Diffuse gastroduodenitis associated with ulcerative colitis: treatment by infliximab.

Diffuse gastroduodenitis resembling ulcerative colitis in respect to macro- and microscopic findings occurs in ulcerative colitis, although it is rare. Reports of gastroduodenitis associated with ulcerative colitis treated with infliximab are rare. A 58-year-old man had tarry stool in March 2011. He had a history of ulcerative colitis that was diagnosed in 1984. He underwent subtotal colectomy in 1991. Endoscopy and radiography revealed diffuse friable mucosa throughout the duodenum and an ulcer in the middle of the descending portion, resulting in a narrow portion.In the stomach, numerous small aphthae were observed in the antrum. Biopsy specimens of the duodenum and antrum showed marked inflammatory cell infiltration in both areas and cryptitis in the duodenum. Standard induction therapy of infliximab was started in April. The ulcer in the descending portion became a scar without diffuse mucosal friability in September 2011.

A case of hepatocellular carcinoma with bleeding gingival metastasis treated by transcatheter arterial embolization.

The patient was a terminally ill 80-year-old man with multiple lung metastases from hepatocellular carcinoma, that had developed following hepatitis-C virus-associated cirrhosis. He was admitted to our hospital with gingival bleeding, and we diagnosed gingival metastasis from hepatocellular carcinoma, based on histological examination. The bleeding could not be controlled, and the patient became dyspneic. After transcatheter arterial embolization, his bleeding was successfully controlled until his death due to respiratory failure. Transcatheter arterial embolization was a safe and effective treatment in our case.

Effect of alcohol consumption on leptin level in serum, adipose tissue, and gastric mucosa.

It has been reported that the stomach is a source of leptin, which is the product of the obese (ob) gene. In the present study, the effect of alcohol on leptin level in serum, gastric mucosa, and adipose tissue was studied to understand the relationship between appetite and alcohol consumption. Male Sprague-Dawley rats were administered 1 ml of 25% ethanol perorally. Leptin levels in the serum, gastric mucosa, and adipose tissue were measured. The serum leptin level was significantly decreased 3 and 6 hr after ethanol administration, although the gastric leptin level was not affected. The leptin level in the adipose tissue was significantly increased 3 hr after administration. We conclude that the decreased serum leptin level after ethanol administration might be due to suppression of leptin secretion from adipose tissue to the systemic circulation. These findings might be important for understanding the relationship between alcohol consumption and appetite.

MEK activation suppresses CPT11-induced apoptosis in rat intestinal epithelial cells through a COX-2-dependent mechanism.

Resistance to chemotherapeutic agents is one of the distinct features of cancer cells. We evaluate the role of activated MEK-ERK signaling in Camptotecin/irinotecan (CPT-11)-induced cell death using constitutively activated MEK1-transfected normal rat intestinal epithelial cells (IEC-caMEK cells). A CPT-11-induced inhibitory concentration of 50% was determined by WST assay. Apoptosis was evaluated by DNA staining and fragmented DNA analysis. Protein expressions were analyzed by western blotting. We also examined the role of cyclooxygenase-2 in the cell systems. IEC-caMEK cells possessed survival advantages compared to control cells. Apoptosis was remarkably suppressed in IEC-caMEK cells. Western blot analysis revealed increased expression of Bcl-2, Bcl-xL, Mcl-1, and COX-2 and decreased expression of Bak in IEC-caMEK cells. The COX-2 selective inhibitor ameliorated the antiapoptotic nature of IEC-caMEK cells. MEK activation suppressed CPT-11-induced apoptosis in IEC-caMEK cells via a COX-2- dependent mechanism. Therefore, MEK-ERK signaling may contribute to the drug-resistant nature of cancer cells.

Attenuation of gastric mucosal inflammation induced by aspirin through inhibition of selective type III phospshodiesterase in rats.

