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Background To provide updates on clinical practice of acute pancreatitis (AP) in Japan, we conducted a nationwide epidemiological survey. Methods This study consisted of a two-staged survey; the number of AP patients was estimated by the first-stage survey and their clinical features were examined by the second-stage survey. We surveyed AP patients who had visited hospitals in 2016. Results The estimated number of AP patients in 2016 was 78,450, with an overall incidence of 61.8 per 100,000 persons. We obtained detailed clinical information of 2994 AP patients, including 706 (23.6%) severe cases classified according to the Japanese severity criteria. The male-to-female sex ratio was 2.0, and the mean age at onset was 59.9 years in males and 66.5 years in females. Alcohol was the most common etiology (42.8%) in males and gallstones in females (37.7%). The AP-associated mortality was 6.1% in severe AP cases, which was decreased by 40% compared to the 2011 survey. Antibiotics were administered to most cases, with carbapenem being frequently used. Enteral nutrition was given in 31.8% of severe cases, but majority cases received after 48 h. Among the 107 patients who received intervention for walled-off necrosis, five patients received surgery-first approach, 66 received endoscopic ultrasound-guided transluminal drainage, and 19 underwent step-up approach. Conclusions We clarified the current status of AP in Japan including the significant reduction of mortality in severe cases, shift to endoscopic approaches for walled-off necrosis, and poor compliance of the recommendations in the guidelines including management of enteral nutrition and antibiotic administration.

Background Gemcitabine plus nab-paclitaxel (GnP) has been a standard treatment for unresectable pancreatic cancer (uPC); however, the current treatment status and usefulness in older adults with uPC remain unclear. Therefore, we aimed to investigate the patient background and compare the efficacy and safety of GnP versus other treatments in older adults with uPC. Patients and Methods In this prospective observational study, we enrolled 233 eligible patients aged ≥76 years with pathologically proven, clinically uPC, and no history of chemotherapy from 55 Japanese centers during September 2018-September 2019. The main endpoints were overall survival (OS), progression-free survival (PFS), and safety. Geriatric assessments were performed upon registration and after 3 months. To adjust for confounders, we conducted propensity score-matched analyses. Results GnP, gemcitabine alone (Gem), best supportive care, and other therapies were administered to 116, 72, 16, and 29 patients, respectively. In the propensity score-matched analysis, 42 patients each were selected from the GnP and Gem groups. The median OS was longer in the GnP group than in the Gem group (12.2 vs. 9.4 months; hazard ratio [HR], 0.65; 95% CI, 0.37-1.13). The median PFS was significantly longer in the GnP group than in the Gem group (9.2 vs. 3.7 months; HR, 0.38; 95% CI, 0.23-0.64). The incidence of severe adverse events was higher with GnP than with Gem; however, the difference was not significant. Conclusion GnP is more efficacious than Gem in patients aged ≥76 years with uPC despite demonstrating a higher incidence of severe adverse events.

Enzymatic biofuel cells (BFCs) directly convert the chemical energy produced by oxidizing fuel into electricity using enzymes as electrocatalysts. However, these cells are characterized by low output and poor long-term durability, which highlights the need for further performance improvement, especially on the cathode side. Herein, we clarify the effect of the pore size and surface morphology of MgO-templated carbon (MgOC) as an electrode material on the amount of electrochemically active bilirubin oxidase (BOD) available on the cathode. This enzyme is widely used as an electrocatalyst for the four-electron cathodic reduction of oxygen. The amount of electrochemically active enzyme can be increased by using an electrode of larger pore size and by increasing the incubation time for enzyme adsorption. However, excess enzyme prevents the mass transfer of O2 to the enzyme adsorbed on the electrode surface. The MgOC surface was electrochemically modified using several substituted aromatic amines to enhance the interaction between the active sites on BOD and the electrode. Our results showed that the use of 6-amino-2-naphthoic acid as the promoter increased the interfacial electron transfer rate between BOD and the carbon surface and enhanced the stability.

