Kencho Miyashita

Three cases of acute or fulminant hepatitis E caused by ingestion of pork meat and entrails in Hokkaido, Japan: Zoonotic food-borne transmission of hepatitis E virus and public health concerns.

Aim:  In developed countries including Japan, the transmission route of indigenous hepatitis E virus (HEV) infection is obscure. Accordingly, public health implications of indigenous HEV infection have not been well addressed. The aim of this study was to clarify the route of transmission of a small outbreak of acute hepatitis E and assess the public health implications of indigenous zoonotic HEV transmission.

Geranylgeranylacetone protects mice from dextran sulfate sodium-induced colitis.

Objective. Geranylgeranylacetone (GGA) has recently been reported to induce heat shock protein (HSP) 70, which has a protective function against inflammation. We investigated the therapeutic effects of oral administration of GGA on dextran sulfate sodium (DSS)-induced colitis in mice.Material and methods. BALB/c mice were given 3% DSS solution orally for 7 days to induce colitis. The disease activity of colitis was assessed clinically every day, and histology in the colon was evaluated at 7 days post-DSS. The levels of myeloperoxidase (MPO) activity, tumor necrosis factor (TNF)-α and interferon (IFN)-γ in the colon tissues were also examined. In addition, expression of HSPs 25, 40, 70 and 90 in the colon tissue was determined by Western blot analysis. Mice were orally administered GGA (50–500 mg/kg) when treatment of DSS started.Results. It was found that GGA significantly reduced the clinical severity of colitis and suppressed the levels of MPO activity, TNF-α and IFN-γ induced by DSS in the colon. On the other hand, GGA enhanced the expression of HSP70 in the colon of mice given DSS. HSP70-positive cells were identified in the epithelial cells of the colon from mice treated with GGA and DSS.Conclusions. Taken together, these results suggest that GGA is a new anti-inflammatory drug that could be useful in the treatment of colitis such as inflammatory bowel disease.

Polaprezinc (N-(3-aminopropionyl)-L-histidinato zinc) ameliorates dextran sulfate sodium-induced colitis in mice

Objective. Polaprezinc (N-(3-Aminopropionyl)-L-histidinato zinc), an anti-ulcer drug, has been reported to have an anti-inflammatory action in several inflammatory diseases. The aim of this study was to investigate the effect of polaprezinc on dextran sulfate (DSS)-induced colitis in mice. Material and methods. Mice with colitis induced by DSS were intrarectally treated with polaprezinc (15 mg/kg) or zinc sulfate (7.5 mg/kg) every day after the administration of DSS for 7 days. Disease activity index (DAI) and histological tissue damage were assessed. Levels of myeloperoxidase (MPO) activity, tumor necrosis factor (TNF)-α and interferon (IFN)-γ in the colon were measured. Expression of heat shock protein (HSP) 25 and HSP70 in the colon was analyzed by Western blot analysis. Results. DAI and histological scores were remarkably reduced in polaprezinc-treated mice with DSS-induced colitis. Polaprezinc suppressed the increase of MPO activity and the production of TNF-α and IFN-γ in the colon tissues of mice with DSS-induced colitis. Expression of HSP25 and HSP70 was remarkably up-regulated in the colon tissues of polaprezinc-treated mice during DSS treatment. Conclusions. Polaprezinc suppresses DSS-induced colitis in mice, partly through inhibition of production of pro-inflammatory cytokine, suppression of neutrophils accumulation and cytoprotection by overexpression of HSPs. Polaprezinc could be useful in the treatment of inflammatory bowel diseases.

Macrophage migration inhibitory factor contributes to the development of acute dextran sulphate sodium-induced colitis in Toll-like receptor 4 knockout mice

Toll‐like receptor 4 (TLR4), which recognizes lipopolysaccharides, plays an important role in the innate immune response. In this study, we investigated the role of TLR4 in the development of experimental colitis with regard to the biological actions of macrophage migration inhibitory factor (MIF) using TLR4 null (–/–) mice. TLR4–/– mice were given 2% dextran sulphate sodium (DSS) in drinking water to induce colitis, which was clinically and histologically as severe as that seen in wild‐type (WT) mice. The level of tumour necrosis factor (TNF)‐α in colon tissues was increased in WT mice but unchanged in TLR4–/– mice. The level of myeloperoxidase (MPO) activity in colon tissues was increased by DSS administration in both TLR4–/– and WT mice. The expression of MIF was up‐regulated in the colons of TLR4–/– mice with acute DSS‐induced colitis. An anti‐MIF antibody significantly suppressed colitis and elevation of matrix metalloproteinase‐13 in TLR4–/– mice. The current results obtained from TLR4–/– mice provide evidence that MIF plays a critical role in the development of acute DSS‐induced colitis.

