Ischaemic colitis during interferon treatment for chronic hepatitis C: report of two cases and literature review.

Ischaemic colitis is known to be a severe emergency complication of interferon (IFN) therapy. However, as ischaemic colitis is an infrequent complication of IFN therapy, limited information is available regarding the safety of resuming IFN therapy after resolution of ischaemic colitis and subsequent recurrence. Here, we report two cases of ischaemic colitis during IFN therapy for chronic hepatitis C. Ischaemic colitis was fully healed within 1 week after its onset and IFN withdrawal, and IFN therapy was resumed following patients' wishes to do so. Ischaemic colitis did not recur after the resumption of IFN therapy, and sustained virological response was achieved in both patients. In this report, we also summarize the findings of 11 cases of IFN-associated ischaemic colitis (nine previously published cases plus our two cases) and review the clinical characteristics of ischaemic colitis during IFN therapy in patients with chronic hepatitis C.

Clinical trial: comparison of alendronate and alfacalcidol in glucocorticoid-associated osteoporosis in patients with ulcerative colitis.

BACKGROUND: Bone loss is often observed in patients with ulcerative colitis, particularly if they require glucocorticoids. AIM: To determine whether the bisphosphonate, alendronate, is safe and effective in preserving bone mass compared to the active vitamin D3, alfacalcidol, in ulcerative colitis patients receiving glucocorticoids. METHODS: Thirty-nine patients with ulcerative colitis and treated with glucocorticoids were randomized to receive alendronate (5 mg/day) or alfacalcidol (1 microg/day) daily for 12 months. Loss of bone mass was evaluated by bone mineral density, bone resorption by urinary N-telopeptide for type I collagen, and bone formation by serum bone alkaline phosphatase. RESULTS: Alendronate, but not alfacalcidol, significantly increased bone mineral density in the lumbar spine. Alendronate decreased serum bone alkaline phosphatase levels, but alfacalcidol did not. Urinary N-telopeptide for type I collagen levels decreased in both groups, but were significantly lower in the alendronate group. There were no significant differences in the adverse events in the two groups. CONCLUSION: Our study indicates that alendronate is a safe, well-tolerated and more effective therapy than alfacalcidol for preventing glucocorticoid-associated bone loss in patients with ulcerative colitis.

STAT3 activation via interleukin 6 trans-signalling contributes to ileitis in SAMP1/Yit mice.

BACKGROUND AND AIMS: SAMP1/Yit mice spontaneously develops intestinal inflammation. Previously, we demonstrated that the signal transducer and activator of transcription (STAT)-3/suppressor of cytokine signalling (SOCS)-3 pathway is pivotal in human inflammatory bowel disease. In our studies in SAMP1/Yit mice, the aim was to investigate whether STAT3 activation contributes to ileitis and to examine the therapeutic effects of this signal blockade. METHODS: Intestinal expression of phospho-STAT3 in SAMP1/Yit mice and control AKR/J mice was examined by western blotting and immunohistochemistry. SOCS3 and interleukin 6 (IL-6) mRNA were determined by northern blotting and reverse transcription-polymerase chain reaction, respectively. We also examined the effects of intravenously injected hyper-IL-6, an IL-6/soluble IL-6 receptor fusion protein, and of soluble gp130-Fc, a specific inhibitor of soluble IL-6 receptor signalling, on STAT3 phosphorylation and disease severity in SAMP1/Yit mice. RESULTS: Phospho-STAT3 was expressed strongly during the disease course in SAMP1/Yit mice but only transiently in AKR/J mice. Phospho-STAT3 was localised to epithelial and mononuclear cells in the diseased intestine of SAMP1/Yit mice. SOCS3 as well as IL-6 mRNAs were expressed in affected intestine. Administration of hyper-IL-6 caused disease exacerbation and enhancement of STAT3 phosphorylation. In contrast, soluble gp130-Fc administration ameliorated the disease and suppressed STAT3 phosphorylation. CONCLUSION: STAT3 signalling is critical in the development of intestinal inflammation in SAMP1/Yit mice. Blockade of this signalling pathway by soluble gp130-Fc may have therapeutic effects in inflammatory bowel disease.

Activation of c-Jun N-terminal kinase (JNK) signalling in experimentally induced gastric lesions in rats.

