CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation.

Immune and inflammatory systems are controlled by multiple cytokines, including interleukins (ILs) and interferons. These cytokines exert their biological functions through Janus tyrosine kinases and signal transducer and activator of transcription (STAT) transcription factors. We recently identified two intrinsic Janus kinase (JAK) inhibitors, JAK binding protein (JAB; also referred to as suppressor of cytokine signaling [SOCS1]/STAT-induced STAT inhibitor [SSI1]) and cytokine-inducible SH2 protein (CIS)3 (or SOCS3/SSI3), which play an essential role in the negative regulation of cytokine signaling. We have investigated the role of STATs and these JAK inhibitors in intestinal inflammation. Among STAT family members, STAT3 was most strongly tyrosine phosphorylated in human ulcerative colitis and Crohn's disease patients as well as in dextran sulfate sodium (DSS)-induced colitis in mice. Development of colitis as well as STAT3 activation was significantly reduced in IL-6-deficient mice treated with DSS, suggesting that STAT3 plays an important role in the perpetuation of colitis. CIS3, but not JAB, was highly expressed in the colon of DSS-treated mice as well as several T cell-dependent colitis models. To define the physiological role of CIS3 induction in colitis, we developed a JAB mutant (F59D-JAB) that overcame the inhibitory effect of both JAB and CIS3 and created transgenic mice. DSS induced stronger STAT3 activation and more severe colitis in F59D-JAB transgenic mice than in their wild-type littermates. These data suggest that hyperactivation of STAT3 results in severe colitis and that CIS3 plays a negative regulatory role in intestinal inflammation by downregulating STAT3 activity.

Pneumomediastinum is a frequent but minor complication during esophageal endoscopic submucosal dissection.

BACKGROUND AND STUDY AIM: Esophageal perforation caused by endoscopic submucosal dissection (ESD) induces serious pneumomediastinum. In the absence of endoscopically detected perforation, postprocedural pneumomediastinum may occur. The aim of this study was to evaluate the association between the clinical factors/courses and pneumomediastinum revealed by chest computed tomography (CT) with special reference to an exposed muscle layer during esophageal ESD. PATIENTS AND METHODS: A total of 58 patients undergoing ESD for esophageal neoplasms between February 2003 and June 2007 also underwent both chest radiography and chest CT within 1 hour after ESD. We studied the association between findings on CT scan and tumor-related and technical factors of esophageal ESD by uni- and multivariate analyses. We also analyzed the clinical factors/courses experienced by all patients. RESULTS: Pneumomediastinum was detected in 18 / 58 patients (31 %) by chest CT compared with only 1 / 58 patients (1.7 %) by chest radiography. ESD-induced exposure of the muscular layer (32 patients) was the only significant factor for pneumomediastinum (18 / 32; P < 0.0001). Clinical factors such as fever, white blood cell count, and C-reactive protein were significantly increased in the group positive for both endoscopically exposed muscular layer and pneumomediastinum (+/+, n = 18) compared with the (-/-) group (n = 26) in the early phase (day 1) after ESD. However, these factors did not affect the length of the fasting period or the length of hospital stay. CONCLUSIONS: In esophageal ESD, pneumomediastinum detected by chest CT only does not cause clinically significant complication. Endoscopic muscle exposure during ESD is a significant risk factor for pneumomediastinum, which causes mild inflammation in the early post-ESD phase.

Local recurrence of colorectal tumors after endoscopic mucosal resection.

We evaluated intramucosal local recurrences of 114 colorectal tumors which were removed by endoscopic mucosal resection (EMR). Removals of all these lesions were judged as successful by endoscopic absence of residual tumor immediately after EMR. The presence of residual tumor was determined by histologic and stereomicroscopic examinations in the lateral margin of resected specimen. There was no evidence of intramucosal local recurrence in 91 lesions with negative margin. However, intramucosal local recurrence occurred in 3 of 23 lesions (13%) with positive margin. Consequently endoscopic follow-up is mandatory in patients with lateral margin positive for tumor tissue in the EMR specimen.

Clinicopathological study of superficial-type invasive carcinoma of the colorectum.

