Increased Expression of S100B and RAGE in a Mouse Model of Bile Duct Ligation-induced Liver Fibrosis

Background@#Liver fibrosis is defined as the accumulation of the extracellular matrix and scar formation. The receptor for advanced glycation end products (RAGE) has been demonstrated to participate in fibrogenesis. S100B is a ligand of RAGE and exerts extracellular functions by inducing a series of signal transduction cascades. However, the involvement of S100B and RAGE in cholestasis-induced liver fibrosis remains unclear. In this study, we investigated S100B and RAGE expression during liver fibrosis in mice that underwent common bile duct ligation (BDL). @*Methods@#BDL was performed in 10-week-old male C57BL/6J mice with sham control (n = 26) and BDL (n = 26) groups. Expression levels of S100B, RAGE and fibrotic markers in the livers from both groups at week 1 and 3 after BDL were examined by western blot and quantitative real-time reverse transcription polymerase chain reaction analysis. Liver fibrotic changes were examined by histological and ultrastructural analysis. @*Results@#Histological staining with Sirius Red and the evaluation of the messenger RNA expression of fibrotic markers showed noticeable periportal fibrosis and bile duct proliferation. S100B was mainly present in bile duct epithelial cells, and its expression was upregulated in proportion to the ductular reaction during fibrogenesis by BDL. RAGE expression was also increased, and interestingly, triple immunofluorescence staining and transmission electron microscopy showed that both S100B and RAGE were expressed in proliferating bile duct epithelial cells and activated hepatic stellate cells (HSCs) of the BDL livers. In addition, in rat HSCs (HSC-T6), treatment with recombinant S100B protein significantly increased fibrotic markers in a dose-dependent manner, and RAGE small interfering RNA (siRNA) suppressed S100B-stimulated upregulation of fibrotic markers compared with cells treated with scramble siRNA and S100B. @*Conclusion@#These findings suggest that the increased expression of S100B and RAGE and the interaction between S100B and RAGE may play an important role in ductular reaction and liver fibrosis induced by BDL.

Increased Expression of S100B and RAGE in a Mouse Model of Bile Duct Ligation-induced Liver Fibrosis

Background@#Liver fibrosis is defined as the accumulation of the extracellular matrix and scar formation. The receptor for advanced glycation end products (RAGE) has been demonstrated to participate in fibrogenesis. S100B is a ligand of RAGE and exerts extracellular functions by inducing a series of signal transduction cascades. However, the involvement of S100B and RAGE in cholestasis-induced liver fibrosis remains unclear. In this study, we investigated S100B and RAGE expression during liver fibrosis in mice that underwent common bile duct ligation (BDL). @*Methods@#BDL was performed in 10-week-old male C57BL/6J mice with sham control (n = 26) and BDL (n = 26) groups. Expression levels of S100B, RAGE and fibrotic markers in the livers from both groups at week 1 and 3 after BDL were examined by western blot and quantitative real-time reverse transcription polymerase chain reaction analysis. Liver fibrotic changes were examined by histological and ultrastructural analysis. @*Results@#Histological staining with Sirius Red and the evaluation of the messenger RNA expression of fibrotic markers showed noticeable periportal fibrosis and bile duct proliferation. S100B was mainly present in bile duct epithelial cells, and its expression was upregulated in proportion to the ductular reaction during fibrogenesis by BDL. RAGE expression was also increased, and interestingly, triple immunofluorescence staining and transmission electron microscopy showed that both S100B and RAGE were expressed in proliferating bile duct epithelial cells and activated hepatic stellate cells (HSCs) of the BDL livers. In addition, in rat HSCs (HSC-T6), treatment with recombinant S100B protein significantly increased fibrotic markers in a dose-dependent manner, and RAGE small interfering RNA (siRNA) suppressed S100B-stimulated upregulation of fibrotic markers compared with cells treated with scramble siRNA and S100B. @*Conclusion@#These findings suggest that the increased expression of S100B and RAGE and the interaction between S100B and RAGE may play an important role in ductular reaction and liver fibrosis induced by BDL.