The c-Jun N-terminal kinase (JNK) participates in intracellular signalling cascades that mediate inflammatory responses. Therefore, the JNK signalling may be involved in gastric injury and inhibition of this pathway may form the basis of a new strategy for the treatment of gastric injury. The aim of this study was to determine whether JNK participates in the formation of gastric lesions in an experimental model. Acute gastric injury was induced in Sprague-Dawley rats by intragastric administration of 100% ethanol. The amount of phospho-JNK in the rat stomach was determined using immunohistochemistry and Western analysis. Animals received subcutaneous injections of a specific JNK inhibitor SP600125 or vehicle and the extent of mucosal damage in the stomach was determined. Western analysis revealed early phosphorylation of JNK and, to a lesser extent, p38 as well as late phosphorylation of the p42/44 extracellular signal-related kinases during the development of gastric lesions. JNK was phosphorylated in epithelial cells and in occasional mononuclear cells present at lesion sites. These cells were rarely found in samples from control specimens. Treatment with SP600125 significantly reduced the extent of gastric lesions. These findings indicate that experimental gastric injury is associated with activation of the JNK signalling pathway, and also suggest that JNK inhibitors may play a role in the treatment of gastric injury in humans.

A form of circulating interleukin-6 receptor component soluble gp130 as a potential interleukin-6 inhibitor in inflammatory bowel disease.

The presence and the role of soluble gp130, the soluble form of a component of the interleukin (IL)-6 receptor complex, were investigated in inflammatory bowel disease. The serum concentrations of soluble gp130 were increased in ulcerative colitis (active disease, median, 93.5 ng/ml; interquartile range, 26-125 ng/ml; inactive disease, 81 ng/ml, 24.8-137.3 ng/ml) and to a lesser extent in Crohn's disease (active disease, 66 ng/ml, 44.4-87.6 ng/ml; inactive disease, 63 ng/ml, 43.5-82.5 ng/ml) compared to normal controls (43 ng/ml, 27-59 ng/ml). Paired analysis of serum samples showed a decrease of IL-6 and soluble IL-6 receptor concentrations in both diseases and an increase of soluble gp130 concentrations, especially in ulcerative colitis, just after the resolution of disease exacerbation. Size fractionation of the serum revealed that a part of the IL-6 co-eluted with soluble gp130 and soluble IL-6 receptor. The IL-6-induced proliferation of murine B9 hybridoma was enhanced by recombinant soluble IL-6 receptor, whereas the proliferation was inhibited by recombinant soluble gp130. These results indicate that soluble gp130 may function as a natural inhibitor of the IL-6 actions in inflammatory bowel disease.

Attenuation of experimental colonic injury by thiazolidinedione agents.

OBJECTIVE: We investigated the potential use and action mechanisms of thiazolidinedione (TZD) agonists for peroxisome proliferator-activated receptor-gamma, namely pioglitazone and netoglitazone, during dextran sulfate sodium (DSS)-induced colitis in mice. METHODS: Colitis was induced by the drinking of 2.5% DSS for 7 days. In the prophylactic protocol, pioglitazone or netoglitazone was administered 2 days before the first DSS exposure and repeated daily for a total of 10 doses. In the therapeutic protocol, pioglitazone was administered 2 days after the first DSS exposure and repeated daily for a total of 10 doses. The effect of pioglitazone on proinflammatory cytokine signaling was examined both in vivo and in vitro. RESULTS: Colitis was significantly attenuated by both pioglitazone and netoglitazone in the prophylactic protocol and by pioglitazone in the therapeutic protocol. The improvement of colitis by pioglitazone was associated with decreased colonic interleukin-6, and phospho-signal transducer and activator of transcription-3 levels. In vitro experiments revealed that culturing lamina propria mononuclear cells in the presence of pioglitazone down-regulated the production of interleukin-6. CONCLUSIONS: These TZD agents should be considered for use as new therapeutic agents in intestinal inflammation such as inflammatory bowel disease. TZD-induced improvement in inflammation is explained, in part, by down-regulation of proinflammatory cytokine signaling.

Decreased expression of CD44, alpha-catenin, and deleted colon carcinoma and altered expression of beta-catenin in ulcerative colitis-associated dysplasia and carcinoma, as compared with sporadic colon neoplasms.

BACKGROUND: To clarify the cell adhesion status in ulcerative colitis (UC)-associated colon neoplasm, expression of cell adhesion molecules were investigated and compared with that of sporadic colon neoplasm. METHODS: A total of 14 low grade dysplasias, 16 high grade dysplasias, and 8 adenocarcinomas associated with UC and 17 sporadic adenomas with mild to moderate dysplasia, 22 adenomas with severe dysplasia, and 15 invasive adenocarcinomas were immunohistochemically examined using monoclonal antibodies against CD44, E-cadherin, alpha- and beta-catenin, and deleted colon carcinoma (DCC). RESULTS: CD44, especially its standard form, and DCC expression was stronger in the sporadic colon neoplasms than in the UC-associated lesions. Although E-cadherin did not show significant differences between the two cases, alpha-catenin was more expressed in sporadic colon adenomas with severe dysplasia and carcinomas than in their UC-associated counterparts. Membranous beta-catenin staining was stronger in UC-associated neoplasms, whereas sporadic lesions had greater cytoplasmic and nuclear expression. CONCLUSIONS: The differences in cell adhesion molecule expression suggests that UC-associated and sporadic colon neoplasms arise from different pathways of tumorigenesis.

