Shoichi Nishise

Increased plasma levels of 8-hydroxydeoxyguanosine are associated with development of colorectal tumors.

Increased oxidative stress is generally thought to be associated with tumorigenesis. In this cross-sectional study, we evaluated plasma 8-hydroxydeoxyguanosine (8-OHdG) levels in patients with colorectal adenoma and cancer, as a surrogate marker of oxidative damage to deoxyribonucleic acid (DNA). We collected blood samples from 58 patients with adenoma, 32 with early cancer, 25 with advanced cancer, and 36 without polyps or cancer (as controls), and measured plasma levels of 8-OHdG by enzyme-linked immunosorbent assay. Univariate analysis by logistic regression showed that an increased level of 8-OHdG was a significant risk for adenoma [odds ratio (OR) 1.393, 95% confidence interval (CI) 1.008–1.926, p = 0.045]. In patients with early cancer, univariate analysis revealed significant differences for age, body mass index (BMI), systolic blood pressure, and 8-OHdG level. Subsequent multivariate analysis revealed that 8-OHdG [OR 1.627, 95% CI 1.079–2.453, p = 0.020] and BMI [OR 1.283, 95% CI 1.038–1.585, p = 0.021] were significant risk factors for early cancer. However, 8-OHdG was not a significant risk factor for advanced cancer. Our results suggest that an increased plasma level of 8-OHdG is associated with development of colorectal adenoma and cancer.

Serum Interleukin-6, Insulin, and HOMA-IR in Male Individuals with Colorectal Adenoma

Purpose: It is widely acknowledged that chronic low-grade inflammation plays a key role in the development of obesity-related insulin resistance and type 2 diabetes. The level of circulating interleukin-6 (IL-6), one of the major proinflammatory adipokines, is correlated with obesity and insulin resistance, which are known to be risk factors for colorectal adenoma. We examined the association between the circulating level of IL-6 and the presence of colorectal adenoma. Experimental Design: In a total colonoscopy-based cross-sectional study conducted between January and December 2008, serum levels of IL-6 were measured in samples of venous blood obtained from 336 male participants attending health checkups (118 individuals with colorectal adenoma and 218 age-matched controls) after an overnight fast. Results: In the colorectal adenoma group, the median levels of serum IL-6 (1.24 vs. 1.04 pg/mL; P = 0.01), triglyceride, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) were to be significantly higher than those in the control group. When restricted to individuals with adenoma, levels of IL-6 were positively correlated with body mass index, insulin, and HOMA-IR. Multiple logistic analyses adjusted to include insulin or HOMA-IR showed that high levels of IL-6 were associated with the presence of colorectal adenoma. There was no significant interaction of IL-6 with HOMA-IR to modify this association. Conclusions: Our findings suggest that increased serum levels of IL-6 are positively associated with the presence of colorectal adenoma in men, independently of insulin and HOMA-IR. Clin Cancer Res; 18(2); 392–9. ©2011 AACR.

Complement Activation Is Involved in Biological Responses to Leukocyte Adsorptive Apheresis

We examined the effects of complement activation on the biological responses of cellulose acetate (CA) beads. Peripheral blood containing the complement activation inhibitor nafamostat mesilate (NM) or heparin was incubated with CA beads in vitro. Thereafter, the fraction of adsorbed granulocytes as well as the generation of complement activation fragments (C3a and C5a) and interleukin 1 receptor antagonist (IL-1ra) were measured. Granulocyte adsorption, complement activation, and IL-1ra release were significantly inhibited in the presence of NM. Adsorption was significantly increased onto CA beads pretreated with plasma containing heparin even in the presence of NM and adding C3a or C5a enhanced IL-1ra release. These results suggested that bound complement fragment (e.g., C3b) on CA beads plays a central role in granulocyte adsorption to CA beads and that C3a and C5a augment the release of anti-inflammatory substances. We therefore conclude that complement activation is involved in these biological responses of leukocyte apheresis.