The deployment of hybrid wide-area OpenFlow networks is essential for the gradual integration of OpenFlow technology into existing wide-area networks. Integration is necessary because it is impractical to replace such wide-area networks with OpenFlow-enabled ones at once. On the other hand, the design, deployment, and operation of such hybrid OpenFlow networks are often conducted intuitively without in-depth technical considerations. In this paper, we systematically discuss the technical aspects of the hybrid architecture for OpenFlow networks based on our experience so far in developing wide-area hybrid OpenFlow networks on JGN2plus and JGN-X, which are nation-wide testbed networks in Japan. We also describe the design and operation of RISE (Research Infrastructure for large-Scale network Experiments) on JGN-X, whose objective is to support a variety of OpenFlow network experiments. key words: OpenFlow, NWGN, testbed networks, operation

We propose a flexible and scalable architecture for a network controller platform used for OpenFlow. The OpenFlow technology was proposed as a means for researchers, network service creators, and others to easily design, test, and virtually deploy their innovative ideas in a large network infrastructure, which will accelerate research activities on Future Internet architectures. The technology enables the independent evolution of the network control plane and the data plane. Rather than having programmability within each network node, the separated OpenFlow controller provides network control through pluggable software. Our proposed network controller architecture will enable researchers to use their own software to control their own virtual networks. Flexibility and scalability were achieved by designing the network controller as a modularized and distributed system on a cluster of servers. Testing showed that a group of servers can efficiently cooperate to serve as a scalable OpenFlow controller. Testing using the nationwide JGN2plus network demonstrated that high-definition video can be delivered through OpenFlow-based point-to-point and point-to-multipoint paths.

症例は35歳日本人女性，海外渡航歴が多く，複数の外国人との交際歴がある．著明な肝機能障害にて入院．血液検査にてB型急性肝炎と診断した．その後，第10病日にgenotype Eであることが判明した．肝炎は遷延化し，第18病日にエンテカビルの投与を開始した．その後，改善傾向を認め，約半年でHBs抗原は陰性化，HBs抗体陽性，HBV DNA感度以下となった．今回本邦では臨床報告の稀なgenotype EによるB型急性肝炎を経験したので報告する．

Interstitial cells of Cajal (ICC) play important roles in autonomic gut motility as electrical pacemakers and mediators of neural regulation of smooth muscle functions. Insufficiency of ICC has been reported in a wide range of gut dysmotilities. Thus, restoration of ICC may be a therapeutic modality in these diseases. Here we provide evidence that transplanted bone marrow (BM) cells can restore gut dysmotility in part via transdifferentiation to ICC. Bone marrow cells obtained from Kit insufficient W/W v mice or syngeneic GFP-transgenic mice with wild-type Kit were transferred to W/W v recipients. Whole gut transit time and gastric emptying were examined 5 and 6 weeks after BM transplantation, respectively, and ICCs were identified in whole mounts, frozen sections and transmission electron immunomicroscopy of the gut smooth muscle layers using specific antibodies. Transplantation of wild-type BM into W/W v mice significantly improved whole gut transit time and gastric emptying. Fluorescent immunohistochemistry revealed GFP+Kit+ cells in the myenteric plexus, deep muscular plexus, and submucosal plexus smooth muscle layers of the stomach, small intestine, and colon, respectively. In the whole mounts, GFP+Kit+ cells were bipolar and spindle shaped, and transmission electron immunomicroscopy showed GFP+ cells rich in mitochondria and endoplasmic reticulum between gut smooth muscle layers, suggesting the presence of GFP+ cells with morphological characteristics of ICC. These results suggest that BM contains cells that may incorporate into ICC networks and improve dysmotility in W/W v mice. Thus, BM transplantation may become to a new therapeutic modality for gut dysmotilities due to ICC insufficiency.

Background: The involvement of bone marrow (BM) in tumor-stroma reactions or tumor development has not been examined in a cancer allograft, which has otherwise been appropriate for assessing therapeutic modalities. We investigated the fate of BM-derived cells in colon cancer allografts and liver metastases in mice. Methods: C57BL/6 mice were irradiated and rescued by BM transplantation from green fluorescent protein (GFP)-transgenic mice. MC38 colon cancer cells were stably transfected with the pDsRed gene in order to identify tumor cells by fluorescence. These were inoculated into the mice to generate subcutaneous allografted tumors or liver metastases. The tumors were observed under confocal microscopy and fluorescent immunohistochemistry to determine the fate of tumor versus BM-derived cells. Results: GFP-positive (GFP+) cells were consistently identified as vimentin+, α-smooth muscle actin (αSMA)+, spindle-shaped stromal cells in both the subcutaneous tumors and the liver metastases. GFP+ cells of leukocyte lineage also infiltrated the tumors. Neither GFP+ CD31+ endothelial cells nor GFP+ DsRed+ cells were detected in the tumor. Conclusions: BM-derived cells frequently and consistently infiltrated the tumor allografts and metastases as interstitial cells and leukocytes. Cells derived from the fusion of BM cells and tumor cells were not observed. This model may be appropriate for the clarification of the effects of anticancer therapies and the study of BM-derived cells in tumor–host interactions.