A Case of Spontaneous Bacterial Peritonitis Caused by Listeria monocytogenes / 대한소화기학회지

Spontaneous bacterial peritonitis (SBP) is a life-threatening complication in patients with ascites caused by advanced liver disease. While gram negative bacteria, such as Escherichia coli and Klebsiella pneumonia are the common pathogens, Listeria monocytogenes has been recognized as a very rare pathogen. Empirical treatment with third generation cephalosporins does not provide adequate antibiotics coverage against L. monocytogenes. Diagnosis is often delayed as it requires confirmation from ascitic fluid culture. Herein, we describe the first case of SBP caused by L. monocytogenes in a patient with advanced alcoholic liver cirrhosis in Korea. Clinicians should be aware of the atypical pathogens, especially in patients with inadequate response to empirical antibiotics.

Pathological characterization of TgElk mice injected with brain homogenate from elk with chronic wasting disease

Chronic wasting disease (CWD) is classified as a transmissible spongiform encephalopathy or prion disease that affects cervids. CWD has been reported in 15 US states, two Canadian provinces, and in imported elk on several farms in Korea. This study was conducted to examine the molecular biological and pathogenic characteristics of a CWD-associated prion isolated in Korea. The epidemiological origin of this pathogen was also determined. Homozygous TgElk mice were infected with a CWD-affected elk brain pool prepared from the brain of an imported Canadian elk. We measured the incubation time of the pathogen, neuropathological changes by immunohistochemical staining, the pattern(s) of scrapie prion protein (PrPSc) deposition, and PrPSc protein profiles by Western blotting. We found that TgElk mice infected with brain homogenate from the elk suffering from CWD showed incubation times, vacuolar degeneration, and PrPSc accumulation similar to those previously reported in the literature. Our results suggest that homozygous TgElk mice efficiently transmit CWD with short incubation times and that this animal can serve a valuable research model and reliable in vivo diagnostic tool.

Pathological characterization of TgElk mice injected with brain homogenate from elk with chronic wasting disease

Chronic wasting disease (CWD) is classified as a transmissible spongiform encephalopathy or prion disease that affects cervids. CWD has been reported in 15 US states, two Canadian provinces, and in imported elk on several farms in Korea. This study was conducted to examine the molecular biological and pathogenic characteristics of a CWD-associated prion isolated in Korea. The epidemiological origin of this pathogen was also determined. Homozygous TgElk mice were infected with a CWD-affected elk brain pool prepared from the brain of an imported Canadian elk. We measured the incubation time of the pathogen, neuropathological changes by immunohistochemical staining, the pattern(s) of scrapie prion protein (PrPSc) deposition, and PrPSc protein profiles by Western blotting. We found that TgElk mice infected with brain homogenate from the elk suffering from CWD showed incubation times, vacuolar degeneration, and PrPSc accumulation similar to those previously reported in the literature. Our results suggest that homozygous TgElk mice efficiently transmit CWD with short incubation times and that this animal can serve a valuable research model and reliable in vivo diagnostic tool.

Dura Mater Graft-Associated Creutzfeldt-Jakob Disease: The First Case in Korea

Since 1987, dura mater graft-associated iatrogenic Creutzfeldt-Jakob disease (dCJD) has been reported in many countries. We report the first case of dCJD in Korea. A 54-yr-old woman, who underwent resection of the meningioma in the left frontal region and received a dura mater graft 23 yr ago presented with dysesthesia followed by psychiatric symptoms and ataxia. Her neurological symptoms rapidly progressed to such an extent that she exhibited myoclonus, dementia, and pyramidal and extrapyramidal signs within 8 weeks. The 14-3-3 protein was detected in her cerebrospinal fluid; however, an electroencephalogram did not reveal characteristic positive sharp wave complexes. Diffusion-weighted magnetic resonance images, obtained serially over 64 days, revealed the rapid progression of areas of high signal intensity in the caudate nucleus and cingulate gyrus to widespread areas of high signal intensity in the cortex and basal ganglia. Pathological examination of brain biopsy specimens confirmed the presence of spongiform changes and deposition of prion protein in the neurons and neuropils.