We investigated the relationship between histological parameters such as the level of invasion (scanty submucosal invasion, sm-s or massive submucosal invasion, sm-m), histologic grade (presence or absence of grade III carcinoma), lymphatic invasion, venous invasion, budding and lymph node metastasis in 33 lesions of superficial-type invasive colorectal carcinoma. On statistical analysis, there was no definite influence of any histological parameter on lymph node metastasis. None of 6 sm-s lesions showed lymph node metastasis, however, 7 sm-m lesions were found to have lymph node metastasis (25.9%). Whereas only 16.7% (1/6) of the lesions showing sm-s had one or more unfavorable histological parameters, 85.2% (23/27) of the lesions showing sm-m had one or more of unfavorable histological parameters. There was a significant difference between the two types of lesions (p<0.003). Consequently, in the treatment of superficial-type invasive carcinoma, sm-s lesions without unfavorable histological parameters could be radically cured by endoscopic mucosal resection alone.

Diagnosis of the level of depth in superficial depressed-type colorectal tumors in terms of stereomicroscopic pit patterns.

We investigated the relationship between stereomicroscopic pit patterns and histological structures in 93 lesions of superficial depressed-type colorectal tumors to assess the possibility of diagnosing the level of invasion by the pit patterns. All 9 lesions with Va (amorphous)-type pit pattern showed massive invasion into the submucosal layer (sm2, sm3). Massive invasion into sm was observed in 66.7% (6/9) of lesions with Vi (irregular)-type pit pattern, whereas 22.2% (2/9) of the lesions invaded the shallow layer of the submucosa (sm1) and 11.1% (1/9) were limited to the mucosa. Among the lesions with pit patterns other than Va and Vi, 93. 3% (70/75) were limited to the mucosa, whereas 6.7% (5/70) invaded the submucosal layer, but all were limited to sm1. These findings show that stereomicroscopic analysis of the pit patterns of the superficial depressed-type colorectal tumors is useful for diagnosing the level of invasion.

Usefulness of the high-frequency ultrasound probe in pretherapeutic staging of superficial-type colorectal tumors.

We evaluated the usefulness of the high-frequency ultrasound probe (HFUP, 20 MHz) to determine the depth of tumor invasion in 45 patients with superficial colorectal tumors. The correct diagnostic rate was 66% (30/45) when the depth of tumor invasion was classified into the following 6 layers: mucosa (m), upper 1/3 (sm1), middle 1/3 (sm2), and lower 1/3 (sm3) areas of the submucosa, muscularis propria (mp), and the subserosa or deeper areas (s). However, when the depth of tumor invasion was evaluated in 3 layers (m-sm1, sm2-sm3, and mp-deeper layer), which is the classification used to select cases for endoscopic mucosal resection, the correct diagnostic rate was 88.9% (40/45). These results suggest that the HFUP is useful to determine the depth of invasion to select treatment for superficial colorectal tumors.

Treatment of ulcerative colitis with germinated barley foodstuff feeding: a pilot study.

BACKGROUND: Germinated barley foodstuff (GBF) has been shown to attenuate intestinal injury in animal models, largely by increasing luminal short-chain fatty acid production. AIM: To investigate the safety and efficacy of GBF in the treatment of ulcerative colitis (UC). METHODS: Ten patients with active UC received 30 g of GBF daily for 4 weeks in an open-label treatment protocol while the baseline anti-inflammatory therapy was continued. The response to treatment was evaluated clinically and endoscopically. Pre- and post-treatment stool concentrations of short-chain fatty acids were measured by gas-liquid chromatography. RESULTS: Patients showed improvement in their clinical activity index scores, with a significant decrease in the score from 6.9+/-1.4 to 2.8+/-1.5 (mean+/-S.E.M., P < 0.05). The endoscopic index score fell from 6.1+/-2.3 to 3.8+/-2.3 (P < 0.0001). Patients showed an increase in stool butyrate concentrations after GBF treatment (P < 0.05). No side-effects were observed. CONCLUSIONS: Oral GBF therapy may have a place in management of ulcerative colitis, but controlled studies are needed to demonstrate its efficacy in the treatment of this disorder.

Influence of nitroglycerin on portal pressure and gastric mucosal hemodynamics in patients with cirrhosis.

