Wen-Shin Lee

Rosuvastatin improves hepatopulmonary syndrome through inhibition of inflammatory angiogenesis of lung.

The hepatopulmonary syndrome (HPS) is characterized by hypoxia and increased intrapulmonary shunts in cirrhotic patients. Emerging evidence showed promising results of treating HPS by abolishment of intrapulmonary inflammation and angiogenesis. Rosuvastatin is a kind of 3-hydroxy-methyl-3-glutamyl coenzyme A reductase inhibitor. In addition to lipid-lowering effects, it has anti-inflammation and anti-angiogenesis properties. We postulated that rosuvastatin treatment can ameliorate HPS. Common bile duct ligation (CBDL) was applied in an experimental HPS animal model. CBDL rats received 2-week rosuvastatin (20 mg/kg/day) treatments from the fifteenth day after operation. The haemodynamic data, blood gas analysis, liver biochemistries, tumour necrosis factor-α (TNF-α) and vascular endothelial growth factor (VEGF) were examined after rosuvastatin treatment. The liver and lung tissues were dissected for histopathological studies and protein analyses. In the parallel groups, intrapulmonary shunts were determined. The haemodynamic and liver biochemistries were not changed after rosuvastatin treatment in CBDL rats, but the alveolar-arterial oxygen pressure gradient was significantly decreased, implying that HPS-induced hypoxia was reversed after rosuvastatin treatment. In addition, rosuvastatin treatment reduced intrapulmonary shunts and plasma levels of VEGF and TNF-α. Besides, the intrapulmonary protein expression of nuclear factor kappa B (NF-κB), VEGF receptor (VEGFR)-1,2 and Rho-associated A kinase were significantly down-regulated and the intrapulmonary angiogenesis was ameliorated. We concluded that rosuvastatin alleviates experimental HPS through blockade of pulmonary inflammatory angiogenesis via TNF-α/NF-κB and VEGF/Rho-associated A kinase pathways down-regulation.

Assessment of first-year post-graduate residents: Usefulness of multiple tools

Background: Objective Structural Clinical Examination (OSCE) usually needs a large number of stations with long test time, which usually exceeds the resources available in a medical center. We aimed to determine the reliability of a combination of Direct Observation of Procedural Skills (DOPS), Internal Medicine in‐Training Examination (IM‐ITE®) and OSCE, and to verify the correlation between the small‐scale OSCE+DOPS+IM‐ITE®‐composited scores and 360‐degree evaluation scores of first year post‐graduate (PGY1) residents. Methods: Between 2007 January to 2010 January, two hundred and nine internal medicine PGY1 residents completed DOPS, IM‐ITE® and small‐scale OSCE at our hospital. Faculty members completed 12‐item 360‐degree evaluation for each of the PGY1 residents regularly. Results: The small‐scale OSCE scores correlated well with the 360‐degree evaluation scores (r = 0.37, p < 0.021). Interestingly, the addition of DOPS scores to small‐scale OSCE scores [small‐scale OSCE+DOPS‐composited scores] increased its correlation with 360‐degree evaluation scores of PGY1 residents (r = 0.72, p < 0.036). Further, combination of IM‐ITE® score with small‐scale OSCE+DOPS scores [small‐scale OSCE+DOPS+IM‐ITE®‐composited scores] markedly enhanced their correlation with 360‐degree evaluation scores (r = 0.85, p < 0.016). Conclusion: The strong correlations between 360‐degree evaluation and small‐scale OSCE+DOPS+IM‐ITE®‐composited scores suggested that both methods were measuring the same quality. Our results showed that the small‐scale OSCE, when associated with both the DOPS and IM‐ITE®, could be an important assessment method for PGY1 residents.

A core competence-based objective structured clinical examination (OSCE) in evaluation of clinical performance of postgraduate year-1 (PGY1) residents

Background: Clinical competency certifications are important parts of internal medicine residency training. This study aims to evaluate a composite objective structured clinical examination (OSCE) that assesses postgraduate year‐1 (PGY1) residents’ acquisition of the six core competencies defined by the Accreditation council for Graduate Medical Education (ACGME). Methods: Six‐core‐competency‐based OSCE was used as examination of the clinical performance of 192 PGY1 residents during their 3‐month internal medicine training between 2007 January and 2009 December. For each year, the reliability of the entire examination was calculated with Cronbach’s alpha. Results: The reliability of six‐core‐competency‐based OSCE was acceptable, ranging from 0.69 to 0.87 between 2007 and 2009. In comparison with baseline scores, the summary scores and core‐competency subscores all showed significant increase after PGY1 residents finished their 3‐month internal medicine training program. Conclusion: By using a structured development process, the authors were able to create reliable evaluation items for determining PGY1 residents’ acquisition of the ACGME core competencies.