A Case of Appendicular Tuberculosis Presenting as Acute Appendicitis / 대한소화기학회지

Tuberculosis may affect primarily all organs and tissues of the body, although some of these show high immunity against the infection. The most common forms of non-pulmonary tuberculosis are tuberculosis of bones and joints (30%), urinary system (24%), lymph nodes (13%), sexual organs (8%), cerebrospinal meninges (4%), and alimentary system (3%). Especially, the commonest presentation of abdominal tuberculosis is ileocecal disease, but isolated appendicular involvement is also rarely seen, occuring in only 1.5% to 3% of cases in the absence of pulmonary or other abdominal involvement. The appendix may either be involoved secondary to ileocecal tuberculosis, or to tuberculosis at another site within the abdomen, or may occur in the even, rarer "isolated" form, without the evidence of disease elsewhere. We report a case of acute appendicitis underwent appendectomy and histopathologic examination of appendix revealed appendicular tuberculosis.

Clinical Usefulness of Proton Pump Inhibitor Intravenous Treatment in Bleeding Peptic Ulcer / 대한소화기내시경학회지

BACKGROUND/AIMS: Recently, high dose PPI intravenous (IV) infusion after endoscopic hemostasis was found to decrease the recurrent bleeding rate. Therefore, we conducted this study to define the effect of endoscopic hemoclipping with PPI IV infusion on the recurrent bleeding rate. METHODS: We conducted a double-blinded prospective randomized control study. A total of 35 patients were endoscopically diagnosed with bleeding peptic ulcer of Forrest classification Ia, Ib, IIa between Jan. 2003 and Sep. 2003 in our hospital. We carried out epinephrine injection therapy around the ulcer, followed by hemoclipping at the exposed vessel. After controlling for endoscopic bleeding, we randomly divided the patients into two groups. One group received a PPI IV infusion (pantoprazole 80 mg/day) and the other group received a placebo for three days. RESULTS: Only one PPI IV-infused patient and one patient receiving placebo showed recurrent bleeding at two days after endoscopic therapy. The PPI IV infusion group showed 100% (17/17) initial hemostatic rate, 5.8% (1/17) recurrent bleeding rate within 3 days, 0% (0/17) recurrent bleeding rate after 3 days, and 0% (0/17) complication rate. For these same values, the placebo group showed 100% (18/18), 5.5% (1/18), 0% (0/18), and 0% (0/18), respectively. CONCLUSIONS: PPI IV infusion showed no addictive hemostatic effect. We think hemoclipping is a very effective hemostatic method, and PPI IV infusion may not be required after appropriate endoscopic management

Comparison of Model for End-stage Liver Disease Score with Discriminant Function and Child-Turcotte-Pugh Scores for Predicting Short-term Mortality in Korean Patients with Alcoholic Hepatitis / 대한소화기학회지