We studied 30 patients with cirrhosis to determine the effect of nitroglycerin on portal and gastric mucosal hemodynamics. Systemic hemodynamics, portal venous pressure (PVP), the hemoglobin index (IHB), and the oxygen saturation index (ISO2) of the gastric mucosa were measured before and after a continuous infusion of nitroglycerin. The patients were divided into two groups according to the presence or absence of major portal-systemic collateral routes on portograms. Nitroglycerin caused a reduction in PVP in all patients. Although there was no significant difference in systemic hemodynamic changes between the two groups, the reduction in PVP in patients with major portal-systemic collaterals was significantly higher than in those without major collaterals. A nitroglycerin infusion, at a dose of 1.0 micrograms/kg per min for 10 min, produced a reduction in both IHB (-16%, P < 0.001) and ISO2 (-13%, P < 0.001) in the gastric mucosa, indicating gastric mucosal ischemia secondary to splanchnic vasoconstriction. These findings suggest that the continuous infusion of nitroglycerin reduces PVP in cirrhotic patients, particularly in those with major portal-systemic collaterals, and reduces the congestion of the gastric mucosa in patients with portal hypertension.

Evaluation of patient outcome following sclerotherapy for esophageal varices.

After excluding terminally all patients, we evaluated a total of 718 patients treated with endoscopic injection sclerotherapy. They involved 350 episodes of acute hemorrhage and 368 prophylactic procedures in patients with risky varices. The 1-year cumulative survival rate was significantly lower in the acute hemorrhage group than in the prophylactic group (P < 0.05). The difference in survival between the two groups was primarily due to the number of deaths in the first 2 months after sclerotherapy (20.1% vs 0.8%, P < 0.0005). Improvements in the sclerotherapy technique significantly reduced the number of deaths from bleeding (9.3% vs 3.4%, P < 0.05), but not those from liver failure following variceal hemorrhage. Prophylactic EIS is advantageous in the treatment of esophageal varices, i.e. it may prevent deaths from liver failure attributed to variceal hemorrhages. The present study shows that preliminary prevention of variceal hemorrhage provides favorable hemostatic efficacy in patients with risky varices.

Influence of extravariceal collateral channel pattern on recurrence of esophageal varices after sclerotherapy.

We investigated the influence of extravariceal collateral channel pattern on the recurrence of esophageal varices after sclerotherapy. One hundred and fifteen patients with cirrhosis and esophageal varices were studied. They were divided into four groups according to extravariceal collateral pattern on portal venography. Group 1 patients had neither paraesophageal veins nor gastrorenal veins (n = 49); group 2 patients had paraesophageal veins only (n = 30); group 3 patients had gastrorenal veins only (n = 25); and group 4 patients had paraesophageal veins plus gastrorenal veins (n = 11). Sclerotherapy was repeated to eradicate esophageal varices and follow-up endoscopic examination were performed. The overall recurrence-free rate at 36 months was 68%. The log-rank test showed the recurrence-free rate to be significantly higher in group 3 (76%) and group 4 patients (89%) than in group 1 patients (51%; P < 0.05 and P < 0.05, respectively). Although the recurrence-free rate was higher in group 4 than in group 2 patients (59%), this did not reach the level of significance (P = 0.10). No significant differences were found between other pairs of groups. These results suggest that gastrorenal veins play an important role in the protection against recurrent esophageal varices after sclerotherapy, while the protective role of paraesophageal veins appears to be small.

Ligation plus low-volume sclerotherapy for high-risk esophageal varices: comparisons with ligation therapy or sclerotherapy alone.

Endoscopic variceal ligation therapy (EVL) seems to be a more effective and safer method than endoscopic injection variceal sclerotherapy (EVS) for treating bleeding esophageal varices. However, EVL may entail a higher recurrence rate than EVS. The aim of this study was to examine whether EVL combined with low-dose EVS reduced the recurrence rate compared to treatment with EVL alone and reduced the complication rate compared to treatment with EVS alone. In this prospective study, 59 patients with cirrhosis and high-risk (F2 or F3, red color sign ++ or ) esophageal varices were enrolled. They were randomly assigned to an EVS group (n = 18), an EVL group (n = 20), and a combination EVL plus low-dose EVS group (n = 21). After the eradication of varices, follow-up endoscopic examinations were carried out for 24 months to determine the recurrence of varices. Complications, e.g., severe dysphagia, fever, renal dysfunction and pleuritis were also evaluated. The recurrence-free rate was significantly lower in the EVL group (60% at 24 months) than in either the EVS group (90%, P < 0.05) or the combination group (88%, P < 0.05). However, no significant difference was found between the EVS group and the combination group. The complication rate was significantly higher in the EVS group (50%) than in either the EVL group (5%, P < 0.01) or the combination group (10%, P < 0.01). The combination therapy seems to be useful to improve the benefits achieved with EVL alone and to reduce the harmful effects induced by EVS alone. EVL plus low-volume EVS is advisable in the treatment of high-risk esophageal varices.