Investigation of Musashi-1 Expressing Cells in the Murine Model of Dextran Sodium Sulfate-Induced Colitis

Musashi-1 (Msi-1), an RNA-binding protein, had been proposed to be a specific marker for neural stem/precursor cells. Msi-1 expressing cells in the intestinal epithelium are also strongly considered as potential stem/precursor cells. To clarify the behavior of those cells in the injury or regeneration phase, we investigated Msi-1 expressing cells of intestinal mucosa in the murine model of dextran sodium sulfate (DSS)-induced colitis. Immunohistochemically, Msi-1-positive cells were found in the area just along the layer of Paneths cells in the small intestine and in the bottom layer of crypts in the large intestine. During DSS administration, the number of PCNA-positive cells in the large intestine increased markedly. In contrast, the number of Msi-1-positive cells decreased slightly with DSS but returned to normal after DSS administration was stopped. The level of mRNA for Msi-1 was consistent with the result of immunohistochemical examinations. Conclusively, we could describe the behavior of intestinal stem/precursor cells during inflammation using Msi-1.

Case Report: Fecal Clearance of α1-Antitrypsin with Lansoprazole Can Detect Protein-Losing Gastropathy

Detecting plasma protein loss from the stomach is quite difficult by measuring fecal alpha1-AT clearance because alpha1-AT is rapidly destroyed in the gastric juice at values below pH 3. We examined protein loss from the stomach using fecal alpha1-AT clearance with lansoprazole, a proton pump inhibitor. A 38-year-old Japanese male presented with hypoproteinemia (total serum protein: 4.4 g/dl). Abdominal scintigraphy using technetium-99m-labeled albumin revealed distinct radioactivity accumulation in the small intestine. It strongly suggested excessive protein loss to the gastrointestinal tract. Although, regular fecal alpha1-AT clearance was within the normal range (<13 ml/day), the fecal alpha1-AT clearance with the administration of lansoprazole was 80.5 ml/day. The results indicated that this method using lansoprazole is simple and useful for detecting protein-losing gastropathy.

Biological Effect of Anaphylatoxin C5a on the Generation of Anti‐inflammatory Substances in Leukocyte Adsorption

Anaphylatoxins, which are involved in both pro‐inflammatory processes and a variety of anti‐inflammatory effects, are produced during granulocyte and monocyte adsorptive apheresis. We noticed the anti‐inflammatory effects of C5a, the strongest anaphylatoxin, in granulocyte and monocyte adsorptive apheresis. The aim of this study was to investigate the effect of C5a on interleukin‐1 receptor antagonist (IL‐1ra) and hepatocyte growth factor (HGF) generation in granulocyte and monocyte adsorption. Peripheral blood containing nafamostat mesilate as an endogenous complement activation inhibitor was divided into four groups: (1) no recombinant C5a added, no contact with cellulose acetate (CA) beads (control group); (2) no C5a added, contact with CA beads; (3) C5a added, no contact with CA beads; and (4) C5a added, contact with CA beads. After incubation, IL‐1ra and HGF in plasma were measured. IL‐1ra was significantly higher in group 3, in which only C5a was added in the absence of CA beads, compared to groups 2 (P < 0.01) and 4 (P < 0.05). HGF was significantly higher only in group 4, in which C5a was added in the presence of CA beads (P < 0.05), but did not increase in the absence of CA beads. C5a can directly induce IL‐1ra generation without the granulocyte and monocyte adsorption stimuli to CA beads, but can synergistically induce HGF generation with the adsorption stimuli, indicating C5a has different effects on IL‐1ra and HGF generation.

Difficulties in the treatment of intestinal amoebiasis in mentally disabled individuals at a rehabilitation institution for the intellectually impaired in Japan.

Background: A mass Entamoeba histolytica infection recurred despite repeated treatments with metronidazole at a rehabilitation institution for individuals with intellectual impairments. Methods: Diloxanide furoate was administered to improve intractable intestinal amoebiasis after a recurring amoebic infection that tends to occur via coprophagy in mentally disabled individuals infected with E. histolytica at an institution (the prevalence rate and positive serology rate were 38.2 and 67.1%, respectively). The therapeutic effect of the drugs was judged by microscopic stool examination and an E. histolytica antigen detection kit. Results: The mass infection was eliminated through the administration of metronidazole and subsequent use of diloxanide furoate. Conclusions: Combination therapy successfully cured and prevented transmission of the mass E. histolytica infection at the institution.