Cilostazol, a selective type III phosphodiesterase inhibitor, is widely used for treatment of ischemic symptoms of peripheral vascular disease. Recent studies have reported that the mechanism of cilostazol is related to suppression of pro-inflammatory cytokine production and improvement of local microcirculation disturbances. The activation of inflammatory cells and pro-inflammatory cytokine production play critical roles in the pathogenesis of aspirin-induced gastric irritation. The aim of the present study was to determine whether cilostazol can ameliorate aspirin-induced gastric mucosal lesions in rats, reduce neutrophil accumulation, and reduce the production of pro-inflammatory cytokines. Gastric lesions were produced by oral gavage of aspirin (200 mg/kg) and HCl (0.15 N, 8.0 ml/kg). Cilostazol (1-10 mg/kg, IP) was injected 30 min before aspirin administration. Also, we measured the gastric mucosal concentrations of myeloperoxidase and interleukin-1 beta, tumor necrosis factor-alpha, and cytokine-induced neutrophil chemoattractants-1, as an index of neutrophil accumulation, and the pro-inflammatory cytokines. Cilostazol ameliorated the gastric mucosal lesions induced by aspirin administration (P<0.01). The gastric contents of myeloperoxidase and pro-inflammatory cytokines were all increased after aspirin administration and significantly reduced by cilostazol treatment. In this study, we demonstrated that a selective type III phosphodiesterase inhibitor, cilostazol, reduced aspirin-induced gastric inflammation and damage via suppression of the production of proinflammatory cytokines. Cilostazol may be useful for preventing gastric mucosal lesions induced by aspirin.

Protective effect of a novel rice extract against ethanol-induced gastric mucosal injury in rat.

The aim of this study was to investigate the protective action of rice extract on ethanol-induced mucosal damage in vivo and wound healing of epithelial cells in vitro. Also, the effect of rice extract on gastric mucosal prostaglandin E(2) level, HSP72 expression, gastric acid secretion, and contribution of vanilloid receptor-mediated action was studied. In addition, using cultured gastric mucosal cells (RGM-1), the effect of rice extract on cytoprotection and wound healing of epithelial cells was evaluated. Rice extract significantly reduced gastric mucosal damage produced by ethanol in vivo, and heat treatment (80 degrees C, 3 min) of this agent did not alter its protective effect. Rice extract also protected RGM-1 from ethanol-induced damage in a dose-dependent manner. Rice extract accelerated wound healing of gastric epithelial cells. Our results demonstrate that rice extract could be an alternative ulcer treatment that provides cytoprotection and enhancement of wound healing not dependent on acid secretion, prostaglandin E(2) level, HSP72 expression, or vanilloid receptors.

Expression of HSP72 in the gastric mucosa is regulated by gastric acid in rats-correlation of HSP72 expression with mucosal protection.

BACKGROUND AND AIM: The real mechanism of adaptive cytoprotection in the gastric mucosa is not well established. In the present study, we investigated the effect of acid suppressing agents on a 72-kDa heat shock protein (HSP72) expression, which is known as endogenous cytoprotective factor, in the gastric mucosa. Also, the association of gastric mucosal protective function against HCl-challenge was compared between HSP72-induced and -reduced group. MATERIALS AND METHODS: Expression of HSP72 was measured by Western blotting in the gastric mucosa before and after administration of famotidine or omeprazole. The gastric mucosal protective function against 0.6 N HCl was compared between control group and HSP72-reduced group. Also, the effect of increased expression of gastric HSP72 by additional administration of zinc sulfate or zinc L-carnosine, which is known as HSP72-inducer, on mucosal protective function was studied. RESULTS: HSP72 expression in the gastric mucosa was reduced by acid suppressing agents. The lowest expression level of HSP72 was observed 12 h (famotidine, H2-receptor antagonist) or 48 h (omeprazole, proton pump inhibitor) after administration. The gastric mucosal protective ability against 0.6 N HCl was also reduced when HSP72 expression was decreased by famotidine or omeprazole. This phenomenon was reversed by HSP72 induction by additional administration of zinc derivatives. CONCLUSION: Our results might indicate that the expression of HSP72 in the gastric mucosa is physiologically regulated by gastric acid, and that HSP72 induction could be important in view of mucosal protection especially when HSP72 expression is reduced by administration of acid suppressing agents such as proton pump inhibitor or H2 receptor antagonist.