Role of extravariceal collateral channels in the development of portal-hypertensive gastropathy before and after sclerotherapy.

We investigated whether extravariceal collateral pattern contributed to the development of portal-hypertensive gastropathy (PHG) before and after sclerotherapy. Ninety-nine patients with cirrhosis and large esophageal varices were examined in this retrospective study. They were divided into four groups according to transhepatic portographic findings: group A (with neither paraesophageal veins nor gastrorenal shunt; n = 46), group B (with paraesophageal veins; n = 27), group C (with gastrorenal shunt; n = 14), and group D (with paraesophageal veins and gastrorenal shunt; n = 12). To assess PHG, endoscopic examinations were carried out before and 1 week and 1 month after sclerotherapy. The severity of PHG was classified according to a modified McCormack's classification and scored as: absence, 0; mild, 1; severe, 2. There were no significant differences in age, sex, cause of cirrhosis, severity of liver dysfunction, and extent of esophageal varices in the four groups. The PHG score before sclerotherapy was significantly higher in group A than in either group C (P < 0.05) or group D patients (P < 0.05). The calculated, integrated incremental change in PHG score after sclerotherapy was significantly higher in group A than in group C (P < 0.01) and group D patients (P < 0.01). Although the integrated change in PHG score was lower in group B than in group A patients, the difference was not significant (P = 0.68). These results suggest that gastrorenal shunt, but not paraesophageal veins, may play a protective role in the development of PHG before and after sclerotherapy.

Upright posture blunts postprandial splanchnic hyperemia in patients with cirrhosis and portal hypertension.

The aim of this study was to compare postprandial hemodynamic changes observed during assumption of the recumbent posture and upright posture in patients with cirrhosis and portal hypertension. Eleven patients with cirrhosis and portal hypertension were studied. Echo-Doppler examinations were performed to measure flow volume in the portal vein (PV), superior mesenteric artery (SMA), and splenic artery (SA) in the fasting condition. Collateral blood flow was indirectly calculated by determining the difference between the sum of SMA, SA, and PV blood flows. After these measurements were done, each patient received a standardized liquid meal and was then randomly assigned to either maintain supine or upright posture, in a crossover design, on 2 different days (recumbent day and upright day). On each study day, the above-mentioned measurements were repeated 30 min and 60 min after the meal. PV blood flow increased significantly after the meal on the recumbent day (P < 0.01) but not on the upright day (P = 0.78). Although there were significant postprandial increases in SMA blood flow on both study days (P < 0.01, P < 0.01), the effect was less pronounced on the upright day than on the recumbent day (P < 0.01). Postprandial SA blood flow showed no change on the recumbent day (P = 0.64), but decreased significantly on the upright day (P < 0.01). The calculated postprandial collateral blood flow increased significantly on the recumbent day (P < 0.05), but showed no change on the upright day (P = 0.53). These results suggest that the upright posture blunts postprandial splanchnic hyperemia in patients with cirrhosis and portal hypertension.

Polyarthritis nodosa with mesenteric aneurysms demonstrated by angiography: report of a case and successful treatment of the patient with prednisolone and cyclophosphamide.

Polyarteritis nodosa is a necrotizing angitis that predominantly affects small and medium-sized arteries. The prognosis of untreated polyarteritis nodosa is very poor. Since symptoms are diverse and no serologic test is specific for polyarteritis nodosa, the diagnosis is difficult and often delayed. We describe a patient with polyarteritis nodosa who had gastrointestinal involvement with multiple aneurysms of the inferior mesenteric artery; only abdominal angiography provided a conclusive diagnosis. Alleviation of symptoms and regression of aneurysms were observed after combination therapy of an immunosuppressive agent, cyclophosphamide, and prednisolone. We emphasize the importance of early diagnosis by angiography and aggressive therapy in patients in whom physical signs indicating definite polyarteritis nodosa are not present.