Epidemiological study on food intake and Helicobacter pylori infection.

We conducted an epidemiological study to investigate the relation of food intake to Helicobacter pylori (H. pylori) infection in an area endemic for H. pylori. In this study, 365 subjects, 104 men and 261 women, were randomly selected from 7,389 adult (over age 20) inhabitants of town A, Japan. The prevalence of immunoglobulin G (IgG) class antibody to H. pylori (anti-H. pylori) was 83.7% and the prevalence of anti-H. pylori increased with age significantly (P < 0.05). Subjects with anamnesis of gastritis, gastroduodenal ulcer and gastric cancer tended to have a higher anti-H. pylori positive ratio (93.5%) than those without (81.0%). But there was no relationship between anti-H. pylori prevalence and sex, blood type, smoking or drinking habits. Daily intake of foods by food groups, nutrients and the concentrations of serum ingredients were compared between 37 anti-H. pylori-positive and 40 negative subjects selected from 365 inhabitants by matching up according to sex and age. The daily intake of cereals, potatoes and starches, and milks tended to be higher in positive than negative subjects, while the daily intake of algae and tea appeared to be a little higher in negative than in positive subjects. The daily zinc intake of antibody-positive subjects was significantly higher (P < 0.05) than in antibody negative subjects. On the other hand, the daily iron intake in negative subjects was significantly higher (P < 0.05) than in positive subjects. The serum concentrations of copper, zinc, and vitamin E tended to be higher in positive than negative subjects. But there were no significant differences in serum ingredients concentrations between antibody negative and positive subjects. Our findings suggest that iron and zinc intakes may effect on H. pylori infection.

Indication for endoscopic resection of submucosal colorectal carcinoma: special reference to lymph node metastasis.

We investigated the relationship between histological factors and lymph node metastasis in 77 lesions with submucosally invasive colorectal carcinomas to establish useful criteria for lesions in which endoscopic treatment alone results in cure of malignancy. There were positive correlations between histological factors, including the level of invasion, the histologic grade, presence or absence of lymphatic invasion, presence or absence of budding, and lymph node metastasis (p < 0.05, p < 0.05, p < 0.005, p < 0.01). The presence or absence of venous invasion did not influence lymph node metastasis. Laparoscopic surgery involving lymph node dissection should be indicated for sm1 carcinoma lesions with unfavorable histological factors. In lesions diagnosed as sm2 or sm3 prior to resection, intestinal resection involving lymph node dissection by laparoscopic surgery should be directly performed without endoscopic resection.In treating submucosally invasive colorectal carcinomas, the level of invasion can be clinically diagnosed, consequently endoscopic resection should be initially performed when lesions are evaluated as sm1 prior to resection. When histological investigation reveals sm1 carcinoma with histologic grade I (well-differentiated) or II (moderately-differentiated), and the absence of lymphatic invasion and budding, endoscopic treatment alone is sufficient.

Butyrate from bacterial fermentation of germinated barley foodstuff preserves intestinal barrier function in experimental colitis in the rat model.

BACKGROUND AND AIMS: The consumption of germinated barley foodstuff (GBF) prevents inflammation and diarrhoea in a colitis model. In this study we investigated the mechanism of the preventative effect of GBF on experimental colitis in rats, in view of production of bacterial butyrate and preservation of intestinal barrier function. METHODS: Sprague-Dawley rats administered with diets supplemented with 3.5% dextran sodium sulphate were used as an experimental colitis model. Butyrate was given to rats orally or intracaecally. Intestinal barrier function was estimated by light microscopic observation of the mucosa, intestinal permeability and bacterial translocation. RESULTS: Mucosal damage was reduced by intracaecal administration of butyrate, but not by oral administration. Bacterial butyrate production and reduction of mucosal damage depended on the dose of GBF in diets. The action of endogenous bacterial butyrate, including the reduction of intestinal permeability and bacterial translocation, was inhibited by administration of an inhibitor of beta-oxidation of short-chain fatty acids. CONCLUSIONS: The feeding of GBF promotes bacterial butyrate production and improves intestinal barrier function in rats, resulting in mitigation of experimental colitis.

