Hitoshi Ichikawa

Cytomegalovirus is frequently reactivated and disappears without antiviral agents in ulcerative colitis patients

OBJECTIVE: The clinical significance of cytomegalovirus (CMV) reactivation complicating ulcerative colitis (UC) patients has been uncertain. It has therefore remained undetermined whether or not CMV reactivation should be treated in UC patients under immunosuppression. The aim of the study was to clarify the natural history of CMV reactivation in UC patients.METHODS: Sixty-nine UC patients with moderate to severe activity were enrolled in the study. All of the patients were treated with prednisolone, and/or immunosuppressants such as cyclosporine A. We sequentially monitored CMV reactivation every 2 wk up until 8 wk using the CMV antigenemia (Ag) assay and plasma quantitative real-time polymerase chain reaction (PCR) assay for CMV.RESULTS: Immunoglobulin (Ig) G for CMV was positive in 48 patients (69.6%) and negative in 21 patients (30.4%). CMV was reactivated in 25 patients out of the 48 seropositive patients (52.1%) during the study period. The CMV Ag and PCR values were low and none of the patients showed any evidence of CMV infection on biopsy specimens by hematoxylin and eosin staining. While gancylovir (GCV) was not used except in two patients, clinical outcomes including rates of remission and colectomy were not significantly different among the CMV reactivation-positive, -negative, and CMV IgG negative groups. Furthermore, CMV disappeared without GCV in most of the CMV reactivation-positive patients.CONCLUSIONS: CMV is frequently reactivated in active UC patients; however, it disappears without antiviral agents. Therefore, antiviral therapies should not be necessary for most UC patients with only CMV reactivation as long as CMV Ag values are low.

Novel endoscopic activity index is useful for choosing treatment in severe active ulcerative colitis patients

AimClinical symptoms are the most important factors used by physicians to evaluate the severity and extent of ulcerative colitis (UC). In this context, colonoscopy is also a useful diagnostic tool. We have recently developed an endoscopic activity index (EAI) to assess the severity of UC. Here, we assess the correlations among the EAI, other endoscopic indices, and clinical scores. The usefulness of the EAI for choosing treatment options, such as intravenous corticosteroid or cyclosporine A (CsA), in severe UC patients was also evaluated.MethodsClinical symptoms and endoscopic finding were evaluated in 396 patients with UC (454 colonoscopies). The EAI was scored using the following six items: ulcer size, ulcer depth, redness, bleeding, edema, and mucus exudates. The patients were also scored using Matts’ grade, Rachmilewitz’s endoscopic index, and the Lichtiger index.ResultsOur results showed that (1) the EAI scores were closely correlated with those of the Lichtiger index, Matts’ grade, and Rachmilewitz’s endoscopic index; (2) the EAI scores significantly decreased in patients who responded to treatment, while Matts’ grade did not change in some responders treated with intravenous CsA and steroid; (3) patients with a higher EAI (14–16) tended to be refractory to corticosteroid therapy (responders 19%) compared to CsA (77%), while steroid treatment was effective in 58% of patients with EAI scores of 11–13.ConclusionsThe EAI is equivalent to other endoscopic indices and relatively more useful in choosing a treatment for patients with severe UC.

Psychological aspects of inflammatory bowel disease

Psychological stress has been described as “a process in which environmental demands tax or exceed the adaptive capacity of an organism, resulting in psychological and biological changes that may place persons at risk for disease.”1 Psychological stress is widely believed to play a major role in functional gastrointestinal disorders, especially irritable bowel syndrome. There is a long history of observations suggesting that psychological stress contributes to the course of infl ammatory bowel disease (IBD). The chronic medical conditions characterizing IBD, chronic diarrhea, bloody stools, abdominal pain, weight loss, malnutrition, and weakness, seem to be exacerbated by physiological and psychological stress. From this viewpoint, we often see an overlap of pathophysiology between IBD and irritable bowel syndrome (IBS). Furthermore, recent studies on IBS have demonstrated that dysregulation of the immune system and its interaction with bacteria/fl ora may contribute to IBS pathophysiology, just as with IBD. Here, we review the role of psychological stress in IBD, including our current preliminary observations of patients with ulcerative colitis (UC), and the possibility of an overlap in pathophysiology between IBD and IBS. The infl uence of psychological stress on gastrointestinal tract homeostasis through corticotrophin-releasing factor, a key player in the brain–gut axis