Local recurrence of early esophageal carcinoma after endoscopic mucosal resection.

We performed endoscopic mucosal resection on 25 patients with early esophageal carcinoma where the depth of invasion was limited to in the lamina propria mucosae (m2) and we observed local recurrent cancer in 2 patients (8%). To reduce the rate of local recurrent cancer, the method of resection was aimed at pathological negative stumps and establishment of a strict standard of judgement on clinically complete resection were considered to be necessary. Furthermore, complete cure was possible even in patients with pathologically positive stumps in cases where no recurrent cancer was observed over a 1 year period following endoscopic mucosal resection.

Increased growth of Bifidobacterium and Eubacterium by germinated barley foodstuff, accompanied by enhanced butyrate production in healthy volunteers.

Germinated barley foodstuff (GBF) derived from the aleurone and scutellum fractions of germinated barley mainly consists of low-lignified hemicellulose and glutamine-rich protein. GBF improves the proliferation of intestinal epithelial cells and defecation, through the bacterial production of short chain fatty acids (SCFA), especially butyrate. In this study we investigated the mechanism of production of butyrate by microflora in humans and in vitro. Daily administration of 9 g GBF for 14 successive days significantly increased fecal butyrate content. Fecal Bifidobacterium and Eubacterium were also significantly increased by GBF administration in healthy volunteers. Ten anaerobic micro-organisms selected from intestinal microflora were cultured in vitro in the medium containing GBF as a sole carbon source (GBF medium). After a 3-day incubation, 7 strains (Bifidobacterium breve, Bifidobacterium longum, Lactobacillus acidophilus, Lactobacillus casei subsp. casei, Bacteroides ovatus, Clostridium butyricum, and Eubacterium limosum) lowered the medium pH producing SCFA. Eubacterium grown together with Bifidobacterium in GBF medium efficiently produced butyrate. On the other hand, GBF changed the intestinal microflora and increased probiotics such as Bifidobacterium in the intestinal tract. As a result, butyrate was produced by the mutual action of Eubacterium and Bifidobacterium. This butyrate is considered to enhance the proliferation of colonic epithelial cells.

Effects of glucagon on superior mesenteric artery and femoral artery haemodynamics in humans.

OBJECTIVE: It remains unclear whether glucagon is a localized splanchnic arterial vasodilator in humans. This study examined this issue by assessing the haemodynamic effect of exogenous glucagon on splanchnic and extrasplanchnic arteries. METHODS: After an overnight fast, flow velocity of superior mesenteric artery and femoral artery was recorded by means of echo-Doppler in 10 controls and 10 patients with cirrhosis. Mean arterial pressure, heart rate and plasma glucagon level were also determined. These measurements were repeated after intramuscular injection of glucagon (1 mg) at 15 min and 30 min. RESULTS: Patients with cirrhosis had much higher glucagon levels than controls (P < 0.01). Plasma glucagon level rose following glucagon administration in controls (P < 0.01) and patients with cirrhosis (P < 0.01). Glucagon administration had no effect on mean arterial pressure, heart rate and femoral artery velocity in controls and patients with cirrhosis. In contrast, superior mesenteric artery velocity significantly increased after glucagon administration in both groups (P < 0.01, P < 0.01), although the effect was less pronounced in patients with cirrhosis than in controls (P < 0.05). CONCLUSION: These data suggest that glucagon might be a localized splanchnic arterial vasodilator. Thus, glucagon may be one of the factors contributing to the pathogenesis of the splanchnic hyperdynamic circulation seen in patients with cirrhosis.

Prognostic factors in cirrhotic patients receiving long-term sclerotherapy for the first bleeding from oesophageal varices.