Bone-marrow-derived cells (BMDCs) transdifferentiate into various types of gastrointestinal cells. The precise transdifferentiation of BMDCs in gut regeneration, however, is controversial. In this study, we examined the transdifferentiation of BMDCs in the regeneration of damaged colonic epithelia. Lethally irradiated wild-type female mice (C57BL/6) were rescued by bone marrow transplantation from male green fluorescent protein transgenic mouse donors. Chronic colitis was induced by administering 3% dextran sulfate sodium (DSS) in the drinking water for 5 days on day 28 after the bone marrow transplantation. The mice were killed on day 25 after DSS administration. BMDC phenotypes were examined by confocal microscopy and fluorescence immunohistochemistry. BMDCs were frequently observed in the vimentin-positive colonic interstitial cells, which also expressed α-smooth muscle actin and had a spindle-like morphology, but did not express leukocyte common antigen. Green-fluorescent-protein-positive cells were rarely or less frequently found in Ki-67-positive proliferating cells, cytokeratin-positive epithelial cells, or CD31-positive endothelial cells. BMDCs frequently transdifferentiated into subepithelial myofibroblasts and fibroblasts, and often continued to reside in the colonic subepithelia after the experimental colitis had healed. In conclusion, our data indicate the fate of BMDCs, which might be involved in the healing process of the colon after DSS-induced colitis. Our data show that BMDCs contribute to colonic interstitial cells after the colitis has healed. Understanding the fate of BMDCs may be important for stem cell therapy by BMDCs.

Cyclooxygenase-2 (COX-2) inhibitors are effective chemopreventive agents against colorectal cancers. For treatment of advanced cancers, combination of COX-2 inhibitors and chemotherapy has been attempted, but the results are still controversial. In the present study, the effects of the COX-2 inhibitor celecoxib on the anticancer potential of chemotherapy, and its mechanisms of action were investigated in point of the angiogenesis, using an advanced cancer model in mice. BALB/c mice were inoculated with colon 26 cells. After the allograft grew up to 5 mm in diameter, the animals received celecoxib, 5FU, or a combination of 5FU and celecoxib (5FU/celecoxib). After 21-days of the treatment, 5FU/celecoxib significantly inhibited the tumor growth and the tumor vessel density compared with the other groups. Celecoxib, 5FU or 5FU/celecoxib significantly suppressed the VEGF content in tumor tissues. 5FU/celecoxib also enhanced IFN-γ levels in tumor tissue, which could be involved in the potent antitumor effects of 5FU/celecoxib. This hypothesis was proven, because in IFN-γ knockout (IFN-γ−/−) mice, the inhibitory effects of 5FU/celecoxib on angiogenesis and tumor growth were significantly impaired compared with that in wild type mice. These results suggest that celecoxib enhances the antitumor effect of 5FU against an advanced colon cancer model by suppressing angiogenesis. In addition to VEGF, IFN-γ has pivotal roles in tumor suppression induced by celecoxib. © 2007 Wiley-Liss, Inc.

The deployment of wide-area OpenFlow networks is essential for the global research community. Since 2011, we started to operat our wide-area OpenFlow networks as a RISE OpenFlow testbed for researchers and developpers. Through our operation, we got some issues. Especially, we focused on the issue caused by topology between sites. By this issue, we cannot assign user's OpenFlow Switches freely. Also, it may give some constraints to user's experiments. To solve this issue, we design and discuss topology management system called “RISE3.0” using OpenFlow.