Tetomilast suppressed production of proinflammatory cytokines from human monocytes and ameliorated chronic colitis in IL‐10‐deficient mice

Background: Tetomilast (OPC‐6535) was originally developed as a compound inhibiting superoxide production in neutrophils. Although its mechanism of action is not completely understood, phosphodiesterase type 4 inhibitory function has been postulated. The therapeutic effect of PDE4 inhibitors has been reported for chronic inflammatory disorders such as chronic obstructive pulmonary diseases. In this study we aimed to examine whether tetomilast could be a novel drug for inflammatory bowel diseases by further clarifying its antiinflammatory effects. Methods: Cytokines from human peripheral blood mononuclear cells were measured by enzyme‐linked immunosorbent assay (ELISA) and Cytokine Beads Array. The transcripts were quantified by reverse‐transcriptase polymerase chain reaction (RT‐PCR). Phosphorylation of transcription factors was examined by phosflow. To examine its in vivo effect, a once‐daily oral dose of tetomilast was tested in murine IL‐10−/− chronic colitis. Results: Tetomilast suppressed TNF‐&agr; and IL‐12 but not IL‐10 production from lipopolysaccharide (LPS)‐stimulated human monocytes. It suppressed TNF‐&agr;, IFN‐&ggr;, and IL‐10 from CD4 lymphocytes. Tetomilast suppressed cytokine production at the transcriptional level but did not alter phosphorylation of p65, ERK, p38, and STAT3. HT‐89, a protein kinase A inhibitor, did not abolish the effect of tetomilast, suggesting that it was independent from the classical cAMP/PKA pathway. IL‐10 was not essential to the inhibitory effect of tetomilast on TNF‐&agr; and IL‐12. Tetomilast ameliorated IL‐10−/− chronic colitis with reduced clinical symptoms, serum amyloid A, and histological scores with decreased TNF‐&agr; mRNA expression. Conclusions: Tetomilast exerts its antiinflammatory effects on human monocytes and CD4 cells. Combined with in vivo data these findings support the feasibility of tetomilast as a novel drug for inflammatory bowel diseases.

Fasting gastric pH of Japanese subjects stratified by IgG concentration against Helicobacter pylori and pepsinogen status.

Background:  The clinical significance of Helicobacter pylori antibody titer has been controversial, and the association between the extent of gastric atrophy or acid secretion and H. pylori antibody concentration has not been elucidated.

Granulocyte and Monocyte Adsorption Apheresis Therapy Modulates Monocyte‐Derived Dendritic Cell Function in Patients With Ulcerative Colitis

The aim of this study was to elucidate the molecular mechanisms responsible for the therapeutic effects of granulocyte and monocyte adsorption apheresis (GMA). We investigated the alterations in circulating monocyte subsets and monocyte‐derived dendritic cell (moDC) function after GMA therapy in ulcerative colitis (UC) patients. Eighteen patients with UC were enrolled: 14 patients were responders, and 4 patients were non‐responders. Peripheral venous blood was obtained within 5 min before and 5 min after GMA therapy. Flow cytometric analysis for monocyte markers (CD14/CD16) was then performed. Monocyte‐derived dendritic cells were obtained and alterations in their phenotype were analyzed by flow cytometry. Their function was also analyzed in a mixed lymphocyte reaction assay between allo‐naïve T lymphocytes. Flow cytometric analysis for intracellular interferon (IFN)‐γ (T‐helper 1 cells) and interleukin (IL)‐4 (T‐helper 2 cells) was then performed for the stimulated T lymphocytes. In patients who responded to GMA, the average numbers of monocytes, especially CD16+ monocytes, were significantly decreased after therapy (P < 0.05). In responders, post‐GMA moDCs expressed significantly lower CD80 and B7‐DC, which are one of the stimulation and maturation markers of dendritic cells, compared to pre‐GMA moDCs. CD83, CD86 and human leukocyte antigen‐DR also showed a tendency to decrease. In responders, naïve T lymphocytes stimulated with post‐GMA moDCs produced significantly less IFN‐γ and IL‐4 compared to those stimulated with pre‐GMA moDCs. The results of our study show that some of the immunosuppressive effects of GMA therapy may be associated with the modulation of monocyte subsets and moDC function.