Zinc L-carnosine protects colonic mucosal injury through induction of heat shock protein 72 and suppression of NF-kappaB activation.

In this study, we investigated the effects of zinc L-carnosine, an anti-ulcer drug, on acetic acid-induced colonic mucosal injury and the correlation of these effects with expression of 72-kDa heat shock proteins (HSP72) and nuclear factor kappa B (NF-kappaB) activation in rat colonic mucosa in vivo. After intrarectal administration of zinc L-carnosine, the rats received intrarectal infusion of 5% acetic acid (1 ml). The colonic mucosal damage was evaluated by macroscopic assessments 24 h after the intrarectal infusion of acetic acid. Expression of HSP72 in rat colonic mucosa was evaluated by Western blot analysis before and after zinc L-carnosine administration. NF-kappaB activation was evaluated by electrophoretic mobility shift assays (EMSA). Zinc L-carnosine inhibited visible damage in rat colonic mucosa by acetic acid. Expression of HSP72 was significantly increased at 6 h after zinc L-carnosine administration. Furthermore, NF-kappaB activation in colonic mucosa was suppressed 6 h after zinc L-carnosine treatment. These results suggested that zinc L-carnosine protects the colonic mucosa against acetic acid by induction of HSP72 and suppression of NF-kappaB activation and zinc L-carnosine may be a novel therapeutic agent for the therapy of inflammatory bowel disease.

Is Mongolian gerbil really adequate host animal for study of Helicobacter pylori infection-induced gastritis and cancer?

BACKGROUND: Many researches have been published to understand the pathogenesis and mechanism of Helicobacter pylori (Hp)-associated diseases, including gastritis followed by gastric cancer, using Mongolian gerbil (MG) model because Hp could be hardly inoculated in other animal species. The aim of this study was to evaluate the induction ability of heat shock protein (HSP70) and protective ability in the gastric mucosa of MG comparing with those of Sprague-Dawley (SD) rats, since HSP70 is a key molecule known to be involved in important biological activities such as apoptosis, carcinogenesis, and cytoprotection from cytotoxic damage. MATERIALS AND METHODS: Basal expression level and induction ability of gastric mucosal HSP70 were evaluated by immunoblotting and densitometric analysis in MG and SD rats before and after HSP-induction by zinc l-carnosine, gastric HSP70 inducer, administration. Mucosal protective ability against water-immersion stress-induced mucosal lesion was also compared. RESULTS: Basal expression level of HSP70 was not significantly different between MG and SD rats. However, HSP70-induction by zinc derivatives was not observed in MG. Mucosal lesion induced by water-immersion stress was significantly severe in MG compared with SD rats. CONCLUSIONS: MG might be special (not ordinary) animal, in which HSP70-induction was absent and has extremely poor mucosal protective ability in view of HSP-dependent cytoprotection in the gastric mucosa. Our results may suggest that MG is not an adequate animal to evaluate the effect of Hp-infection-associated gastric inflammation followed by development of gastric cancer.

Systemic stress increases serum leptin level.

BACKGROUND AND AIM: Leptin, the product of the obese (ob) gene, is a circulating peptide mainly synthesized by adipocytes. Leptin inhibits food intake and decreases body weight. A recent report has suggested that the gastric mucosa is also the source of leptin, and that the stomach leptin also contributes to the regulation of the serum leptin level. The aim of the present study was to investigate the effect of water-immersion stress on serum, stomach and adipose tissue leptin levels to understand the relationship between stress and eating behavior. METHODS: Male Sprague-Dawley rats were used in this experiment. The leptin level in the serum, gastric mucosa and adipose tissue was measured using ELISA system before and after the initiation of water-immersion stress. RESULTS: The serum leptin level was significantly increased by water-immersion stress. The peak was observed 9 h after the initiation of the stress (P < 0.01). However, the gastric leptin level significantly decreased 6 and 9 h after the stress. The adipose tissue leptin level significantly increased 3 h after the stress. CONCLUSIONS: The results suggest that changes in serum leptin levels could be associated with stimulation of leptin secretion from the gastric mucosa and leptin production in the adipose tissue by systemic stress and that leptin might be regulated by stress-related events.