Transgenic over-expression of macrophage migration inhibitory factor renders mice markedly more susceptible to experimental colitis

Enhanced production of macrophage migration inhibitory factor (MIF) is recognized in patients with inflammatory bowel disease (IBD) and mice with experimental colitis; however, the precise molecular function of MIF in colitis is not fully understood. To further investigate this matter, we examined the pathological features of MIF transgenic mice with dextran sulphate sodium (DSS)‐induced colitis. We generated transgenic mice carrying a murine MIF cDNA driven by a cytomegalovirus enhancer and a β‐actin/β‐globin promoter. Mice were orally administered 1–4% DSS in drinking water for 7 days. Clinical disease activity, survival and histological features were evaluated. The level of myeloperoxidase (MPO) activity in the colon tissue was measured to assess neutrophil infiltration. The level of corticosterone in the serum was measured by enzyme linked‐immunosorbent assay (ELISA). MIF mRNA and protein were markedly up‐regulated in the colon and serum obtained from MIF transgenic mice. The severity of the colitis induced by 1% DSS treatment was markedly higher in MIF transgenic mice than in wild‐type mice. We also found that MPO activity was significantly higher in MIF transgenic mice than wild‐type mice in response to DSS stimulation. Interestingly, the corticosterone level remained unchanged in MIF transgenic mice. MIF enhances DSS‐induced colitis, in part via neutrophil accumulation and inhibition of glucocorticoid bioactivity.

Regulation of Toll-like receptor 4 expression in mouse colon by macrophage migration inhibitory factor

Recent studies have indicated that macrophage migration inhibitory factor (MIF) and Toll-like receptor (TLR) play an important role in the regulation of innate immune responses. In this study, we investigated the effect of MIF on the expression of TLR4, a receptor that recognizes lipopolysaccharide, in colon using MIF-deficient mice. TLR4 mRNA expression in the colon tissues was determined by northern blot analysis. Western blot analysis and immunohistochemistry in the colon tissues were performed to evaluate the expression of TLR4 protein. The expressions of TLR4 mRNA and protein were remarkably down-regulated in colon tissues of MIF-deficient mice compared with wild-type mice and up-regulated by treatment with recombinant MIF. Immunohistochemical study revealed the presence of TLR4–positive staining in mononuclear cells in the lamina propria and intraepithelial mononuclear cells as well as weak staining in epithelial cells and crypts in colon tissues of wild-type mice. In contrast, MIF-deficient mice did not show TLR4-positive staining in the colonic mucosa. In MIF-deficient mice injected with recombinant mouse MIF (rMIF), TLR4-positive staining cells were observed in colon tissues similar to the findings in wild-type mice. Administration of dextran sulfate sodium (DSS) up-regulated the expression of TLR4 in the colons of WT mice but not in those of MIF-deficient mice. Furthermore, pretreatment with rMIF up-regulated the expression of TLR4 in response to DSS in MIF-deficient mice. Our results suggest that MIF affects the expression of TLR4 in mouse colon under both normal and colitic conditions.

^18F-FDG PET/CT imaging for a gastrointestinal mantle cell lymphoma with multiple lymphomatous polyposis

Multiple lymphomatous polyposis (MLP) is an uncommon type of gastrointestinal lymphoma characterized by the presence of multiple polyps along the gastrointestinal tract. Most of this entity is in fact considered the counterpart of gastrointestinal tract involvement for mantle cell lymphoma (MCL). To our knowledge, there have been no reports on [fluorine-18]-fluorodeoxy-glucose ((18)F-FDG)-positron emission tomography (PET)/computed tomography (CT) imaging for gastrointestinal MCL with MLP. We present the results of (18)F-FDG PET/CT imaging in a patient with gastrointestinal tract involvement of MCL showing continuous MLP from the stomach to the rectum and intestinal intussusception. FDG-PET/CT findings were false negative in typical MLP spreading widely over the gastrointestinal tract, but uptake was noted in large lesions with deep infiltration considered atypical as MLP. On FDG-PET/CT imaging, the Ki-67 proliferative index, which is a cell proliferation marker, showed neither correlation with the presence of uptake nor the maximum standardized uptake value.