To accommodate a wide variety of application services, the network virtualization environment (NVE) has received much attention. In an NVE, infrastructure providers (InPs) provide service providers (SPs) with virtual networks (VNs) using the InPs' substrate resources for the SPs' application services. Service providers have flexible requirements of topology, quality of service (QoS), and their dynamic changes on VNs. To meet all these requirements, traditional approaches based on performance guarantee relying only on InPs are inefficient and sometimes infeasible because they result in significant operational cost. We propose an architecture in which SPs can select appropriate resources from available resources and dynamically use the allocated resources depending on their application characteristics and user situations to meet their demands. In the proposed architecture, SPs can improve VN performance through resource control, and InPs are not required to have any performance guaranteed networks. Therefore, the proposed architecture can balance QoS and resource efficiency. We also present the basic design of the proposed architecture and show use cases and a prototype implementation using OpenFlow technologies.

The deployment of wide-area OpenFlow networks is essential for the global research community. Although OpenFlow's first target was campus network, we cannot ignore its wide-area deployment, especially from the perspective of Future Internet (FI) R&D. In this paper, we propose design and implementation of the “Extended RISE controller”(eRISE). The eRISE is a modified version of RISE controller which is OpenFlow controller for our OpenFlow testbed network “RISE”(Research Infrastructure for large-Scale network Experiments). Also, we discuss “Interdomain” function for OpenFlow testbed. Finally, we discuss about current issues and future works.

The approach of deploying hybrid wide-area Open-Flow networks is essentially important for gradual deployment of the OpenFlow technology into existing wide-area networks because it is impractical to replace such wide-area networks with OpenFlow-enabled ones at once. On the other hand, the design, deployment, and operation of such hybrid OpenFlow networks are often conducted intuitively without in-depth technical considerations. In this paper, we discuss systematically the technical and architectural aspects of hybrid OpenFlow networks based on the experiences obtained so far in the development of our wide-area hybrid OpenFlow networks on JGN2plus/JGN-X, which is nation-wide network testbed in Japan. We also describe the design and operation of RISE (Research Infrastructure for large-Scale network Experiments) on JGN-X, whose objective is to support a variety of OpenFlow network experiments.

The Internet architecture has been reconsidered along with newly emerging diverse Internet applications, and cooperation between applications and networks becomes desired. Inherently, an application service provider concentrates on serving its own application with the high performance while an infrastructure service provider needs to consider an efficient and fair use of its physical resources to simultaneously support different applications. We propose an architecture that coordinates requirements of both types of providers based on network virtualization technologies in general and Open Flow framework in particular. In our architecture, an application service provider can easily construct a virtual network for its application service, while an infrastructure provider can achieve an efficient use of physical resource adaptively within the restriction to maintain a required performance of supporting virtual networks.

An 83-year-old man was admitted with renal dysfunction, anemia, and peripheral leukocytosis. His peripheral leukocyte count was 41000/µl. A computed tomography scan revealed a solid cystic mass in the liver, mural thickening in the ascending colon and nodules in the right lower lung field. Colonoscopy revealed ascending colon cancer, and analysis of the biopsy specimens revealed well-differentiated adenocarcinoma. However, although a liver abscess was suspected, pus and bacteria were not found in the cystic lesion of the liver mass, the solid lesion of the mass was diagnosed as carcinoma. The serum concentration of granulocyte colony-stimulating factor (G-CSF) was elevated to 256 pg/ml. Because his general condition worsened, we could not treat these tumors, but he died 38 days after admission. Autopsy revealed adenosquamous carcinoma of the liver, well-differentiated adenocarcinoma of the ascending colon, urothelial carcinoma of the urinary bladder, and metastatic squamous cell carcinoma of the lung. Immunohistochemical analysis revealed positive staining for G-CSF in the liver tumor sample.

In this paper, we present an introduction to our architecture for a virtualized network infrastructure and explain its enabling technologies including OpenFlow and Network OS for integrated control plane. To enable easy innovation within network research area, infrastructure virtualization to share a physical infrastructure among researchers and an idea of having programmability in control plane have been paid much attention. For example, OpenFlow defines atomic behaviors for packet handing within each switching element and a protocol interface to manipulate such behaviors from a control server, thus users can program their own network behaviors by injecting their own control programs into the server. In the same way, other protocols may be combined for optical and wireless nodes, or for network measurement. In addition to network control, other components in an infrastructure, such as virtual machines or data storage, would be controllable in the same way. Therefore, by integrating such control interfaces and creating integrated control plane, we propose a basic idea for virtualized infrastructure on which infrastructure creators have their own virtual infrastructure instance coupled with their own control programs on their virtualized control plane. Since on the control plane, a variety of control programs of many creators are installed to control a variety of infrastructure components, and they sometimes cooperates for mashing-up, or are sometimes isolated for virtualization, the role of a platform software of the control plane can be complex but very important. In this paper, we propose a network OS as a platform for such integrated control plane. It can be regarded as an OpenFlow controller but is extended to control entire infrastructure including OpenFlow switches and other IT and network resources. We develop a service model associated with its data structure and control module, and a model to construct a virtual infrastructure by defining the connections among the services. Then, we briefly explain our research projects developed on the network OS.