Over-expression of 70-kDa heat shock protein confers protection against monochloramine-induced gastric mucosal cell injury.

The major heat shock protein, HSP70, is known to be involved in cytoprotection against environmental stresses mediated by their function as a "molecular chaperone". Monochloramine (NH(2)Cl) is a potent cytotoxic oxidant generated by neutrophil-derived hypochlorous acid and Helicobacter pylori urease-induced ammonia. In this study, to evaluate the cytoprotective effect of HSP70 against NH(2)Cl-induced gastric mucosal cell injury, rat gastric mucosal cells (RGM-1) were stably transfected with pBK-CMV containing the human HSP70 gene (7018-RGM-1) or pBK-CMV alone (pBK-CMV-12) as control cells. These cells were treated with various concentrations of NH(2)Cl. Cell Viability was determined by MTT assay and the direct plasma membrane damage was analyzed by lactate dehydrogenase (LDH) release assay. Apoptosis was determined by DNA fragmentation analysis. NH(2)Cl caused injury to pBK-CMV-12 cells in a concentration-dependent manner. NH(2)Cl-induced gastric cell injury was significantly diminished in HSP70 over-expressing cell line (7018-RGM-1) both necrosis and apoptosis compared to the control cell line (pBK-CMV-12) transfected with CMV vector alone. These result suggest that overexpression of HSP70 plays an important role in protecting gastric cells against NH(2)Cl-induced injury.

Attenuation of gastric mucosal inflammation induced by aspirin through activation of A2A adenosine receptor in rats.

AIM: To determine whether a specific adenosine A(2A) receptor agonist (ATL-146e) can ameliorate aspirin-induced gastric mucosal lesions in rats, and reduce neutrophil accumulation and production of pro-inflammatory cytokines. METHODS: Gastric lesions were produced by oral gavage of aspirin (200 mg/kg) and HCl (0.15 mol/L, 8.0 mL/kg). 4-{3-[6-Amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester (ATL-146e, 2.5-5 mug/kg, IP) was injected 30 min before the administration of aspirin. Tissue myeloperoxidase (MPO) concentration in gastric mucosa was measured as an index of neutrophil infiltration. Gastric mucosal concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were determined by ELISA. Also, we examined the effect of ATL-146e on tissue prostaglandin E2 (PGE2) production and gastric secretion. RESULTS: Intragastric administration of aspirin induced multiple hemorrhagic erosions in rat gastric mucosa. The total length of gastric erosions (ulcer index) in control rats was 29.8+/-7.75 mm and was reduced to 3.8+/-1.42 mm after pretreatment with 5.0 g/kg ATL-146e (P<0.01). The gastric contents of MPO and pro-inflammatory cytokines were all increased after the administration of aspirin and reduced to nearly normal levels by ATL-146e. Gastric mucosal PGE2 concentration was not affected by intraperitoneal injection of ATL-146e. CONCLUSION: The specific adenosine A(2A) receptor agonist, ATL-146e, has potent anti-ulcer effects presumably mediated by its anti-inflammatory properties.

Effect of cilostazol, a selective type-III phosphodiesterase inhibitor, on water-immersion stress-induced gastric mucosal injury in rats.