Crohn's disease in Turner's syndrome with X-chromosomal mosaicism of 45 XO and 47 XXX

countries, 61% to 89% of the patients who complained of recurrent chest pain have been reported to not have organic coronary heart disease, but rather, noncardiac chest pain (NCCP), which has been found to be caused by gastroesophageal acid reflux in up to 60% of NCCP patients.1 Therefore, we consider that, in at least 35% of patients with recurrent chest pain, the pain may be easily controlled by the administration of acid-suppressing drugs. In Japan, there are no data available concerning the prevalence of NCCP in patients with recurrent chest-pain symptoms. Therefore, we conducted a retrospective multicenter study to determine the number of patients with NCCP among those with recurrent chest pain who required an investigation by coronary angiography. All patients with recurrent chest pain and investigated by coronary angiography for the first time in 2003 and 2004 at four medical centers in Japan (Kasai Municipal Hospital, Awaji Prefectural Hospital, Tottori Municipal Hospital, and Shimane Central Prefectural Hospital) were enrolled in the study. Clinical and laboratory data were collected from the medical records. The presence or absence of organic coronary heart disease was also confirmed from the coronary angiography radiomorphological records. Patients with organic coronary arterial diseases were designated as having cardiac chest pain (CCP), while those without organic coronary disease were designated as having NCCP. Statistical analyses were performed using the Mann-Whitney U-test and the c2 test as appropriate. After receiving their consent, we enrolled 952 patients in this study, with 633 found to have organic coronary artery disease. Therefore, 34% of all patients with recurrent chest pain were diagnosed as having NCCP. When the clinical characteristics were compared between patients with CCP and those with NCCP, there were significant differences in age, blood pressure, smoking habit, high-density lipid (HDL)-cholesterol, and hemoglobin (Hb)A1C. Further, the NCCP patients showed a higher proportion, of females than the CCP patients, while CCP patients more frequently had a smoking habits. As for risk factors of arteriosclerosis, HbA1C was higher and HDL-cholesterol was lower in patients with CCP, while blood pressure was slightly higher in the NCCP patients. These results indicate that a significant percentage of patients with recurrent chest pain in Japan are diagnosed with NCCP. The pathogenesis of chest pain observed in patients with NCCP has been reported to be multifactorial, and musculoskeletal pain and pain with an esophageal origin are considered to be the major causes of NCCP.2 Because the number of patients with GERD has been steadily increasing, future investigations of the prevalence of patients with GERD-related chest pain among those with NCCP are necessary.

Late duodenal metastasis from renal cell carcinoma with newly developed malignant lymphoma: A case report

Duodenal metastasis from renal cell carcinoma (RCC) is rare. The current case report presents a very rare case of late duodenal metastasis from RCC with newly developed malignant lymphoma (diffuse large B-cell lymphoma: DLBCL) at the same time. A 64-year-old man with systemic lymph nodes swelling who had undergone left nephrectomy for RCC 25 years previously, was admitted to the present hospital. Inguinal lymph node biopsy was performed, leading to a diagnosis of DLBCL. fluorine-18-fluorodeoxy-glucose (18F-FDG)-positron emission tomography (PET)/computed tomography (CT) revealed multiple lymph nodes, spleen, and ileocecal lesions. CT revealed an obvious hypervascular tumor involving the duodenum/pancreatic head. The tumor was false-negative on 18F-FDG-PET/CT. On esophagogastroduodenoscopy, the tumor was detected in the descending portion of the duodenum and was observed to be consistent with the submucosal tumor with a central ulcer, resembling those of ulcer-forming DLBCL. A biopsy was then performed carefully, and a clear cell RCC-derived metastatic cancer was diagnosed. Ileocolonoscopy revealed mucosal thickening of the terminal ileum, and led to a diagnosis of DLBCL infiltration with biopsy. To the best of the authors knowledge, this is the first case report of the coexistence of metastatic cancer from RCC and malignant lymphoma in the small intestine simultaneously. It was necessary to make a careful differential diagnosis in the imaging studies.

Observational cohort study of 1st line bevacizumab combined with chemotherapy in metastatic colorectal cancer (HGCSG0802): Sub-group analysis by the GERCOR index.

743 Background: The GERCOR index based on performance status and serum LDH was reported to be useful to predict survival for patients with previously untreated mCRC. However, the validity of the GERCOR index has not been reported in patients treated with bevacizumab (Bev)-based first line chemotherapy. Methods: 115 patients with mCRC treated with Bev contained first line chemotherapy were registered from 15 centers in Japan. Univariate and multivariate analysis for overall survival (OS) were performed using patient characteristics. Survival analyses were performed with the Kaplan-Meier method, log-rank test and the Cox proportional hazards model. The analysis was also designed to determine whether the GERCOR index could be extended to progression-free survival (PFS). Results: All data were available for prognostic categorization in 108 patients. Patients with the GERCOR index of low, intermediate and high risk were 45, 57, and 6, respectively. The pts characteristics between low risk (L) and intermediate/...