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.

Evaluation of the effect of ulinastatin on the production of macrophage colony-stimulating factor in vitro for potential combination therapy with leukocyte adsorption.

Macrophage colony-stimulating factor (M-CSF) induces normal intestinal macrophages that have anti-inflammatory effects. Thus, M-CSF-rich conditions in colonic tissues seem to contribute to the improvement of pathological conditions in patients with inflammatory bowel diseases (IBD). However, it has not been clarified whether current therapies for IBD, including granulocyte/monocyte adsorptive apheresis using an Adacolumn, and ulinastatin, a serine protease inhibitor, affect the production of M-CSF. To clarify the effects of these therapies on M-CSF production, we investigated whether monocyte adsorption to cellulose acetate (CA) beads (carriers for Adacolumn therapy) and ulinastatin augmented M-CSF production in in vitro experiments. Peripheral blood was incubated with and without CA beads, and then M-CSF production was measured. Additionally, peripheral blood containing serial dilutions of ulinastatin was incubated with CA beads followed by measurement of M-CSF production. Monocyte adsorption to CA beads did not affect M-CSF production. A high concentration of ulinastatin augmented M-CSF production without inhibiting monocyte adsorption to CA beads, although a low concentration of ulinastatin conversely suppressed M-CSF production. The present study found that a high concentration of ulinastatin, which was administrated with CA beads, increased the production of M-CSF. Our results suggest that a combination of ulinastatin and Adacolumn therapy may provide more clinical efficacy for the treatment of IBD in terms of the production of M-CSF.

Increased levels of serum glucose-dependent insulinotropic polypeptide as a novel risk factor for human colorectal adenoma.

Obesity and insulin resistance are thought to be risk factors for colorectal adenoma. Glucose-dependent insulinotropic polypeptide (GIP) stimulates insulin secretion from the pancreas and promotes fat accumulation in adipocytes. The association between serum GIP and the risk of colorectal adenoma has not been examined previously. We investigated this association in 370 subjects who underwent total colonoscopy during thorough physical checkups between January and December 2008. We used a cross-sectional design and classified the subjects into a colorectal adenoma group and a control group without adenoma according to their endoscopic findings. Serum GIP concentrations in samples of venous blood obtained after an overnight fast were measured using a sandwich enzyme-linked immunosorbent assay kit. The mean levels of fasting GIP (34.9 ± 49.5 vs 25.0 ± 20.1 pg/mL, P = .04), triglyceride, glucose, and insulin and the values of the homeostasis model assessment of insulin resistance in the colorectal adenoma group were significantly higher than those in the control group. Multiple logistic regression analysis showed that the highest quartile of fasting GIP levels was associated with a significantly high risk of colorectal adenoma (odds ratio, 2.1; 95% confidence interval, 1.08-3.96; P = .01) in comparison with the lowest quartile. Quartile analysis demonstrated that increased levels of GIP were related to increased levels of fasting insulin and values of homeostasis model assessment ß-cell. These results suggest that an increased level of fasting GIP is associated with an increased risk of colorectal adenoma.

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.

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.

Differential immunophenotypic analysis of dendritic cell tumours.

AIMS: The phenotypic and biological characteristics of dendritic cell (DC) tumours have not been fully elucidated. The aim of this study was to compare the immunophenotypic characteristics of DC-related markers and cell-cycle-associated markers among DC tumours and finally to utilise them for differential diagnosis of DC tumours. METHODS: Tissue sections from 28 patients with DC tumours were immunohistochemically examined using DC-related and cell-cycle-associated markers. RESULTS: The Langerhans cell histiocytosis (LCH) and Langerhans cell sarcoma (LCS) samples were positive for S-100 protein, CD1a, Langerin, fascin, DEC-205 and DC-SIGN. Interdigitating dendritic cell sarcoma (IDCS) was positive for S-100 protein and fascin and negative for Langerin. In addition, two IDCS samples were positive for CD1a, DEC-205 and DC-SIGN. The labelling indices of Ki-67, cyclin A, cyclin B1 and acetylated histone H3 on the LCS and IDCS specimens were significantly higher than those on the LCH specimens. The expression of p53 was also significantly higher in the LCS specimens than in the LCH specimens. The numbers of infiltrating CD123(+) and FOXP3(+) cells were also significantly higher in the LCS samples than in the LCH and IDCS samples. Follicular dendritic cell sarcoma was distinguished from other DC tumours by the lack of DC-SIGN, Langerin and DCE-205. CONCLUSIONS: These results suggest that Langerin can be used to distinguish LCS from IDCS, and DC-SIGN and DEC-205 can be used to identify DC tumour cells. The frequency of cell-cycle-associated markers can be used for the differential diagnosis of malignant and benign DC tumours.