BACKGROUND: Cilostazol, a specific type-III phosphodiesterase inhibitor, is widely used for the treatment of ischemic symptoms of peripheral vascular disease. Recent studies have reported that the mechanism of cilostazol is related to the suppression of pro-inflammatory cytokine production and improvement of local microcirculation disturbances. The pathogenesis of stress-induced gastric mucosal lesions is characterized by the activation of inflammatory cells and the production of inflammatory cytokines. The effects of cilostazol on the development of gastric mucosal lesions have not been reported. In the present study, we examined the effect of a cilostazol on water-immersion stress-induced gastric mucosal lesions. METHODS: Rats were subjected to water-immersion stress with or without pretreatment with a single intraperitoneal injection of the selective type-III phosphodiesterase inhibitor, cilostazol. We measured the gastric mucosal lesion and the concentrations of myeloperoxidase (MPO), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1), as an index of neutrophil accumulation and pro-inflammatory cytokine production. RESULTS: Cilostazol ameliorated the gastric mucosal injury induced by water-immersion stress (P<0.001). The gastric contents of MPO, TNF-alpha, IL-1beta, and CRO/CINC-1 were all increased after water-immersion stress and were reduced to almost normal levels by cilostazol. CONCLUSIONS: In this study, we demonstrated that a selective type-III phosphodiesterase inhibitor, cilostazol, inhibited stress-induced gastric inflammation and damage via suppressing the production of pro-inflammatory cytokines. Cilostazol may be useful for preventing gastric mucosal lesions.

Rolipram, a specific type IV phosphodiesterase inhibitor, ameliorates aspirin-induced gastric mucosal injury in rats.

Inhibition of type IV phosphodiesterase (PDE IV) activity reduces the production of various proinflammatory cytokine and suppresses neutrophil activation. Nonsteroidal anti-inflammatory drugs such as aspirin induce gastric mucosal lesions. In the pathogenesis of aspirin-induced gastric mucosal lesion, the contributions, of activated inflammatory cells and proinflammatory cytokine production are critical. The specific PDE IV inhibitor rolipram is known to be a potent inhibitor of inflammation by increasing intracellular cyclic AMP in leukocytes. The aim of the present study was to determine whether rolipram can ameliorate aspirin-induced gastric mucosal lesions in rats and whether the agent can inhibit the inrease in neutrophil accumulation and the production of proinflammatory cytokines. Gastric lesions were produced by administration of aspirin (200 mg/kg) and HCI (0.15 N; 8.0 ml/kg). Rolipram was injected 30 min before aspirin administration. The tissue myeloperoxidase concentration in gastric mucosa was measured as an indicat or of neutrophil infiltration. The gastric mucosal concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were determined by ELISA. The intragastric administration of aspirin induced multiple hemorrhagic erosions in rat gastric mucosa. Gastric mucosal lesions induced by aspirin were significantly inhibited by treatment with rolipram. The mucosal myeloperoxidase concentration was also suppressed by rolipram. Increases in the gastric content of TNF-alpha and IL-1beta after aspirin administration were inhibited by pretreatment with rolipram. We demonstrated that the specific type IV PDE inhibitor, rolipram, could have a potent antiulcer effect, presumably mediated by its anti-inflammatory properties.

Selective A2A adenosine agonist ATL-146e attenuates acute lethal liver injury in mice.

BACKGROUND: D-Galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver injury is an experimental model of fulminant hepatic failure in which tumor necrosis factor-alpha (TNF-alpha) plays a pivotal role. We examined the effects of a highly selective adenosine A2A receptor agonist (ATL-146e) on GalN/LPS-induced fulminant hepatic failure. METHODS: Mice were given an intraperitoneal dose of GalN (800 mg/g body weight)/LPS (100 ng/g body weight) with and without ATL-146e (0.01 microg/kg) treatment. Liver injury was assessed biochemically and histologically. Also, TNF-alpha levels in the serum were determined. RESULTS: The serum liver enzyme (ALT) level in vehicle-treated mice was 20 960 +/- 2800 IU/ml and was reduced by 63% to 7800 +/- 1670 IU/ml by treatment with 0.01 microg/kg per minute ATL146e, P < 0.05. Treatment with ATL-146e significantly reduced serum TNF-alpha and greatly reduced inflammation assessed by histopathologic examination compared with control mice treated with GalN/LPS. ATL-146e also reduced lethality at 12 h from 65% to 13%. CONCLUSION: The present findings suggest that the highly selective adenosine A2A receptor agonist (ATL-146e) prevents endotoxin-induced lethal liver injury by suppression of TNF-alpha secretion.

Selective adenosine A receptor agonist, ATL-146e, attenuates stress-induced gastric lesions in rats.