OBJECTIVE AND DESIGN: The aim of this study was to identify prognostic factors in cirrhotic patients receiving long-term sclerotherapy for their first bleeding from oesophageal varices. METHODS: Ninety-eight patients with acute bleeding from oesophageal varices receiving long-term endoscopic injection sclerotherapy were retrospectively investigated. Thirteen variables (five qualitative and eight quantitative) related to clinical, biological, and radiographic features were collected at admission. The qualitative variables were: gender, hepatocellular carcinoma, cause of cirrhosis, ascites and degree of encephalopathy. The quantitative variables were age, bilirubin, albumin, prothrombin index, number of sessions of sclerotherapy, volume of ethanolamine oleate, time taken to reach the hospital and shock index. These variables were examined with a multivariate analysis using stepwise logistic regression procedures and a prognostic index was calculated from the Cox equation. The predictive power of the final Cox model was prospectively tested in 43 patients with cirrhosis receiving long-term sclerotherapy for their first variceal bleeding. RESULTS: Of the 13 variables studied in a multivariate analysis using a logistic regression model, four had an independent prognostic value: the presence of hepatocellular carcinoma, bilirubin, albumin and time taken to reach the hospital. When the Cox model was examined in an independent set of 43 patients, there were no statistically significant differences between the observed and expected survival. CONCLUSION: Prognosis of patients with bleeding from oesophageal varices is related to residual liver function and time taken to reach the hospital. Furthermore, the presence of hepatocellular carcinoma is an additional risk factor.

Effects of omeprazole and lansoprazole on fasting and postprandial serum gastrin and serum pepsinogen A and C.

BACKGROUND/AIMS: The aim of this study was to examine effects of two H+/K(+)-ATPase antagonists (omeprazole and lansoprazole) on fasting and postprandial serum gastrin and serum pepsinogens A and C. MATERIALS AND METHODS: In 8 healthy volunteers, either 20 mg of omeprazole or 30 mg of lansoprazole once daily for 7 days were administered in a double blind and randomized design. After a two-week period to "wash out" the drug, each treatment was then crossed over. Fasting and postprandial serum gastrin and serum pepsinogens A and C levels were measured at baseline and at the end of the treatment. RESULTS: Omeprazole increased fasting levels of serum gastrin and serum pepsinogen A and C. A similar finding was observed after lansoprazole administration. The test meal increased serum gastrin level but did not serum pepsinogens A and C either before or after omeprazole and lansoprazole administration. In addition, the integrated meal stimulated incremental serum gastrin were not modified after omeprazole and lansoprazole administration. CONCLUSIONS: This data suggests that both omeprazole and lansoprazole increase fasting serum gastrin and serum pepsinogen A and C levels, but have no effects on postprandial serum gastrin and pepsinogens levels.

Early gastric cancer in the remnant stomach.

BACKGROUND/AIMS: Early gastric cancer in the remnant stomach is rare. Periodical endoscopic examinations are mandatory for patients with partial gastrectomy for a good prognosis. Our goal is to improve the surgical management of gastric cancer in the remnant stomach. We have retrospectively investigated a total of 15 rare cases of early gastric cancer after partial gastrectomy. METHODOLOGY: From 1976 to 1994, a total of 2,102 cases of gastric cancer were resected in our Department. Among these resected cases, 845 cases were histologically diagnosed as having early gastric cancer of the stomach. Of these, 15 patients had previously undergone a partial gastric resection. The time interval between the initial partial gastrectomy and the second resection of the remnant stomach, was more than 10 years for 8 patients (Group 1) and less than 10 years for 7 patients (Group 2). Here we investigate these rare cases of remnant early gastric cancer. RESULTS: The incidence of early gastric cancer in the remnant stomach was 1.8% (15/845). The cancer location in the remnant stomach was around the stoma and suture line in 75% of Group 1 and in 28.6% of Group 2. The incidence rate of mucosal cancer (m-cancer) was 87.5% for Group 1, and 14.3% for Group 2. Total gastrectomy was selected for 37.5% of Group 1, and for 100% of Group 2. No lymph node metastasis was discovered in both groups. The postoperative mortality was zero in both groups. One patient from Group 2, later died of liver metastasis 2 years after the second total gastrectomy, while the other 9 patients continued to live for more than 5 years with no gastric cancer recurrence to date. CONCLUSIONS: The outcome for patients with gastric cancer in the remnant stomach is generally considered poor. However, the outcome of early gastric cancer in the remnant stomach was good without major postoperative complications. Therefore, to improve surgical management of remnant-stump gastric cancer, early diagnosis is most important, using periodic endoscopic follow-up examinations, especially around the stoma. When mucosal cancer around the stoma is diagnosed, subtotal gastrectomy can be selected even in gastrectomized patient for a good prognosis.