NAD(P)H oxidase plays a crucial role in PDGF-induced proliferation of hepatic stellate cells

The proliferation of hepatic stellate cells (HSCs) is a critical step in hepatic fibrogenesis. Platelet-derived growth factor (PDGF) is the most potent mitogen for HSCs. We investigated the role of nonphagocytic NAD(P)H oxidase-derived reactive oxygen species (ROS) in PDGF-induced HSC proliferation. The human HSC line, LI-90 cells, murine primary-cultured HSCs, and PDGF-BB were used in this study. We examined the mechanism of PDGF-BB-induced HSC proliferation in relation to the role of a ROS scavenger and diphenylene iodonium, an inhibitor of NAD(P)H oxidase. We also measured ROS production with the aid of chemiluminescence. We showed that PDGF-BB induced proliferation of HSCs through the intracellular production of ROS. We also demonstrated that HSCs expressed key components of nonphagocytic NAD(P)H oxidase (p22phox, gp91phox, p47phox, and p67phox) at both the messenger RNA and protein levels. Diphenylene iodonium suppressed PDGF-BB-induced ROS production and HSC proliferation. Coincubation of H2O2 and PDGF-BB restored the proliferation of HSCs that was inhibited by diphenylene iodonium pretreatment. Phosphorylation of the mitogen-activated protein kinase (MAPK) family constitutes a signal transduction pathway of cell proliferation. Our data demonstrate that NAD(P)H oxidase-derived ROS induce HSC proliferation mainly through the phosphorylation of p38 MAPK. Moreover, an in vivo hepatic fibrosis model also supported the critical role of NAD(P)H oxidase in the activation and proliferation of HSCs. In conclusion, NAD(P)H oxidase is expressed in HSCs and produces ROS via activation of NAD(P)H oxidase in response to PDGF-BB. ROS further induce HSC proliferation through the phosphorylation of p38 MAPK.     

Gastric Mucosal Injury Induced by Local Ischemia-Reperfusion in Rats (Role of Endogenous Endothelin-1 and Free Radical)

We investigated the role of an endogenousvasoconstrictor peptide endothelin-1 (ET-1) and freeradicals in local gastric ischemia-reperfusion injury inrats. Local gastric ischemia was induced by clamping the left gastric artery for 15 min andreperfusion was done for 10-30 min in the presence of150 mM exogenous HCl intragastrically. Local gastricischemia and reperfusion resulted in significantmacroscopic and microscopic gastric mucosal damage togetherwith elevation of gastric tissue ET-1 concentration.Gastric tissue ET-1 was found to increase after 15 minof ischemia alone and also with 30 min of reperfusion. A novel nonpeptide endothelin receptorantagonist, bosentan, or a combination of radicalscavengers (superoxide dismutase, catalase, anddeferoxamine) both attenuated gastric mucosal injury.However, the greater protection observed with bosentan thanwith radical scavengers might reflect a preferentialrole of endothelin-1 in this type of injury.     

An autopsy case of acute pancreatitis with a high serum IgG4 complicated by amyloidosis and rheumatoid arthritis

We report an autopsy case of acute pancreatitis with a high serum IgG4 concentration complicated by systemic amyloid A amyloidosis and rheumatoid arthritis (RA). The patient was a 42-year-old Japanese female with a 22-year history of rheumatoid arthritis. She was diagnosed with myasthenia gravis when she was 31-year old. At the onset of pancreatitis, the patient was anti-nudear antibody-positive, and had high serum gamma globulin and IgG4 levels. Dexamethasone and conventional therapy induced clinical remission and significantly decreased the serum IgG4 and gamma globulin. However, despite the decreased disease parameters, the patient developed a bleeding pseudocyst and died of cardiac failure. In the autopsy examination, it was determined that pancreatitis was probably caused by ischemia due to vascular obstruction caused by amyloid deposition in the pancreas. Even though acute pancreatitis is a rare complication in RA patients, we speculate that an autoimmune pancreatitis-related mechanism and ischemia due to vascular obstruction by amyloid deposition might be attributable to a single source that leads to acute pancreatitis in our particular case.     

Double-barreled wet colostomy

An easy and simple method for constructing a urinary diversion in patients undergoing pelvic exenteration for advanced rectal cancer is described. This procedure features double-barreled colostomy with a segment of the sigmoid colon 8 to 10 cm distal to the stoma as a urinary conduit.Read at the meeting of the Japanese Research Society for Cancer of the Colon and Rectum, Tokyo, Japan, July 29, 1994.     

Transesophageal cross-sectional echocardiography

A transesophageal cardiac imaging system is described. This system employs hand-held mechanical sector and linear scanners each having a flexible tube and a small ultrasonic transducer contained within a small oil bag easily swallowed by adults. In the sector scanner, a small transducer in the esophagus rotates alternately and horizontal heart images are displayed. In the linear scanner, a small transducer in the esophagus moves up and down and vertical heart images are displayed. The system was evaluated in 31 adult subjects. In all subjects, stable high quality heart images were observed continuously from base to apex as the transducer was being withdrawn or advanced in the esophagus. In horizontal scans, entire heart images were observed at the level of the atrioventricular valves. In vertical scans, the bifurcation of the pulmonary artery could be observed clearly. There was little difference in the image quality among subjects.     