BACKGROUND: Activation of adenosine A(2A) receptors reduces the production of various pro-inflammatory cytokines and suppresses neutrophil activation. Water-immersion restraint is well known to cause gastric mucosal lesions due to stress. The pathogenesis of stress-induced gastric mucosal lesions is characterized by activation of inflammatory cells and production of inflammatory cytokines. Agonists of adenosine A(2A) receptors are known to be anti-inflammatory, but the effects of these compounds on the development of gastric mucosal lesions has not been reported. In the present study, the effect of a potent and selective adenosine A(2A) receptor agonist, ATL-146e, on water-immersion stress-induced gastric mucosal lesions was studied. METHODS: Rats were subjected to water-immersion stress with or without pretreatment with a single intraperitoneal injection of a potent and selective agonist of the adenosine A(2A) receptor. The gastric concentrations of myeloperoxidase (MPO), as an index of neutrophil accumulation, and the pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), were measured. RESULTS: The total length of gastric erosions (ulcer index) in control rats was 21.6 +/- 3.23 mm and was reduced by 86% to 3.1 +/- 0.83 mm by pretreatment with 5.0 microg/kg ATL146e (P < 0.001). The gastric content of MPO, TNF-alpha and IL-1beta were all increased after water-immersion stress and reduced to near normal levels by ATL-146e. CONCLUSION: A specific adenosine A(2A) agonist inhibits stress-induced gastric inflammation and damage. A(2A) agonist compounds may be useful for preventing ulcers and appear to act by blocking gastric inflammation.

Specific type IV phosphodiesterase inhibitor ameliorates thioacetamide-induced liver injury in rats.

BACKGROUND AND AIMS: Rolipram is a specific type IV phosphodiesterase inhibitor that suppresses the activity of immune cells and the production of pro-inflammatory cytokines. In this study, we assessed the effect of rolipram on acute liver injury using thioacetamide (TAA)-induced liver injury in rats as a model. METHODS: Rats were treated with rolipram (0.5-5 mg/kg, intraperitoneally) or vehicle and injected 30 min later with TAA (100 mg/kg, subcutaneously). Serum transaminase concentrations and tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta) and growth related oncogene/cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1) levels were measured and livers were examined for microscopic changes. Dose-dependent protection against TAA liver injury was based on transaminase levels and inflammatory cytokine production, and was measured 9 h after TAA when the peak release of cytokines occurred. RESULT: Rolipram suppressed liver injury based on serum aspartate transaminase (AST), alanine transaminase (ALT) and histology and reduced TNF-alpha, IL-1beta and GRO/CINC-1 levels. Rolipram, at doses of 0.5-5 mg/kg, suppressed serum transaminase and TNF-alpha production in a dose-dependent manner, and these effects were significant at doses of 2.5 and 5 mg/kg. CONCLUSION: In our rodent model of acute liver injury, rolipram clearly reduced liver damage and inhibited pro-inflammatory cytokine production. These results suggest that specific type IV phosphodiesterase inhibitors, such as rolipram, have potent hepatoprotective effects that are associated with suppressing inflammatory cytokine production.

[Statistical study on the case of aural foreign bodies].

Although aural foreign bodies are very frequently seen in daily practice, few reports systematically analyze a large case population. We report 509 cases seen at our clinic during the 16 years from January 1986 to December 2001. All were clinically confirmed during the same period among a total of 68,579 new visitors and cases with aural foreign bodies accounted for 0.74%. Cases seen during routine outpatient clinic hours were 161 (31.6%), and others seen in emergencies were 348 (68.4%). Among these were 307 men (60.3%) and 202 women (39.7%). The right side involved 251 (49.3%), the left side 241 (47.3%), and bilateral 4 (0.8%). Monthly distribution showed an average of 42.4 cases a month, peaking during the months of July and August, when temperatures are highest. Age distribution showed an average of 25.4 years old, ranging from 1 month to 90 years of age. Those under 9 years numbered 182 (35.8%) and were the peak incidence by age. In classification by organic and inorganic, organic materials accounted for 206 (40.5%) and inorganic for 288 (56.6%). Organic materials appeared to be related to monthly distribution, i.e. more cases in hot months.