Decreased levels of plasma adiponectin associated with increased risk of colorectal cancer.

AIM: To investigate the association between adiponectin levels and risk of colorectal adenoma and cancer (early and advanced). METHODS: A cross-sectional study in a cohort of hospital-based patients was conducted between January 2004 and March 2006 at Yamagata University Hospital. Male subjects, who had colorectal tumors detected by endoscopic examination, were enrolled according to inclusion and exclusion criteria. Based on the T factor of the TNM system, intraepithelial carcinoma and submucosally invasive carcinoma were defined as early cancer, and invasion into the muscularis propria or deeper was defined as advanced cancer. The plasma levels of glucose, insulin, total cholesterol, triglyceride, high sensitivity C-reactive protein, insulin like growth factor (IGF)-1, IGF binding protein-3, adiponectin, leptin, and resistin were measured. Each factor level was designated low or high, and the risk of adenoma or cancer was estimated by univariate and multivariate logistic regression analysis. RESULTS: We enrolled 124 male subjects (47 with adenoma, 34 with early cancer, 17 with advanced cancer, and 26 without tumors as controls). In patients with adenoma, high triglyceride and low adiponectin were associated with a significant increase in the odds ratio (OR) by univariate analysis. Only a low adiponectin level was related to increased adenoma risk, with an adjusted OR for low level (< 11 microg/mL) to high (>or=11 microg/mL) of 5.762 (95% confidence interval (CI): 1.683-19.739, P = 0.005). In the patients with early cancer, high body mass index, high triglyceride, and low adiponectin were associated with a significant increase in OR in univariate analysis. In multivariate analysis, only low adiponectin was significantly associated with early cancer, with an adjusted OR of 4.495 (95% CI: 1.090-18.528, P = 0.038). However, in patients with advanced cancer, low adiponectin was not recognized as a significant risk factor for advanced cancer. CONCLUSION: A decreased level of adiponectin is strongly associated with an increased risk of colorectal adenoma and early cancer. These data call for further investigation, including a controlled prospective study.

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.

Plasma level of granulocyte-colony stimulating factor during granulocyte and monocyte adsorptive apheresis in patients with ulcerative colitis.

BACKGROUND/AIMS: Cytapheresis with extra-corporeal circulation for ulcerative colitis is effective but its mechanisms are still unclear. Granulocytecolony stimulating factor (G-CSF) strongly mobilizes bone marrow-derived cells and serves as antiinflammatory factor. We investigated plasma levels of G-CSF during granulocyte and monocyte adsorptive apheresis (GCAP). METHODOLOGY: Nineteen cases of ulcerative colitis were measured plasma concentration of G-CSF during the first session of GCAP therapy. RESULTS: G-CSF were significantly increased in the column inflow at 30 min compared with the baseline (Wilcoxon test, p < 0.01), and also increased through the column (Wilcoxon test, p < 0.01). The ratio of the increase in the column outflow at 60 min was 1.5-fold compared with the baseline. However, we could not show a significant relation between G-CSF level and clinical efficacy. CONCLUSIONS: This is the first report concerning G-CSF during CAP. G-CSF is increased due to GCAP and appears to be a candidate which should be further investigated.

[Non pulsatile active bleeding from the gastrointestinal mucosa without ulceration during anticoagulation therapy -consideration on bleeding from angiodysplasia during anticoagulation therapy-].

We reported 3 cases of the uncommon type of persistent gastrointestinal bleeding during anticoagulation therapy due to cardiovascular disorders or collagen disease. Endoscopic observation showed non pulsatile active bleeding from apparently normal mucosa, without any ulcer or obvious vascularectasia. The outflow of bleeding was string-like and continuous. Based on previous reports, we considered the possibly of these cases unique bleeding angiodysplasia and angiodysplasia during anticoagulation therapy. The frequency of this type of bleeding may increase, as anticoagulation therapy has become more common. We should pay attention to such lesions when we treat gastrointestinal bleeding.

[A case of primary orbital adenocarcinoma responding to chemoradiation].