Production of Interleukin-10 by Combining a Granulocyte and Monocyte Adsorption Carrier With Ulinastatin

Interleukin (IL)‐10 is an anti‐inflammatory cytokine mainly produced by monocytes and is essential for the induction of anti‐inflammatory intestinal macrophages with macrophage colony‐stimulating factor (M‐CSF). Thus, IL‐10‐ and M‐CSF‐rich conditions in colonic tissues seem to contribute to the improvement of pathological conditions in patients with inflammatory bowel diseases (IBD). We have already reported that ulinastatin, a serine protease inhibitor, increases M‐CSF production during granulocyte/monocyte (GM) adsorption to cellulose acetate (CA) beads (carriers for Adacolumn therapy). However, the effects of ulinastatin on IL‐10 production have not been clarified. The aim of the present study was to clarify the effects of ulinastatin on IL‐10 production during GM adsorption by in vitro experiments. Peripheral blood was divided into four groups: (Control) no ulinastatin added, no contact with CA beads; (1) no ulinastatin added, contact with CA beads; (2) ulinastatin added, no contact with CA beads; and (3) ulinastatin added, contact with CA beads. After incubation, IL‐10 in the plasma was measured. Compared with the level in the Control group, plasma IL‐10 was significantly higher only in group 3, in which ulinastatin was added in the presence of CA beads, but did not increase in the absence of CA beads. These results suggest that ulinastatin synergistically increases IL‐10 production with monocyte adsorption stimuli. By increasing not only M‐CSF but also IL‐10, a combination of ulinastatin and Adacolumn therapy may improve clinical efficacy for the treatment of IBD in terms of the induction of anti‐inflammatory intestinal macrophages.

Release of Interleukin‐1 Receptor Antagonist by Combining a Leukocyte Adsorption Carrier With Ulinastatin

Both granulocyte/monocyte adsorptive apheresis (GMA) and ulinastatin, a serine protease inhibitor, are reported to be effective in patients with ulcerative colitis; however, combination therapy with GMA and ulinastatin has not been attempted. Investigating the effect of ulinastatin on GMA is required for combination therapy since the inhibition of serine protease suppresses the reaction of GMA. To clarify the effects of ulinastatin on GMA, we investigated whether granulocyte adsorption to cellulose acetate beads (carriers for GMA) and interleukin‐1 receptor antagonist (IL‐1ra) release were inhibited by ulinastatin. Peripheral blood containing ulinastatin, a different serine protease inhibitor (gabexate mesilate), or signal‐transduction inhibitors was incubated with cellulose acetate beads in vitro, and the ratios of adsorbed granulocytes and IL‐1ra release were measured. Granulocyte adsorption and IL‐1ra release were significantly suppressed with increasing gabexate mesilate concentrations; however, the adsorption was not significantly inhibited by ulinastatin. Furthermore, IL‐1ra release was augmented by the addition of a high dose of ulinastatin or PD98059 as compared to a low dose. The activation levels of extracellular signal‐regulated protein kinase may regulate IL‐1ra release induced by the carrier, because both ulinastatin and PD98059 inhibit extracellular signal‐regulated protein kinase. High concentrations of ulinastatin increased IL‐1ra release without inhibiting granulocyte adsorption to cellulose acetate beads. This result warrants clinical trials of a combination of ulinastatin and GMA for the treatment of ulcerative colitis.

Diagnosis and treatment of eosinophilic esophagitis in clinical practice

Eosinophilic esophagitis (EoE) is a chronic and abnormal Th2 type immunological response characterized by intense eosinophilic inflammation localized within the esophagus. This leads to esophageal dysfunction and remodeling accompanied by subepithelial fibrosis. Recently, EoE has been recognized as one of the major causes of dysphagia or food impaction in adults. The prevalence of EoE has been increasing over the past several decades, particularly in Western countries. EoE should be differentiated from secondary esophageal eosinophilia (EE) in gastroesophageal reflux disease (GERD) and eosinophilic gastroenteritis, involving the entire gastrointestinal tract. EoE is an uncommon condition in Asia compared with Western countries. With the growing interest and awareness of this condition during the past decade, reports of this disease are increasingly emerging in Asian countries including Japan. Typical EoE does not respond to proton pump inhibitor (PPI) therapy according to the current Western diagnostic guidelines. However, some cases of EE exhibit symptomatic relief and histological improvement in response to PPI [i.e., PPI-responsive esophageal eosinophilia (PPI-REE)]. The understanding of the clinical manifestations and unique endoscopic images of EoE, differences and similarities between GERD, PPI-REE, and EoE will all serve as the differential diagnosis. Further knowledge of the indications and efficacy of PPI therapy and topical steroid therapy will also aid in the management of these diseases. In this article, we will review the current diagnosis and treatment of EoE in clinical practice.