BACKGROUND/AIMS: Alcoholic hepatitis is an acute or acute-on-chronic inflammatory syndrome associated with significant morbidity and mortality. Traditionally, Maddrey discriminant function (DF) score and Child-Turcott- Pugh (CTP) score have been used for stratifying the prognosis of alcoholic hepatitis. Recently, the model for end-stage liver disease (MELD) score has been applied to alcoholic hepatitis and some investigators consider MELD score as a better prognostic indicator for severe alcoholic hepatitis. Therefore, this analysis was aimed to compare MELD score with DF and CTP scores for predicting the short-term mortality in Korean patients with alcoholic hepatitis. METHODS: The medical records of patients hospitalized with alcoholic hepatitis between January 1, 1999 and December 31, 2004 at Hanyang University Guri-Hospital were analyzed retrospectively. RESULTS: Of the 138 medical records reviewed, 74 cases fulfilled the inclusion criteria (61 males and 13 females; mean age 47.1 years). Twelve patients (16.2%) died within 90 days after admission. Univariate analysis demonstrated that variables such as ascites, hepatic encephalopathy, splenomegaly, international normalized ratio, CTP, and DF scores were significantly correlated with increased 90-day mortality while MELD score was not. According to the multivariate analysis, only CTP score was statistically significant (p=0.012) while DF and MELD scores were not significant for predicting 90-day mortality. The survival analysis with Cox regression test showed higher DF and CTP scores, but not MELD score, significantly increased the risk of in-hospital mortality. CONCLUSIONS: This study demonstrates that DF and CTP scores are independent predictors of short-term mortality in patients with alcoholic hepatitis.

A Case of Primary Omental Torsion Presenting as an Acute Abdominal Pain / 대한소화기학회지

Torsion of greater omentum is a rare cause of acute abdomen. However, it should be included in the differential diagnoses in addition to acute cholecystitis, acute appendicitis, cecal diverticulitis, and other variable causes of acute abdomen. Diagnosis is usually made at laparotomy for suspected appendicitis. In some cases, computed tomography demonstrates a successful preoperative detection of omental torsion. We report a case of surgically and pathologically proven torsion with subsequent infarction of greater omentum presented as an acute abdominal pain.

Abdominal Obesity, Insulin Resistance, and the Risk of Colonic Adenoma / 대한소화기학회지

BACKGROUND/AIMS: Abdominal obesity and hyperinsulinemia or insulin resistance are of interest in connection with colon carcinogenesis. We conducted a prospective case controlled study for the evaluation of relationship between abdominal obesity, insulin resistance, and colorectal adenoma. METHODS: Fifty patients with colorectal adenoma and fifty healthy subjects were included in this study. Total colonoscopic examinations were performed in all the subjects. Fasting blood sugar (FBS), insulin, homeostasis model assessment (HOMA-IR), triglyceride (TG), cholesterol (CROL), BMI (body mass index), WHR (waist hip ratio), percent body fat (PBF) and obesity degree (OD) were measured. HOMA-IR was considered to represent insulin resistance. Diabetic patients were excluded from this study. RESULTS: There were no differences in sex, serum insulin, FBS, HOMA-IR, TG, CROL between adenoma and control group. Subjects with high BMI, WHR, percent body fat, and obesity were more likely to have colonic adenoma. Multiple logistic regression analysis after adjusting confounding factors, had revealed that WHR was the most important independent risk factor for colon adenoma. CONCLUSIONS: Abdominal obesity was most closely related to colonic adenoma. However, insulin resistance was not related to colonic adenoma. A larger case controlled study is needed.

Pulmonary Toxicity by Pegylated Interferon alpha-2a in a Patient with Chronic Hepatitis C / 대한간학회지

The combination therapy with pegylated interferon alpha and ribavirin has increasingly prescribed for chronic hepatitis C. Although many side effects of interferon such as flu-like symptoms, gastrointestinal and neuropsychiatric symptoms are well known, only several cases of interferon-induced pulmonary toxicity have been reported. Interferon-induced pulmonary toxicity usually develops from 2 weeks to 12 weeks after treatment for HCV infection. Diagnosis is commonly based on clinical findings such as a dry cough, dyspnea, hypoxemia, and a restrictive pattern in pulmonary function testing, bilateral diffuse parenchymal infiltrations, histopathological findings of interstitial pneumonitis, and exclusion of any other causative agents. Prompt withdrawal of the drug is the cornerstone of treatment. We report a case of PEG-IFN alpha-2a induced pulmonary toxicity in a 50-year-old male patient with hepatitis C. To our knowledge, this is the first case of pegylated interferon alpha-2a induced pulmonary toxicity in Korea.

