Shinya Ashizuka

Effect of adrenomedullin administration on acetic acid-induced colitis in rats.

Adrenomedullin (AM) administered intracolonically ameliorated the severity of acetic acid-induced colonic ulceration in rats. Ulcers were induced by subserosal injection of acetic acid into the colon. AM-treated group was administered 0.25-1.0 microg of AM in 0.5 ml of saline intracolonically once a day; the control group received only saline. AM administration dose-dependently and significantly reduced the size of the ulcerative lesions, the associated edema, and the infiltration of the affected area by inflammatory cells. AM also reduced tissue levels of interleukin-6, but not interferon-gamma. AM reduces the severity of acetic acid-induced colitis in rats, probably by inhibiting the production and/or release of Th-2 cell-derived factors such as interleukin-6.

Adrenomedullin treatment reduces intestinal inflammation and maintains epithelial barrier function in mice administered dextran sulphate sodium.

Hyperactivation and hyperpermeability of the intestinal epithelium is a hallmark of IBD. AM has been shown to reduce the severity of colitis in the acetic acid and TNBS‐induced colitis model, however the mechanism of the therapeutic effect of AM against the colitis has not been clarified. Here, we show that the protective capability of AM is associated with suppression of inflammation and maintenance of the intestinal epithelial barrier function. In the DSS‐induced colitis model, intra‐rectal AM‐treated mice showed a reduction in loss of body weight and severity of colitis. AM‐treatment suppressed phosphorylation of STAT1 and STAT3 in the colonic epithelium, and altered the cytokine balance in the intestinal T cells, with lower levels of IFN‐γ and TNF‐α but higher levels of TGF‐β. Expression of the epithelial intercellular junctions such as tight and adherence junctions were sustained in the AM‐treated mice. In contrast, the epithelial junctions were down‐regulated in the control mice, leading to loss of epithelial barrier integrity and enhanced permeability. Collectively, these data indicate a broad spectrum of AM‐induced effects with respect to protection against DSS‐induced colitis, and suggest a potential therapeutic value of this treatment for IBD.

Adrenomedullin as a Potential Therapeutic Agent for Inflammatory Bowel Disease

Adrenomedullin (AM) was originally isolated from human pheochromocytoma as a biologically active peptide with potent vasodilating action but is now known to exert a wide range of physiological effects, including cardiovascular protection, neovascularization, and apoptosis suppression. A variety of tissues, including the gastrointestinal tract, have been shown to constitutively produce AM. Pro-inflammatory cytokines, such as tumor necrosis factor-α and interleukin-1, and lipopolysaccharides, induce the production and secretion of AM. Conversely, AM induces the downregulation of inflammatory cytokines in cultured cells. Furthermore, AM downregulates inflammatory processes in a variety of different colitis models, including acetic acid-induced colitis and dextran sulfate sodium-induced colitis. AM exerts antiinflammatory and antibacterial effects and stimulates mucosal regeneration for the maintenance of the colonic epithelial barrier. Here, we describe the first use of AM to treat patients with refractory ulcerative colitis. The results strongly suggest that AM has potential as a new therapeutic agent for the treatment of refractory ulcerative colitis.

Adrenomedullin: a novel therapy for intractable ulcerative colitis.

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Leukocytapheresis for Ulcerative Colitis: A Comparative Study of Anticoagulant (Nafamostat Mesilate vs. Dalteparin Sodium) for Reducing Clinical Complications

Abstract:  Leukocytapheresis (LCAP) is a therapeutic strategy for extra corporeal immunomodulation that has been used to treat several immunological disorders, including ulcerative colitis (UC), with encouraging results, inducing remission in steroid‐resistant patients. However, we have experienced some complications during or after LCAP therapy. Common adverse effects include fever, chills, nausea, vomiting, and hypotension. One of the reasons for these adverse effects might be the use of nafamostat mesilate (NM) as an anticoagulant. In the present study, 75 patients with UC were divided into two groups, an NM group and a dalteparin sodium (DS) group. The clinical efficacy of these treatments, improvement after treatment, changes in leukocyte differential count, and adverse effects after LCAP therapy were then compared. The clinical efficacy, improvement after treatment, and changes in leukocyte classification were not significantly different between the two groups, while some adverse effects were observed in the NM group but not in the DS group. In conclusion, LCAP therapy is a useful therapy for patients with moderate to severe UC who fail to respond to glucocorticoid therapy, however, a safe anticoagulant should be used to avoid its related adverse effects.