Aliskiren reduces portal pressure in cirrhotic rats.

To the Editor: Emerging evidences show that the renin angiotensin system (RAS) takes part in the pathogenesis of liver fibrosis and portal hypertension. There is marked upregulation of intrahepatic RAS components in experimental liver injury (1). Activation of RAS could increase intrahepatic angiotensin II and then stimulate transforming growth factor b-1 to mediate and exacerbate liver fibrosis (2). Therefore, manipulations of the RAS could have potential therapeutic benefits for patients with liver cirrhosis. Aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy3-(3-methoxypropoxy)phenyl]-octanamide hemifumarate) is a direct renin inhibitor which blocks the upstream of RAS and lowers blood pressure (3). Apart from the arterial blood pressure-lowering effect, aliskiren has been demonstrated to increase endothelial nitric oxide synthase (eNOS) biosynthesis (4). We conducted this preliminary study to evaluate the effects of aliskiren treatment on the common bile duct ligated (BDL)induced cirrhotic rats. Male Sprague-Dawley rats with secondary biliary cirrhosis induced by BDL were used for experiments. BDL rats received either subcutaneously injection of 20 mg/kg/day aliskiren or distilled water (control) treatments for 10 days (from day 33 to day 42 after a BDL operation), and followed by measurements of systemic and portal hemodynamics, and renal and liver biochemistries. There was no mortality of rats between the aliskiren-treated and control groups. The body weights and heart rates were similar between aliskiren-treated and control groups (Table 1). Chronic aliskiren treatment significantly reduced mean arterial pressure and portal pressure. There were no differences in the heart rates and levels of alanine transaminase, aspartate transaminase, total bilirubin and creatinine between these two groups. It is the first time, to our knowledge, that direct renin inhibition by aliskiren induces systemic vasodilatation and reduces portal pressure in BDL-induced cirrhotic rats. The systemic arterial and portal hypotensive effects of aliskiren may come from a reduction of systemic and portal resistance or a decrease of splanchnic blood flow, and it warrants further investigation. The hepatic and renal biochemistries are not exacerbated after aliskiren treatments which imply chronic aliskiren treatment does not elicit a major hepatic and renal damage. However, further study to investigate the intrahepatic and collateral resistance, splanchnic blood flow, renal blood flow and glomerular filtration rate of cirrhotic rats after aliskiren treatment is necessary. Aliskiren is largely eliminated through the hepatobiliary route as an unchanged drug and, to a lesser extent, through oxidative metabolism by cytochrome P450 3A4 (5). Vaidynnathan et al. have reported that hepatic impairment did not influence the pharmacokinetics of aliskiren and exacerbate liver function after aliskiren treatment in cirrhotic patients (5). Similarly, this current study also demonstrated that there was no significant difference in the liver biochemistry between the aliskiren-treated and control groups of BDLinduced cirrhotic rats. Angiotensin II is associated with increased dynamic and static intra-hepatic resistance, and inhibition of angiotensin II by angiotensin receptor blocker may

Aliskiren reduces portal pressure in portal hypertensive rats

Eur J Clin Invest 2012; 42 (5): 526–533

Effects of raloxifene on portal hypertension and hepatic encephalopathy in cirrhotic rats

ABSTRACT Raloxifene, a selective estrogen receptor modulator, has been used extensively for osteoporosis. In addition to the effect of osteoporosis treatment, emerging evidences show that raloxifene affects the vascular function in different tissues. Cirrhosis is characterized with portal hypertension and complicated with hepatic encephalopathy. Portal hypertension affects portal‐systemic shunt which leads to hepatic encephalopathy that the vascular modulation might influence severity of hepatic encephalopathy. Herein, we evaluated the impact of raloxifene on bile duct ligation (BDL)‐induced cirrhotic rats. The female Sprague‐Dawley rats received BDL plus ovariectomy or sham‐operation. Four weeks later, rats were divided into 2 subgroups respectively to receive of raloxifene (10 mg/kg/day) or saline (vehicle) for 14 days. On the 43th day, motor activities and hemodynamic parameters were measured. Hepatic and vascular mRNA and protein expressions were determined. The histopathological change of liver was examined. We found that the liver biochemistry, ammonia level and motor activity were similar between cirrhotic rats with or without raloxifene administration. The hemodynamic parameters were not significantly different except that raloxifene reduced portal venous inflow. Raloxifene exacerbated hepatic fibrosis and up‐regulated hepatic endothelin‐1 and cyclooxygenase 2 protein expressions. In addition, raloxifene modulated the mRNA expressions of endothelial nitric oxide synthase, cyclooxygenase and endothelin‐1 in the superior mesenteric artery and collateral vessel. In conclusion, raloxifene aggravates hepatic fibrosis and decreases portal venous inflow in cirrhotic rats without adversely affecting portal hypertension and hepatic encephalopathy. The modulation of hepatic and vascular endothelin‐1, endothelial nitric oxide synthase and cyclooxygenase expressions may play a role in the mechanism.