A Case of Acute Cholecystitis Secondary to Hemobilia after Percutaneous Liver Biopsy / 대한소화기학회지

Percutaneous liver biopsy is well established for the diagnosis and follow-up of many liver diseases. Although it is rather safe, major complications, such as bleeding into the peritoneal or thoracic cavity, hemobilia, enteric perforation and intrahepatic hematoma, have been reported related to the procedure. Recently, incidence of such major complications has been decreased since the introduction of ultrasonography-guided liver biopsy. We report a case of 59-year-old female patient with acute cholecystitis secondary to hemobilia 2 days after ultrasonography-guided percutaneous liver biopsy.

A Case of Acute Appendicitis following Diagnostic Colonoscopy / 대한소화기내시경학회지

Colonoscopy is a relatively safe procedure with few complications. However, it may be accompanied with complications such as bleeding, perforation and, rarely, acute appendicitis. Acute appendicitis occurs when the appendiceal opening is obstructed by lymphoid hyperplasia, fecalith or foreign materials. In case of late detection, acute appendicitis can results in perforation and panperitonitis. Therefore early diagnosis and proper management is mandoctory. We experienced a 70-year-old female patient who visited for abdominal pain and tenderness after the diagnostic colonoscopy and was found to develop acute appendicitis. Herein, we report the case with the review of literatures.

A Case of Primary Hepatic Leiomyosarcoma Presenting with Multiple Subcutaneous Scalp Mass / 대한소화기학회지

Leiomyosarcoma is an uncommon tumor which arises from various sites including uterus, stomach, retroperitoneum, superficial soft tissues, bladder, kidney, and lung. Primary hepatic leiomyosarcoma is a very rare tumor and fewer than 70 cases of primary hepatic leiomyosarcoma have been reported since the first publication in Japan. And there was only one case report of cutaneous metastasis from hepatic leiomyosarcoma. We recently experienced a case of primary hepatic leiomyosarcoma presenting as subcutaneous palpable mass. Herein we report this case with a review of literatures.

A Case of Nodular Regenerative Hyperplasia of Liver that mimicked Primary Biliary Cirrhosis / 대한간학회지

Nodular regenerative hyperplasia (NRH) of the liver is a rare disease that is characterized by multiple regenerative nodules in the hepatic parenchyma without fibrosis. The exact pathogenesis of NRH has not been established, but it's been suggested that obliteration of portal veins may initiate the nodular transformation. It is also known that this disease is associated with autoimmune disease, myeloproliferative disease, lymphoproliferative disease, primary biliary cirrhosis, and some chemotherapy agents. The patients with NRH are usually asymptomatic, yet if they have symptoms, the most common clinical manifestations are those of portal hypertension, including splenomegaly and esophageal varices with or without bleeding. We report a case of nodular regenerative hyperplasia that presented with clinical manifestations similar to those of primary biliary cirrhosis.

Importance of Age and Other Risk Factors in NSAID-induced Gastropathy / 대한소화기학회지

BACKGROUND/AIMS: It is clinically important to analyze the risk factors of NSAID-induced gastropathy because there could be no symptoms. Age is the most important risk factor according to previous reports. The aim of this study was to find risk factors of NSAID-induced gastropathy and to confirm the association between NSAID-induced gastropathy and age. METHODS: We retrospectively assessed 300 patients who conducted an upper gastroscopy during the course of chronic NSAID treatment. RESULTS: Median age of patients group is 51.4 +/- 12.2 years. In multivariate analysis, age and ulcer history are two significant risk factors. Median age is 46.7 +/- 10.7 years for the patients with nonspecific gastroscopic finding, 53.0 +/- 12.5 for those with erosion, 57.6 +/- 10.0 for those with ulcer, and 63.2 +/- 8.9 for those with hemorrhage. The proportion of ulcer patients is as follows: 6% in the patients of under 40 years old, 14.9% in patients of the 40s, 20% in patients of the 50s, 30.9% in patients of the 60s, 33.3% in patients over 70 years. The proportion of nonspecific findings is 62.2% in patients of the 40s, 37.8% in patients of the 50s, and 29% in patients over 60 years. CONCLUSIONS: Age is the most important risk factor of the NSAID-induced gastrointestinal mucosal injury. A larger randomized prospective control study will be required in the future for more conclusive results.