Abrogating tolerance against unidentified antigens is a critical step in the pathogenesis of ulcerative colitis (UC). T cell anergy, one of the main mechanisms of tolerance, has been shown to be induced by E3 ubiquitin ligases, such as gene related to anergy in lymphocytes (GRAIL), Itch, and c-Cbl in mice. However, it is not well known whether these E3 ligases play roles in human diseases. The pathophysiological role of the E3 ligases in patients with UC was investigated. At first, the expression of GRAIL, Itch, and c-Cbl in human anergic T cells was analyzed by quantitative RT-PCR and Western immunoblotting. Next, the mRNA expression of the E3 ligases was analyzed in peripheral CD4+T cells of 20 patients with UC and 10 healthy volunteers (HV). mRNA expression was analyzed in patients with active UC before and after treatment with prednisolone and leukocytapheresis. Anergic human CD4+T cells expressed significantly higher levels of GRAIL, Itch, and c-Cbl than nonanergic cells. GRAIL expression was significantly higher in patients with UC in remission than in patients with active disease and in HV ( P < 0.01). The level of GRAIL expression was also significantly increased in patients with active disease whose clinical activity index scores improved after treatment ( P < 0.05). There were no significant differences in Itch and c-Cbl expression among patients with active UC, patients with UC in remission, and HV. These data suggest that GRAIL plays an important role in maintaining remission in patients with UC.

Mesenchymal stem cells (MSCs) are attractive cell sources in regenerative medicine. We examined the effects of topical MSCs implantation on an experimental model of inflammatory bowel disease. Putative MSCs, isolated from bone marrow aspirates of male rats by dish adherence and expanded in vitro, were characterized by flow cytometry, reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, and differentiation assays. Experimental colitis was induced by intraluminal instillation of 2,4,6-trinitrobonzene sulfonic acid (TNBS) in the colons of male rats. The putative MSCs and unselected fresh bone marrow cells were injected into the colonic submucosa surrounding the area exposed to TNBS. The healing process of the injury was examined macroscopically and immunohistologically. Multipotent MSCs positive for CD29 and CD90, and negative for CD31 and CD34, were implanted into colon tissue surrounding the lesion; a majority of the engrafted cells were positive for vimentin. The implantation significantly accelerated healing of the damaged mucosa compared with vehicle-injected controls. The MSCs expressed vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-beta1 in vitro and after the implantation. In conclusion, we found that MSCs were successfully topically implanted in the colon and that they were associated with accelerated healing of TNBS-induced colitis. The beneficial effects of the MSCs might be mediated, at least in part, by their ability to differentiate into colonic interstitial cells and by their ability to provide VEGF and TGF-beta1 to the injured area.

Mesenchymal stem cells (MSCs), a subpopulation of adult somatic stem cells, are an attractive stem cell source in regenerative medicine because of their multipotentiality. We examined the effects of MSC transplantation on gastric ulcer healing. Putative MSCs, isolated from bone marrow aspirates of male rats by dish adherence and expanded in culture, were characterized by flow cytometry and reverse transcription-polymerase chain reaction. Gastric ulcers were induced by serosal application of acetic acid on the anterior wall of the stomach in female rats. Either MSCs (labeled with PKH67; 1×107 cells) or vehicle was injected into the gastric wall surrounding the ulcer. The healing process of the ulcer and the influence of anti-vascular endothelial growth factor (VEGF) antibody were examined. CD29-positive, CD90-positive, CD34-negative, and CD45-negative MSCs expressed mRNAs for VEGF and hepatocyte growth factor (HGF). The MSCs were transplantable to the gastric tissue surrounding the ulcer, where a majority of the engrafted cells were positive for vimentin. The transplantation significantly accelerated gastric ulcer healing compared with controls. The engrafted MSCs also expressed VEGF and HGF. Administration of anti-VEGF neutralizing antibody dose dependently reduced the MSC-induced promotion of ulcer healing. In conclusion, MSC transplantation accelerated gastric ulcer healing, possibly through the induction of angiogenesis in the gastric mucosa via the secretion of VEGF. The beneficial effects of MSCs might be mediated not only by their differentiation into gastric interstitial cells, but also by their ability to supply angiogenic factors.