Detection of circulating tumor cells in patients with pancreatic cancer: a preliminary result

Background/Purpose

It has been reported that circulating tumor cells (CTCs) can be used to predict survival in metastatic breast cancer. In this preliminary study, we examined the level of CTCs in pancreatic cancer (PC) patients to elucidate whether we could predict survival in PC.

Methods

The eligible subjects, at Tokyo Medical University Hospital, were 26 patients with PC, 11 with chronic pancreatitis, and 10 healthy volunteers. Three PC patients underwent surgery, 18 patients (who were stage IV) were treated with gemcitabine (GEM), and 5 patients received best supportive care (BSC).

Results

The CTC count was 1/7.5 ml blood or higher (defined as positive) in 11 of the 26 patients (42%; mean, 16.9/7.5 ml blood; range, 1-105/7.5 ml blood). Gemcitabine was administered to 6 of the 11 CTC-positive patients (3.8 courses on average). The treatment was continued for more than three courses in 2 patients, in both of whom the CTC count was only 1/7.5 ml blood. Operation was performed in 1 of the 11 CTC-positive patients. The remaining 4 patients of the 11 CTC-positive patients received only BSC. CTC was negative in 15 patients with PC (stage II, 1; stage III, 1; stage IVa, 7; and stage IVb, 6) and in the subjects with benign conditions. The median survival times (MSTs) of the CTC-positive and-negative patients were 110.5 and 375.8 days (P < 0.001). When the analysis was limited to the 14 stage-IVb patients, the MSTs of the CTC-positive and-negative patients were 52.5 and 308.3 days (P < 0.01).

Conclusions

The present study demonstrated that the detection of CTCs in peripheral blood may be useful to predict prognosis in patients with PC.     

Balloon-occluded retrograde transvenous obliteration improves liver function in patients with cirrhosis and portal hypertension

BACKGROUND AND AIM: Balloon-occluded retrograde transvenous obliteration (B-RTO) is a novel therapeutic method for the treatment of large gastric fundal varices with spontaneous splenorenal shunt (SRS). However, the effects of B-RTO on liver function remain unknown. METHODS: Fourteen patients with portal hypertension and gastric varices with SRS were studied, consisting of four patients with acute bleeding, five with high-risk varices, and five with refractory portosystemic encephalopathy. Hepatic venous catheterization was performed to evaluate hepatic blood flow and liver function using the continuous indocyanine green (ICG) infusion method. To assess the metabolic activity of the hepatocyte, the intrinsic clearance of ICG was calculated. In all patients, endoscopic study was performed before and 1 week and 1 month after the B-RTO, and followed every 6 months thereafter. After baseline measurements, B-RTO was performed. Four weeks after the B-RTO, the same catheter measurements were repeated. RESULTS: The B-RTO was successful in all patients. Contrast-enhanced computed tomography showed complete obliteration of the SRS prior to the follow-up measurements. Endoscopic eradication of the fundal varices was obtained 6 months after B-RTO in all patients and encephalopathy was improved within 1 week after B-RTO. Following the B-RTO, hepatic blood flow (441 +/- 214 vs 668 +/- 299 mL/min, P < 0.0001) and the intrinsic clearance of ICG (233 +/- 123 vs 285 +/- 148 mL/min, P < 0.05) were significantly increased. Furthermore, intrahepatic resistance decreased after the B-RTO (P < 0.005). CONCLUSION: From short-term assessment, B-RTO increases hepatic blood flow and improves the metabolic activity of the liver in patients with portal hypertension.     

A single nucleotide polymorphism in Prostate Stem Cell Antigen is associated with endoscopic grading in Kyoto classification of gastritis

The risk allele of a single nucleotide polymorphism (SNP) rs2294008 in the Prostate stem cell antigen (PSCA) gene is strongly associated with gastric cancer. Although the Kyoto classification score is believed to be an indicator of gastric cancer risk, it lacks supporting genetic evidence. We investigated the effect of this risk allele of PSCA SNP on the Kyoto score. Participants without a history of gastric cancer or Helicobacter pylori (H. pylori) eradication underwent esophagogastroduodenoscopy, H. pylori evaluation, and SNP genotyping. The Kyoto score is the sum of scores obtained from endoscopy-based atrophy, intestinal metaplasia, enlarged folds, nodularity, and diffuse redness. The Kyoto score is novel in the light of scoring for gastritis. A total of 323 patients were enrolled (number of individuals with genotype CC: 52; CT: 140; TT: 131, average age: 50.1 years, male: 50.8%). The patient baseline characteristics including age, sex, body mass index, smoking, drinking, family history of gastric cancer, and H. pylori status had no association with PSCA SNP. The Kyoto score was higher in T (CT or TT genotype; risk allele) carriers than in CC carriers. Atrophy, enlarged folds, and diffuse redness scores were higher in T allele carriers (risk allele) than in CC genotype individuals. In multivariate analysis, the Kyoto score was independently associated with PSCA SNP (OR: 1.30, p = 0.012). Thus, the Kyoto score was associated with a genetic predisposition.