The Recurrence Rate of Colon Polyp after Polypectomy and the Interval of Surveillance Colonoscopy: Predictors of Early Development of Advanced Polyp / 대한소화기학회지

BACKGROUND/AIMS: Surveillance of individuals with colon polyps is important for the prevention of colon cancer, and its interval is based on the clinical status. Our aims were to determine the recurrence rate of advanced polyp after polypectomy and estimate the adequate interval of surveillance colonoscopy as well as the risk factors of recurrence in Korea. METHODS: Ninety-seven patients who underwent follow-up colonoscopy after initial colonoscopic polypectomy were retrospectively studied. All polyps were endoscopically removed with electrocautery. RESUTLS: Mean number of initial polyps were 2.2 and advanced polyps were observed in 40% of the patients. The cumulative recurrence rate of colon polyp was 13.8% within 1 year, and 60% within 3 years, while that of advanced polyps was 2.5% and 31% within 1 and 3 years, respectively. The significant difference was noted according to the initial polyp number in both overall and advanced polyp recurrence rate. The age at the diagnosis of colon polyps was a significant factor only in overall polyp recurrence rate. Patients who initially had one polyp showed 15% of advanced polyp recurrence within 3 years. CONCLUSIONS: Recurrence of advanced polyp is very rare within one year after polypectomy. Patients with single polyp have low risk and thus, their surveillance may be delayed beyond the standard 3 years. When surveillance colonoscopy is to be performed for the patients with 2 or more polyps, initial polyp number and age should be considered.

Successful Treatment of Protein-Losing Enteropathy Induced by Intestinal Lymphangiectasia in a Liver Cirrhosis Patient with Octreotide: A Case Report

A 47-yr-old man with hepatitis B virus associated liver cirrhosis was admitted to our hospital with diarrhea and generalized edema and diagnosed as protein-losing enteropathy due to intestinal lymphangiectasia by intestinal biopsy and 99mTc albumin scan. During hospitalization, he received subcutaneous octreotide therapy. After 2 weeks of octreotide therapy, follow-up albumin scan showed no albumin leakage, and the serum albumin level was sustained. We speculate that liver cirrhosis can be a cause of intestinal lymphangiectasia and administration of octreotide should be considered for patients with intestinal lymphangiectasia whose clinical and biochemical abnormalities do not respond to a low-fat diet.

Detection of JC Virus in the Brains of Korean Glioblastoma Multiforme Patients

OBJECTIVE: The ubiquitous human polyomavirus, JC virus(JCV) is the etiologic agent of the fatal demyelinating central nervous system(CNS) disease, progressive multifocal leukoencephalopathy(PML). Recent studies have reported the detection of the JCV in samples derived from several type of human neural tumors and suggested the possible association of JCV with CNS tumors. Here we report for the first time, the presence of JCV in Korean glioblastoma multiforme(GM) patients. METHODS: Two Korean GM patients were assayed for JCV. To detect JCV, we performed immunohistochemical analysis using anti-JCV and anti-glial fibrillary acidic protein(GFAP) serum and polymerase chain reaction(PCR) using primers. RESULTS: JCV antigen was detected in cytoplasm abundantly in cells of this tumor case. Also, GFAP immunoreactivity was predominantly observed in cytoplasm of the cells that were morphologically bizarred appearing astrocytes in GM. In addition, both of the large T antigen gene and the VP1 gene were detected and this result correspond with previous result of immunohistochemistry. CONCLUSION: Although it is not certain that GM is associated with the JCV, we are attempted to elucidate the possible implication of JCV in the tumorigenesis of certain human malignant gliomas.