Patients with inflammatory bowel disease (IBD) share several immunologic similarities with rheumatoid arthritis (RA). Patients with RA have significantly increased levels of serum agalactosyl immunoglobulin G (IgG). Our aim was to investigate the clinical significance of analyzing the oligosaccharide structure of serum IgG in patients with IBD.Serum IgG oligosaccharide structures were analyzed using high-performance liquid chromatography in 60 patients with Crohn's disease (CD), 58 patients with ulcerative colitis (UC), 27 healthy volunteers (HV), and 15 disease controls (DC). The activity and mRNA level of beta-1,4-galactosyltransferase (Beta4GalT) in antibody-secreting cells were investigated in these subjects.The agalactosyl fraction of the fucosylated IgG oligosaccharides (G0F/G2F) in CD and UC was significantly greater than that in HV and DC (P0.001). The percentage of subjects with a high G0F/G2F in CD, UC, HV, and DC was 72%, 33%, 0%, and 0%, respectively. G0F/G2F, which is significantly correlated with disease severity in both CD and UC, had higher sensitivity to diagnose IBD compared with anti-Saccharomyces cerevisiae antibody. Moreover, G0F/G2F was significantly correlated with the prognosis of UC patients: patients with a high G0F/G2F did not maintain long-term remission. The activity and mRNA level of Beta4GalT were significantly elevated in UC but not in CD.G0F/G2F is a potentially effective diagnostic marker of disease activity in both CD and UC, and of the clinical course in UC. A pathophysiologic difference between CD and UC was also demonstrated.

The therapeutic potential of bone marrow (BM)-derived cells in ulcers is not known. This study aimed to clarify (1) cell types that are derived from the BM which infiltrate ulcers; (2) whether BM-derived cells or gastric myofibroblasts can be used for cell transplantation to treat ulcers; and (3) the phenotypes of such transplantable cells.(1) Wild-type mice were transplanted with BM cells of green fluorescent protein (GFP)-transgenic mice. Acetic acid-induced gastric ulcers were produced in mice after BM transplantation. (2) BM cells and gastric myofibroblasts were isolated from GFP-transgenic mice. Bone marrow cells attached to plastic dishes were selected for expansion. Gastric ulcers were induced, and BM-derived cells, myofibroblasts, or phosphate-buffered saline were injected around ulcers. The ulcer healing process was examined macroscopically and histologically. (3) Expression of growth factors and cytokines in transplantable cells was examined by reverse transcriptase-polymerase chain reaction.(1) GFP-positive cells with interstitial phenotypes were observed at the ulcerated area. (2) Ulcer healing was significantly promoted by the injection of BM-derived cells compared to controls on day 7, but not on day 3. The BM-derived cells were observed in the tissue surrounding the ulcer. However, myofibroblasts were not found. (3) The BM-derived cells expressed hepatocyte growth factor, transforming growth factor-beta(1), and other stromal factors before transplantation, and had mesenchymal phenotypes after transplantation.BM-derived cells are involved in the ulcer healing. BM-derived cells, but not myofibroblasts, are locally implantable to ulcers. Thus, BM-derived cells can be transplanted to accelerate ulcer healing.

