid receptor antagonism on livers of rats with biliary cirrhosis.
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ABSTRACT: Recent studies have shown that the activated endocannabinoid system participates in the increase in IHR (intrahepatic resistance) in cirrhosis. The increased hepatic production of vasoconstrictive eicosanoids is involved in the effect of endocannabinoids on the hepatic microcirculation in cirrhosis; however, the mechanisms of these effects are still unknown. The aim of the present study was to investigate the effects of chronic CB(1) (cannabinoid 1) receptor blockade in the hepatic microcirculation of CBL (common bile-duct-ligated) cirrhotic rats. After 1 week of treatment with AM251, a specific CB(1) receptor antagonist, IHR, SMA (superior mesenteric artery) blood flow and hepatic production of eicosanoids [TXB(2) (thromboxane B(2)), 6-keto PGF(1alpha) (prostaglandin F(1alpha)) and Cys-LTs (cysteinyl leukotrienes)] were measured. Additionally, the protein levels of hepatic COX (cyclo-oxygenase) isoforms, 5-LOX (5-lipoxygenase), CB(1) receptor, TGF-beta(1) (transforming growth factor beta(1)), cPLA(2) [cytosolic PLA(2) (phospholipase A(2))], sPLA(2) (secreted PLA(2)) and collagen deposition were also measured. In AM251-treated cirrhotic rats, a decrease in portal venous pressure was associated with the decrease in IHR and SMA blood flow. Additionally, the protein levels of hepatic CB(1) receptor, TGF-beta(1), cPLA(2) and hepatic collagen deposition, and the hepatic levels of 5-LOX and COX-2 and the corresponding production of TXB(2) and Cys-LTs in perfusates, were significantly decreased after 1 week of AM251 treatment in cirrhotic rats. Furthermore, acute infusion of AM251 resulted in a decrease in SMA blood flow and an increase in SMA resistance in CBL rats. In conclusion, the chronic effects of AM251 treatment on the intrahepatic microcirculation were, at least partly, mediated by the inhibition of hepatic TGF-beta(1) activity, which was associated with decreased hepatic collagen deposition and the activated PLA(2)/eicosanoid cascade in cirrhotic livers.Clinical Science 06/2007; 112(10):533-42. · 4.61 Impact Factor -
Article: Model for end-stage liver disease score to serum sodium ratio index as a prognostic predictor and its correlation with portal pressure in patients with liver cirrhosis.
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ABSTRACT: The models for end-stage liver disease (MELD) and serum sodium (SNa) are important prognostic markers in cirrhosis. A novel index, MELD to SNa ratio (MESO), was developed to amplify the opposing effect of MELD and SNa on outcome prediction. A total of 213 cirrhotic patients undergoing hepatic venous pressure gradient (HVPG) measurement were retrospectively analyzed. The MESO index correlated with HVPG (r=0.258, P<0.001) and Child-Pugh score (rho=0.749, P<0.001). Using mortality as the end point, the area under receiver operating characteristic curve (AUC) was 0.860 for SNa, 0.795 for the MESO index and 0.789 for MELD (P values all >0.3) at 3 months. Among patients with Child-Pugh class A or B, the MESO index had a significantly higher AUC compared with MELD (0.80 vs. 0.766, P<0.001). A MESO index <1.6 identified 97% of patients who survived at 3 months and the predicted survival rate was 96.5%. In survival analysis, MESO index >1.6 independently predicted a higher mortality rate (relative risk: 3.32, P<0001) using the Cox model. The MESO index, which takes into account the predictive power of both MELD and SNa, is a useful prognostic predictor for both short- and long-term survival in cirrhotic patients.Liver international: official journal of the International Association for the Study of the Liver 05/2007; 27(4):498-506. · 3.82 Impact Factor -
Article: Sildenafil decreased pulmonary arterial pressure but may have exacerbated portal hypertension in a patient with cirrhosis and portopulmonary hypertension.
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ABSTRACT: Portopulmonary hypertension is a recognized but uncommon complication of cirrhosis. Liver transplantation may be contraindicated in patients with severe portopulmonary hypertension. In order to decrease the pulmonary arterial pressure, intravenous administration of epoprostenol has been shown to provide substantial beneficial results in these patients. Additionally, a recent case report demonstrated that long-term oral administration of sildenafil decreased pulmonary arterial pressure, but its effects on splanchnic hemodynamics were not measured. We report on a patient with cirrhosis and portopulmonary hypertension and the changes in the hemodynamic status after an oral administration of sildenafil. This case report clearly delineates that sildenafil decreases pulmonary arterial pressure but may exacerbate portal hypertension and hyperdynamic circulation in patients with cirrhosis and portopulmonary hypertension.Journal of Gastroenterology 07/2006; 41(6):593-7. · 4.16 Impact Factor -
Article: Hemodynamic effects of one week of carvedilol administration on cirrhotic rats.