Validation of the behavior and concept based assessment of professionalism competence in postgraduate first-year residents

Background: The evaluation of professional behaviors and concepts of postgraduate first‐year (PGY1) residents has been identified as an area for development. This study examined the efficiency of the professionalism‐assessing objective structured clinical examination (OSCE), 360° evaluation, and mini‐Clinical Examination Exercise scores (mini‐CEX; p‐OSCE, p‐360° evaluation, and p‐mini‐CEX scores). Methods: Between January 2009 and January 2012, 189 PGY1 residents were evaluated for behavior‐ and concept‐based professionalism competence based on the above three methods using two checklists unique to each case. Data were analyzed for reliability, inter‐rater agreement, interval changes, and gender‐related difference for each method. Results: The test reliabilities of p‐OSCE, p‐360° evaluation, and p‐mini‐CEX were acceptable. Further, the reliability of concept and combined p‐OSCE was higher than that of behavior p‐OSCE. In addition, the concept OSCE p‐scores and behavior 360° evaluation p‐scores were significantly improved after 6 months of training. The inter‐rater agreements were relatively good in p‐OSCE and p‐360° evaluation. Interestingly, male PGY1 residents had higher behavior 360° evaluation p‐scores from nurses than those of females, whereas female PGY1 residents had higher behavior 360° evaluation p‐scores from patients than those of males. Behavior and concept OSCE p‐scores were positively correlated with behavior 360° evaluation p‐scores. In comparison with p‐360° evaluation, the combination of p‐360° evaluation + OSCE + mini‐CEX significantly increases their reliabilities. Conclusion: The current study suggests that the p‐OSCE, p‐360° evaluation, and p‐mini‐CEX are feasible methods for evaluating professionalism in clinical training of PGY1 residents. Combination of the above three evaluations, participation, and support from multiple constituencies and multiple representatives provides good reliability and adds credibility in the assessment of professionalism competence.

Metformin reduces intrahepatic fibrosis and intrapulmonary shunts in biliary cirrhotic rats

Background Liver fibrosis causes portal hypertension which dilates collateral vasculature and enhances extra‐hepatic angiogenesis including intrapulmonary shunts, which subsequently complicates with hepatopulmonary syndrome. Metformin is an anti‐diabetic agent which possesses anti‐inflammation and anti‐angiogenesis properties. This study evaluated the effect of metformin treatment on liver and lung in a non‐diabetic rat model with biliary cirrhosis induced via common bile duct ligation (CBDL). Methods CBDL rats were fed with metformin 150 mg/kg/day during the 8th–28th day post operation. The hemodynamic and biochemistry parameters were tested, and blood gas analysis was performed. The liver and lung were dissected for protein analysis and immuno‐histochemical stains. Intrapulmonary shunting degree was determined using color microsphere method. Results Metformin treatment neither induced obvious hypoglycemic event nor altered hemodynamics in cirrhotic rats. The plasma levels of alanine aminotransferase were significantly reduced by metformin (control vs. metformin: 269 ± 56 vs. 199 ± 21 IU/L, P = 0.02). Sirius Red stains and CD‐68 stains showed that metformin reduced intrahepatic fibrosis and CD‐68‐positive macrophages. Metformin did not influence hypoxia and intrapulmonary angiogenesis; however, it significantly reduced intrapulmonary shunts (31.7 ± 10.1 vs. 15.0 ± 6.6%, P = 0.006.). Furthermore, metformin reduced the protein expressions of COX‐2 and PI3K in liver and COX‐1 in lung. Conclusion Metformin reduced liver injury and improved hepatic fibrosis in cirrhotic rats. It also attenuated the intrapulmonary shunts. However, the effects of metformin on pulmonary angiogenesis and hypoxia were insignificant.

Selective cyclooxygenase-1 inhibition improves collateral vascular reactivity in biliary cirrhotic rats