Lipopolysaccharides stimulate adrenomedullin synthesis in intestinal epithelial cells: release kinetics and secretion polarity

Adrenomedullin (AM), a potent vasodilator peptide initially isolated from a human pheochromocytoma, functions as an antimicrobial peptide in host defense. In this study, we investigated changes in AM levels in intestinal epithelial cells and the mechanism of its secretion and cellular polarity after exposure to lipopolysaccharides (LPS). When a rat small intestinal cell line (IEC-18 cells) was exposed to LPS, enzyme-linked immunosorbent assay revealed a dose-dependent increase in AM together with an increase in AM mRNA expression, as determined by real-time polymerase chain reaction. Up-regulation of AM by LPS was dose-dependently inhibited by LY294002, PD98059, SP600125 and calphostin-C, suggesting the involvement of the phosphatidylinositol 3 kinase, extracellular signal-regulated kinase, c-Jun NH2-terminal kinase and protein kinase C pathways, respectively, in this process. When polarized IEC-18 cells in a Transwell chamber were stimulated with LPS, AM secretion was directed primarily toward the side of LPS administration (either the apical or basolateral side). In situ hybridization revealed that AM mRNA was expressed in epithelial cells and in the connective tissue in the lamina propria of the jejunum after intraperitoneal or oral administration of LPS. Higher levels of AM mRNA expression were observed in rats treated with LPS via the intraperitoneal route, compared with those treated via the oral route. These findings suggest that intestinal AM plays an important role in mucosal defense in the case of intestinal luminal infection, as well as in the modulation of hemodynamics in endotoxemia.

A case of severe cholestatic jaundice with hyperthyroidism successfully treated with methimazole

Liver dysfunction is a common complication observed in patients with hyperthyroidism, however the dysfunction is always mild and obvious jaundice is rarely observed. We present the case of a 43-year-old man who suffered from hyperthyroidism complicated by severe jaundice. The jaundice likely occurred as a secondary consequence of cholestasis due to hyperthyroidism, since other causes such as drug-induced or autoimmune liver dysfunction were ruled out. Treatment with methimazole improved severe cholestatic jaundice in parallel with normalization of thyroid function. The mechanism of cholestasis as a secondary complication of hyperthyroidism has not been uncovered and there is no specific biochemical marker for cholestasis due to this hormonal disease at present. This case serves as a reminder that severe jaundice can be a manifestation of simple hyperthyroidism, and that administration of antithyroid drugs is an effective treatment for severe cholestatic jaundice in such cases.

Serum Nitrate/Nitrite Concentration Correlates with Gastric Juice Nitrate/Nitrite: A Possible Marker for Mutagenesis of the Proximal Stomach

Background/Aims: In the normal acid-secreting stomach, luminally generated nitric oxide, which contributes to carcinogenesis in the proximal stomach, is associated with the concentration of nitrate plus nitrite (nitrate/nitrite) in gastric juice. We investigated whether the serum nitrate/nitrite concentration is associated with that of gastric juice and whether it can be used as a serum marker. Methods: Serum and gastric juice nitrate/nitrite concentration, Helicobacter pylori antibody, and gastric pH were measured in 176 patients undergoing upper endoscopy. Results: Multiple regression analysis revealed that serum nitrate/nitrite concentration was the best independent predictor of gastric juice nitrate/nitrite concentration. On single regression analysis, serum and gastric juice nitrate/nitrite concentration were significantly correlated, according to the following equation: gastric juice nitrate/nitrite concentration (µmol/l) = 3.93 – 0.54 × serum nitrate/nitrite concentration (µmol/l; correlation coefficient = 0.429, p < 0.001). In analyses confined to subjects with gastric pH less than 2.0, and in those with serum markers suggesting normal acid secretion (pepsinogen-I >30 ng/ml and negative H. pylori antibody), the serum nitrate/nitrite concentration was an independent predictor of the gastric juice nitrate/nitrite concentration (p < 0.001). Conclusion: Measuring the serum nitrate/nitrite concentration has potential in estimating the gastric juice nitrate/nitrite concentration. The serum nitrate/nitrite concentration could be useful as a marker for mutagenesis in the proximal stomach.