Effect of transcatheter arterial chemoembolization on kidney hemodynamics and function in patients with cirrhosis and hepatocellular carcinoma.

BACKGROUND/AIMS: Transcatheter arterial chemoembolization (TACE) may have deleterious effect on the kidney in patients with cirrhosis and hepatocellular carcinoma. The aim of the study was to test this hypothesis. METHODS: Twenty-four patients with cirrhosis and hepatocellular carcinomas were included. They consisted of 16 patients undergoing a single TACE and eight patients undergoing diagnostic angiography. Doppler ultrasonography was used to measure hepatic artery pulsatility index (HA-PI) and renal artery pulsatility index (RA-PI) before and 1 day and 10 days after the procedure. Similarly, kidney function was assessed by measuring creatinine clearance. In addition, plasma renin activity, noradrenaline, and endothelin-1 were also measured. RESULTS: In patients receiving diagnostic angiography, no significant changes in HA-PI were observed after the procedure. In contrast, HA-PI increased significantly 1 day after the procedure (19%, p<0.01) in patients undergoing TACE, although it returned to baseline value 10 days after the procedure. In patients undergoing diagnostic angiography, no significant changes in RA-PI were observed after the procedure. Similarly, no detectable changes in RA-PI were noted in patients undergoing TACE. A transient small reduction in creatinine clearance was noted after the procedure in patients undergoing diagnostic angiography (-12%, p<0.05) and in those undergoing TACE (-11%, p<0.05). However, the effect was similar in the two groups (two-way ANOVA, p=0.72). No significant changes in plasma renin activity, noradrenaline, and endothelin-1 were observed after either diagnostic angiography or TACE. CONCLUSIONS: These results suggest that TACE per se has no deleterious effect on the kidney hemodynamics and function in patients with cirrhosis and hepatocellular carcinoma.

Affinity of 5-thio-L-fucose-containing Lewis X (LeX) trisaccharide analogs to anti-LeX monoclonal antibody.

5-Thiofucose-containing LeX trisaccharide analogs Gal beta(1,4)[5SFuc alpha(1,3)]GlcNAc-OMe (2) and Gal beta(1,4)[5SFuc beta(1,3)]GlcNAc-OMe (4) were synthesized via 5-thiofucosylation of methyl 2-azido-lactoside derivative 6 by the trichloroacetimidate method. Inhibitory activity of these analogs for the binding of LeX to anti-Lex antibody was evaluated by enzyme immunoassay, indicating that anti-LeX strictly recognizes alpha-configuration of the fucose moiety and its binding pocket includes no advantageous region, such as hydrophobic area, for recognizing the ring sulfur atom of 5-thiofucosyl LeX analog 2.

Syntheses of two trimannose analogs each containing C-mannosyl or 5-thio-C-mannosyl residue: their affinities to concanavalin A.

C-Mannosyl residue-containing trimannose ManC alpha(1,6)[Man alpha(1,3)Man] (2) and 5-thio-C mannosyl residue-containing trimannose 5SManC alpha(1,6)[Man alpha(1,3)Man] (3) were synthesized via a glycosyl radical addition to enone derivative of mannose (6). Dissociation constants for the binding of these trisaccharides to concanavalin A (ConA) were determined by a fluorescence anisotropy inhibition assay: Kd = 198 and 31 microM, respectively. The unexpectedly large Kd value for the compound 2 compared with the compound 3 and the natural trimannose 1 demonstrates a characteristic of C-glycoside.

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.

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.

Is Enterobius gregorii Hugot, 1983 (Nematoda: Oxyuridae) a distinct species?

A series of 849 male pinworms collected from a 64-yr-old Japanese male was examined. They were classified by the spicule morphology into 87 Enterobius vermicularis (Linnaeus, 1758), 754 Enterobius gregorii Hugot, 1983, and 6 immature adults, whereas 2 worms lacked spicules. The worm length of E. vermicularis was significantly larger than E. gregorii. The shape and length of the distal tubular portion of the spicule were identical in these forms, whereas the basal portion was different. The immature adults just after the final molt or still within the cuticle of the fourth stage had only a distal tubular portion, indicating that the basal portion is added during subsequent development. Moreover, various transitional forms were observed in the spicule morphology in the worms with intermediate body size between E. vermicularis and E. gregorii, showing that the basal portion of the spicule of E. vermicularis develops after the completion of E. gregorii-type basal portion. It is suggested that E. gregorii is a young stage of E. vermicularis.

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.