Background: Evidence has demonstrated that overproduction of prostacyclin (PGI2) is critical in the pathogenesis of splanchnic hyposensitivity to vasoconstrictors in the cirrhotic state. The biosynthesis of PGI2 is through cyclooxygenase (COX). This study evaluated which isoform of COX is dominant in the mechanism of collateral vascular reactivity of biliary cirrhotic rats. Methods: Three groups of formalin‐injected common bile duct‐ligated (FBDL) induced cirrhotic rats received two doses of: (1) selective COX‐1 inhibitor (SC‐560 2 mg/kg); (2) COX‐2 inhibitor (NS‐398 2 mg/kg); (3) dimethyl sulfoxide (control). Subsequently, the rats were kept in metabolic cages for 24 hours to collect urine. Thereafter, the systemic and portal hemodynamics and renal function were measured. In another series, using in‐situ collateral perfusion model, the collateral vascular responses to arginine vasopressin (AVP) were measured in the subject rats after preincubation of vehicle (Krebs solution), SC‐560 (5 &mgr;M) or NS‐398 (10 &mgr;M). Results: The mean arterial pressure, heart rate, and portal pressure were similar among SC‐560‐treated, NS‐398‐treated, and control groups. Additionally, there was no significant difference in the calculated creatinine clearance rates among these three groups. SC‐560 preincubation significantly enhanced the pressor effect of AVP at the concentration of 3M × 10−9 M (11.0 ± 1.0 mmHg vs. 6.4 ± 0.6 mmHg, p = 0.002) in the cirrhotic rats. Conclusion: There was no significant hemodynamic change and renal toxicity after acute administration of COX inhibitor in the FBDL‐induced cirrhotic rats. Preincubation of selective COX‐1, but not COX‐2, inhibitor could enhance collateral vascular response to AVP, indicating that COX‐1 plays a major role in the collateral vascular reactivity.

Effect of ivabradine, a funny current inhibitor, on portal hypertensive rats

Background: Ivabradine is a funny current inhibitor which is administered to patients with congestive heart failure to reduce their heart rate (HR) and attenuate oxidative stress. Chronic liver diseases are characterized by portal hypertension and hyperdynamic circulation with tachycardia. The present study aimed to investigate the effect of ivabradine on portal hypertension. Methods: Male Sprague–Dawley rats received partial portal vein ligation (PVL) to induce portal hypertension. The PVL rats were randomly allocated to receive either vehicle or ivabradine treatment for 10 days. Then the hemodynamic data were collected. The levels of oxidative stress markers and the mRNA expression of nitric oxide synthase (NOS) were measured in the collateral vessel, the superior mesentery artery and the liver. In addition, the collateral vascular responsiveness to arginine vasopressin (AVP) was examined in the ivabradine-treated and vehicle-treated PVL rats. Results: Treatment with ivabradine significantly lowered the HR (174 ± 20 vs. 374 ± 9 beats/min; p < 0.001) and the superior mesentery arterial flow (SMAf) (6.6 ± 0.3 vs. 9.1 ± 0.7 mL/min/100 g BW; p = 0.005) of the PVL rats compared with the control group. The mean arterial pressure, cardiac index, systemic vascular resistance, portal pressure and serum levels of oxidative stress markers were not significantly affected by ivabradine treatment. In addition, the NOS expression and collateral vascular responsiveness to AVP were not significantly influenced by ivabradine treatment, either. Conclusion: Ivabradine reduced the HR and SMAf in PVL rats, which alleviated the hyperdynamic circulatory state and splanchnic hyperemia of portal hypertension. However, whether these effects would help alleviate portal hypertension-related complications requires further clinical investigations.BACKGROUND Ivabradine is a funny current inhibitor which is administered to patients with congestive heart failure to reduce their heart rate (HR) and attenuate oxidative stress. Chronic liver diseases are characterized by portal hypertension and hyperdynamic circulation with tachycardia. The present study aimed to investigate the effect of ivabradine on portal hypertension. METHODS Male Sprague-Dawley rats received partial portal vein ligation (PVL) to induce portal hypertension. The PVL rats were randomly allocated to receive either vehicle or ivabradine treatment for 10 days. Then the hemodynamic data were collected. The levels of oxidative stress markers and the mRNA expression of nitric oxide synthase (NOS) were measured in the collateral vessel, the superior mesentery artery and the liver. In addition, the collateral vascular responsiveness to arginine vasopressin (AVP) was examined in the ivabradine-treated and vehicle-treated PVL rats. RESULTS Treatment with ivabradine significantly lowered the HR (174 ± 20 vs. 374 ± 9 beats/min; p < 0.001) and the superior mesentery arterial flow (SMAf) (6.6 ± 0.3 vs. 9.1 ± 0.7 mL/min/100 g BW; p = 0.005) of the PVL rats compared with the control group. The mean arterial pressure, cardiac index, systemic vascular resistance, portal pressure and serum levels of oxidative stress markers were not significantly affected by ivabradine treatment. In addition, the NOS expression and collateral vascular responsiveness to AVP were not significantly influenced by ivabradine treatment, either. CONCLUSION Ivabradine reduced the HR and SMAf in PVL rats, which alleviated the hyperdynamic circulatory state and splanchnic hyperemia of portal hypertension. However, whether these effects would help alleviate portal hypertension-related complications requires further clinical investigations.