Novel Procedure of Endoscopic Submucosal Dissection Using Double Graspers for Early Stage Gastric Cancer

Novel Procedure of Endoscopic Submucosal Dissection Using Double Graspers for Early Stage Gastric Cancer Hiroyuki Imaeda, Yasushi Iwao, Haruhiko Ogata, Hitoshi Ichikawa, Hidekazu Suzuki, Nagamu Inoue, Mikiji Mori, Naoki Hosoe, Tatsuhiro Masaoka, Manabu Nakashita, Koichi Aiura, Hiroshi Nagata, Koichiro Kumai, Toshifumi Hibi Background and Aim: Endoscopic submucosal dissection (ESD) for early stage gastric cancer (EGC) has improved the success rate for en bloc resection. It has been also reported that several techniques of traction of lesions are useful for ESD; however, these are complicated and invasive. The aim of this study is to assess the usefulness of ESD using double graspers for EGC. Subjects and Methods: Subjects were 23 lesions of EGC, which were histopathologically differentiated adenocarcinomas within the mucosa and without ulcers. Mean size of the lesions was 16.3 mm, range from 10-35 mm. Sixteen of 23 lesions were at the gastric body, 5 at the antrum and 2 at the angulus. A short hood was attached to the distal tip of an endoscope. After marking around lesions, 10% glycerin with indigocarmine and epinephrine was injected into the submucosa. After circumferential cutting around the lesions using a needle knife at a Endo-Cut mode, the endoscope was pulled out once. Next, a grasper (inside grasper) inserted through an accessory channel of the endoscope grasped the tip of the other grasper (outside grasper), which was outside the endoscope. Both graspers and endoscope were inserted into the stomach, and the anal side of the lesions was grasped by the outside grasper controlled by the endoscope and the inside grasper. Thereafter, the inside grasper was released and pulled out. Finally, with traction of the lesions towards the oral side by the outside grasper, the submucosal layer of lesions was dissected using the needle knife at a forced coagulation mode. Hemostasis for bleeding was carried out using the needle knife at a spray coagulation mode or clips. Results: (1) All lesions were able to be grasped with the outside grasper. (2) Traction of the lesion towards the oral side by the outside grasper was able to make the submucosal layer wider and more visible. Therefore, dissection could be more easily carried out under direct vision, with both safety and certainty. (3) Both the endoscope and the outside grasper was able to be moved easily and independently. (4) All lesions were able to be resected en block. (5) No bleeding requiring blood transfusion or a perforation occurred. Conclusion: ESD using double graspers is very useful for easily dissecting EGC with safety and certainty not only at the body but also the angulus and the antrum. M1339 New Diagnostic and Therapeutic Strategy: Combination of Capsule Endoscopy (CE) and Double-Balloon Endoscopy (DBE) Michiko Iwamoto, HIronori Yamamoto, Hiroto Kita, Keijiro Sunada, Yoshikazu Hayashi, Hiroyuki Sato, Kentaro Sugano, Katuro Shirakawa, Tetuya Nakamura, Akira Terano Background: Capsule endoscopy (CE) and double-balloon endoscopy (DBE) both offer visualization of the entire small intestine (SI). CE is considered an effective diagnostic procedure, while DBE is potentially a therapeutic as well as a diagnostic technique but DBE requires both oral and anal approaches to view entire SI. Aim: To determine if the combination of CE and DBE is a useful as a diagnostic and therapeutic strategy for SI diseases. Methods: Thirteen patients with melena and anemia who had no specific findings by previous esophagogastroduodenoscopy (EGD) and colonoscopy were examined by both CE and DBE. CE was performed prior to DBE in order to both compare the findings of both tests, and to determine if CE data about the location of lesions CE was helpful in to the endoscopist performing DBE. Results: Visualization of the entire small bowel was adequate in all subjects. CE and DBE both identified the same source of bleeding in 9 of 13 (69%) subjects, 1 bleeding polyp, 2 arteriovenous malformations (AVM), 2 submucosal tumors (SMT), 1 bleeding small intestinal ulcer, 1 segmental edematous lesion, 1 gastric ulcer, 1 gastric antral vascular ectasia (GAVE); in one additional patient no lesions were seen by either exam. In 3 cases, SMTwas suggested by CE but not found by DBE. Endoscopic treatment was performed in 6 patients (1 polypectomy, argon plasma coagulation in 3 patients, 2 for AVMs and 1 for GAVE, and clipping for 1 bleeding gastric ulcer.) Surgical resection was performed for 2 SMT. In 1 patient with bleeding small intestinal ulcer, capsule retention occurred near the ring like stricture DBE with Balloon dilatation of the stricture to 15 mm allowed the capsule to pass naturally within 2 days. DBE was helpful for this case. Conclusion: In this small series the combination of CE and DBE appeared to be complementary. The identification and localization of lesions by CE was useful to the endoscopist performing DBE and DBE with stricture dilatation allowed a retained capsule to pass.