Background and aims: Immunoglobulin (Ig) G carries N-linked oligosaccharides at the Cgamma2 domain.We have reported that agalactosyl fraction in the fucosylated IgG oligosaccharides was increased in inflammatory bowel disease (IBD) and that agalactosyl IgG is an effective serological marker in IBD, especially in Crohns disease (CD) (Am J Gastroenterol. 2008). The mRNA level and activity of beta-1,4-galactosyltransferase I (Beta4GalT I), which is indispensable for attaching galactose to IgG oligosaccharides, were significantly lower in B cells and plasma cells of patients with CD than in those of ulcerative colitis patients. To clarify the pathophysiology of agalactosyl IgG elevation in IBD, we investigated the role of oligosaccharide alterations in colitis by using Beta4GalT I deficient mice. Methods: Beta4GalT I hetero-type mice (HT) and littermate wild-type mice (WT) were used because Beta4GalT I null mice were semi-lethal and Beta4GalT I activity in HT was reported to be half in WT. Both HT and WT were administered with 3% dextran sodium sulfate (DSS; MW 3500050000) ad libitum for 7 days. Solution was replaced to normal water for 3 days and mice were sacrificed at day 10. The severity of colitis was evaluated by the colon length, the body weight loss and the histological examination. CD4+, CD11b+ and CD19+ cells were separated from mononuclear cells from the spleen, mesenteric lymph nodes and lamina propria by MACS system. Cytokine productions in the culture supernatants of these cells were measured by ELISA. Results: Agalactosyl oligosaccharide structures of serum IgG were increased in Beta4GalT I HT compared to WT littermates and the IgG oligosaccharides in HT showed similar pattern as CD patients in terms of agalactosylation. When DSS colitis was induced in HT and WT, HT showed significantly less shortening in the colon length and less body weight loss than WT. Furthermore, histological score was significantly lower in HT than in WT. Thus, DSS-induced colitis was significantly ameliorated in HT compared to WT. Production of IL-10 in splenocytes of HT, especially in CD11b+ macrophages, was increased compared to that in WT. IgG oligosaccharide structures were not altered by DSS administration. Conclusions: Decrease in Beta4GalT I activity ameliorated murine DSS colitis. Agalactosyl IgG might not be the cause of colitis and is suggested to play a protective role for the colonic inflammation.

of MT and Trp. Furthermore, treatment with MT and Trp suppressed the expression of mRNAs for proinflammatory cytokines in ulcer area, but failed to affect the expression of HIF-1α and VEGF. Conclusions: MT promotes ulcer healing. This effect is mediated by suppression of proinflammatory cytokines and release of gastrin and PGE2 , the most potent stimulants of gastric mucosal cell proliferation and mucosal repair. Ulcer healing effects of MT can be interfered by the inhibition of MT2R and COX-2-PG or NOS-NO system.

Background and Aims Insufficient tolerance against luminal antigens is suggested to cause inflammatory bowel diseases including ulcerative colitis (UC). T cell anergy is one of the mechanisms regulating immune tolerance. Recently, some E3 ubiquitin ligases are reported to downregulate downstream signals of T cell receptor and induce T cell anergy. The aim of this study was to investigate the state of T cell anergy in healthy subjects and UC patients by quantitating the expression of E3 ubiquitin ligases, GRAIL, c-Cbl, Itch, all of which are reported to induce anergy on T cells. Patients and Methods Peripheral mononuclear cells were obtained from 20 UC patients (active UC: 12, UC in remission: 8) and 10 healthy volunteers (HV) by either centrifugal leukocytapheresis or sampling of peripheral blood. CD4+ T cells were isolated by magnetic cell sorter and expressions of GRAIL, c-Cbl, and Itch mRNA in these cells were measured by real-time quantitative RT-PCR. The level of GRAIL, c-Cbl, and Itch mRNA expression were compared between in active UC patients, UC patients in remission, and HV. The expression of these ubiquitin ligases were followed in 6 active UC patients who were treated by corticosteroid and centrifugal leukocytapheresis. Results Anergic CD4+ T cells obtained by ionomycin treatment In Vitro revealed higher GRAIL, c-Cbl, and Itch expression when compared with non-anergic T cells. GRAIL was predominantly expressed on CD4+ T cells whereas c-Cbl and Itch were also expressed on non-CD4+ T cell subsets. The GRAIL expression in CD4+ T cells of UC patients in remission was significantly higher than that of active UC patients or that of HV (p

sensitive clinical isolate, NCTC 10418) into the volar aspect of subject forearms. The ensuing local inflammatory response was measured daily for 72 hours, as increases in local blood flow by laser Doppler imaging (MoorLDI®, Moor Instruments). Blood samples from each time-point were assayed for acute phase reactants (CBC, CRP, ESR and serum albumin). The responses of 19 patients (6 F) with quiescent UC (4 colectomies), and 14 HC (8 F) were compared. Patients were either on no medication (n=8) or mesalazine alone (≤ 2.4g/ day). Results: Blood flow following E. coli challenge was maximal in all subjects at 24 hours, returning to baseline by 72 hours in HC. Blood flow at 48 (p=0.014) and 72 (p=0.035) hours, and neutrophil counts (p