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ABSTRACT: Carvedilol is a nonselective beta-blocker with alpha(1)-adrenergic blocking activity. It has been shown to decrease portal pressure in cirrhotic patients. The current study was undertaken to evaluate the possible mechanism of carvedilol on hemodynamics in cirrhotic rats with portal hypertension produced by common bile duct ligation. Male Sprague-Dawley rats received either a sham operation or common bile duct ligation. Three weeks after surgery, both sham-operated and cirrhotic rats were randomly assigned to receive vehicle or carvedilol 5 mg.kg(-1).12 h(-1) by gastric gavage for 1 week. Hemodynamic measurements, serum biochemistry, serum nitrate/nitrite and 6-keto-PGF(1alpha) levels, and aortic mRNA expression of eNOS and COX-1 were performed on the eighth day after drug administration. Carvedilol treatment did not affect serum biochemistry in either sham-operated or cirrhotic rats. In sham-operated rats, administration of carvedilol significantly decreased the heart rate without affecting other hemodynamic values. In contrast, in cirrhotic rats, administration of carvedilol significantly decreased the cardiac index, portal pressure, heart rate, and portal territory blood flow, and it significantly increased systemic and portal territory vascular resistances. The hepatocollateral resistance was significantly decreased, but the hepatic arterial blood showed no significant changes. In sham-operated rats treated with carvedilol, serum nitrate/nitrite and 6-keto-PGF(1alpha) levels were not affected. In contrast, cirrhotic rats receiving carvedilol showed a significant decrease in serum nitrate/nitrite and 6-keto-PGF(1alpha) levels, associated with a decrease in aortic mRNA expression of eNOS and COX-1 compared with those receiving vehicle. Carvedilol decreased portal pressure through a reduction of splanchnic blood flow associated with a decrease in hepatocollateral resistance. Additionally, administration of carvedilol decreased endothelial-related vasodilatory activities.Journal of Gastroenterology 05/2006; 41(4):361-8. · 4.16 Impact Factor -
Article: Roles of anandamide in the hepatic microcirculation in cirrhotic rats.
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ABSTRACT: Cannabinoids have been reported to participate in the pathogenesis of peripheral vasodilatation in cirrhosis. However, their roles in increased intrahepatic resistance (IHR) in cirrhotic livers are unknown. We aimed to investigate the effects of cannabinoids in the hepatic microcirculation of cirrhotic rats produced by bile duct ligation. In isolated liver perfusion, portal perfusion pressure (PPP) and the production of eicosanoids in the perfusate were measured. In addition, various hepatic protein levels [cyclooxygenase (COX) isoform and 5-lipoxygenase (5-LOX)] were also determined. Finally, concentration-response curves for PPP and the corresponding production of eicosanoids in response to anandamide (1.44 x 10(-10)-1.44 x 10(-3) M) after indomethacin (COX inhibitor), piriprost (5-LOX inhibitor), or furegrelate (thromboxane A(2) synthase inhibitor) preincubation were obtained. The study showed that cirrhotic livers had significantly higher levels of PPP, COX-2 and 5-LOX protein expression, and production of thromboxane B(2) (TXB(2)) and cysteinyl leukotrienes (Cys-LTs) than normal livers. Anandamide induced a dose-dependent increase in PPP in both normal and cirrhotic livers. The anandamide-induced increase in PPP was found concomitantly with a significant increase in TXB(2) and Cys-LT production in the perfusate. In response to anandamide administration, cirrhotic livers exhibited a significantly greater increase in IHR and production of TXB(2) and Cys-LTs than normal livers. Indomethacin and furegrelate, but not piriprost, significantly ameliorated the anandamide-induced increase in IHR in cirrhotic livers. In conclusion, anandamide plays, in part, an important role in increased IHR of cirrhotic livers. The anandamide-induced increase in IHR in cirrhotic livers may be mediated by increased COX-derived eicosanoid (mainly thromboxane A(2)) production.AJP Gastrointestinal and Liver Physiology 03/2006; 290(2):G328-34. · 3.43 Impact Factor -
Article: Recent advances in hepatopulmonary syndrome.
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ABSTRACT: Hepatopulmonary syndrome is defined as the clinical triad of advanced liver disease, arterial deoxygenation and intrapulmonary vascular dilatation. Its pathogenesis is not completely understood. Excessive pulmonary nitric oxide production seems to be one of the factors that contribute to the intrapulmonary vascular dilatation. Other mediators such as endothelin-1 and the heme oxygenase-1/carbon monoxide system have recently been found to be important contributors. The major clinical manifestations are arterial hypoxemia, clubbed fingers and spider nevi. Orthodeoxia is the characteristic clinical feature. Contrast-enhanced echocardiography is the preferred screening test. 99mTechnetium macroaggregated albumin (Tc-99m MAA) lung perfusion scan can further specify the diagnosis of hepatopulmonary syndrome and quantify the magnitude of shunting. No clearly effective medical treatments have been found. Although liver transplantation seems feasible to reverse this situation, it is associated with increased postoperative morbidity and mortality. A preoperative arterial oxygen tension of 50 mmHg or less and Tc-99m MAA shunt fractions of 20% or more are strong predictors of postoperative mortality that can be used to stratify patients with better outcome.Journal of the Chinese Medical Association 12/2005; 68(11):500-5. · 0.79 Impact Factor
Top co-authors
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Institutions
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2005–2011
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Taipei Veterans General Hospital
- • Gastroenterology Division
- • Division of General Medicine
Taipei, Taipei, Taiwan
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2007–2008
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National Yang Ming University
- • Institute of Clinical Medicine
- • Faculty of Medicine
Taipei, Taipei, Taiwan
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