Primary orbital adenocarcinoma is very rare. There are not any reports about the treatment of this disease, except for surgery. We experienced a case of primary orbital adenocarcinoma, which we successfully treated by chemoradiation using 5-FU and cisplatin. It is very important to collect and record cases of rare diseases responding to certain chemotherapy regimens.

A multi center study of granulocyte and monocyte adsorption apheresis therapy for ulcerative colitis-clinical efficacy and production of interleukin-1 receptor antagonist.

Granulocyte and monocyte adsorption apheresis (GCAP) is a useful strategy for intractable ulcerative colitis, but its mechanisms of therapy is not fully explained. Previously, depleting activated granulocytes and monocytes (GMs) and modifying product of proinflammatory cytokines had been proposed. In addition, activated GMs are releasing anti-inflammatory cytokines, interleukin-1 receptor antagonist (IL-1ra) that may contribute to the clinical efficacy of GCAP therapy. Hence, to investigate contribution of IL-1ra as well as to confirm clinical efficacy of this therapy based on clinical activity index (CAI), we performed a multicenter study. Twenty-five of 38 (65.8%) patients achieved remission state (CAI < or = 4) and two of 38 (5.3%) revealed clinical improvement. Almost effective cases significantly decreased CAI even at 3rd session of GCAP. Plasma level of IL-1ra from outflow of the GCAP column at 30 min was significantly increased rather than inflow. Median exact elevated level of IL-1ra was 221 pg/ml and median of increasing ratio was 1.6 times. Furthermore, the responsive patients, who well released the IL-1ra at outflow more than 100 pg/ml compared with inflow, tended to show clinical effectiveness. While, the increased ratio of IL-1ra in effective cases did not differ from ineffective cases, and there were no significant relationship with improvement of CAI score. These conflict results suggest that the increase of IL-1ra at outflow is not a direct factor to the clinical improvement, but the induction of clinical improvement is accompanied by the release of IL-1ra. The IL-1ra may be involved in the multiple steps for the improvement induced by GCAP.

Osteonecrosis of the lateral femoral condyle in a patient with ulcerative colitis: report of a case.

Osteonecrosis is a major complication in patients with ulcerative colitis (UC). It appears most commonly in the femoral head, but sometimes occurs in the proximal humerus or femoral condyle. A 27-year-old Japanese woman presented with severe pain in the left knee in 2006. Osteonecrosis was found in the left lateral femoral condyle, and osteochondral autografting was performed. Ten and a half years prior to this episode, at the age of 17 years, she had been diagnosed as having UC, and after 18 months of medication, she had undergone total colectomy. A total prednisolone dose of 3020 mg had been administered before the operation, but the true pathogenesis-i.e. idiopathic or steroid-associated osteonecrosis-had not been determined at that time. The osteonecrosis occurred long after prednisolone therapy had been discontinued, and the total dose of prednisolone was not considered to be unusually high. In this case, osteochondral autografting was ultimately required for treatment of the osteonecrosis. However, conservative therapy is indicated for early-stage cases and should result in a good course. We report this case to draw attention to this relatively rare complication of UC and to facilitate early detection of similar lesions.

Significance of rapid turnover proteins in protein-losing gastroenteropathy.

BACKGROUND/AIMS: We investigated the significance of rapid turnover proteins (retinal-binding protein, pre-albumin and transferrin) in protein-losing gastroenteropathy. METHODOLOGY: We evaluated the levels of these proteins in 12 patients with protein-losing gastroenteropathy. RESULTS: The protein-losing gastroenteropathy patients showed very low level of total serum protein of 4.3 +/- 0.7 g/dL, albumin 2.1 +/- 0.4 g/dL, and IgG 682 +/- 232 mg/dL. However, retinal-binding protein was 4.4 +/- 1.9 mg/dL (normal range; 2.5-8.0 mg/dL), pre-albumin 29.3 +/- 7.9 mg/dL (21-43 mg/dL) and transferrin 226 +/- 62 mg/dL (205-370 mg/dL). The levels of rapid turnover proteins, particularly retinal-binding protein and pre-albumin were almost preserved within the normal range, despite hypoproteinemia. CONCLUSIONS: If there is a patient with severe hypoproteinemia and preserved levels of rapid turnover proteins, protein-losing gastroenteropathy should be suspected and we get a strong proof to do the following examinations such as a fecal clearance of alpha-1 antitrypsin.