Sa1895 The First Clinical Pilot Study of Adrenomedullin Therapy in Refractory Ulcerative Colitis: the Initial Six Cases

were analyzed. 68.4% of the CD patients received infliximab, 31.6% adalimumab. 21.1% of the CD patients received previous episodic/continuous biological therapy. Extraintestinal manifestations were present in 54.5% of the patients. Concomitant immunosuppressions at induction therapy were steroids in 62% and azathioprine in 81.8% of patients. Medical records were captured prospectively; data of the CD and UC groups were analyzed separately. Results: 78.5% of the patients were in remission after a one-year treatment period. Dose intensification was needed in 13.8% of CD and in 11.4% of UC patients. Biological therapy had to be restarted because of clinical flare after remission in 45.9% of CD patients and in 28.6% of UC patients after a median of 8 months. 41.1% of these IBD patients with restarted biologics were in remission at the end of the second year. In a logistic regression analysis corticosteroid use at induction (p=0.034, OR: 1.58, 95% CI: 1.04-2.41), previous anti-TNFα therapy (p=0.03, OR: 2.84, 95% CI: 1.11-7.30) and dose intensification (p=0.008, OR: 6.25, 95% CI: 1.62-24.2) were associated with the need for restarting biological therapy in CD. Numerically, need for restarting of biological therapy was more common in men, in smokers and in patients who underwent appendectomy. None of the examined factors were associated to the need for restarting biological therapy in UC. Discussion. Biological therapy had to be restarted in almost half of the CD patients after the discontinuation within a median of 8 months after the discontinuation, despite being in remission at one-year. Steroid use, previous biological therapy and dose intensification but not CRP was identified as predictors for the need for restarting biological therapy.

Meckel diverticulum diagnosed by double-balloon enteroscopy and treated laparoscopically: case report and review of the literature.

Meckel diverticulum is one of the causes of gastrointestinal bleeding; however, preoperative conclusive diagnosis is very difficult even with the use of various radiologic modalities. The development of double-balloon enteroscopy enables us to diagnose various bleeding source, including Meckel diverticulum, in the small intestine. We herein report a case of bleeding Meckel diverticulum, diagnosed by double-balloon enteroscopy and treated successfully by laparoscopic surgery, and review of the literature.

Effect of a concomitant elemental diet with maintenance anti-tumor necrosis factor-α antibody therapy in patients with Crohn's disease: A multicenter, prospective cohort study: Elemental diet during biologics therapy

The aim of this study was to clarify the additional effect of a concomitant elemental diet (ED) for patients with Crohns disease on maintenance anti‐tumor necrosis factor‐α antibody (anti‐TNF).

Capsule endoscopy findings for the diagnosis of Crohn’s disease: a nationwide case–control study

BackgroundCapsule endoscopy can be used to identify the early stage of small bowel Crohn’s disease (CD). We evaluated significant small bowel capsule endoscopy (SBCE) findings that can lead to early diagnosis of CD.MethodsWe retrospectively accumulated clinical and SBCE data of 108 patients (63 with and 45 without CD). Types of small bowel mucosal injuries, including erosion, ulceration, and cobblestone appearance, and the alignment of diminutive lesions were compared between patients with and without CD. Inter- and intra-observer agreement in the determination of lesions was assessed in 25 pairs of SBCE from the two groups.ResultsUnder SBCE, cobblestone appearance (33% vs. 2%, p < 0.0001), longitudinal ulcers (78% vs. 20%, p < 0.0001), and irregular ulcers (84% vs. 60%, p < 0.01) were more frequently found in patients with CD. Linear erosion (90% vs. 38%, p < 0.0001) and irregular erosion (89% vs. 64%, p < 0.005) were also more frequent in patients with CD. Furthermore, circumferential (75% vs. 9%, p < 0.0001) and longitudinal (56% vs. 7%, p < 0.0001) alignment of diminutive lesions, mainly observed in the 1st tertile of the small bowel, was more frequent in patients with CD. Good intra-observer agreement was found for ulcers, cobblestone appearance, and lesion alignment. However, inter-observer agreement of SBCE findings differed among observers.ConclusionsCircumferential or longitudinal alignment of diminutive lesions, especially in the upper small bowel, may be a diagnostic clue for CD under SBCE, while inter-observer variations should be cautiously considered when using SBCE.

Rendezvous biliary recanalization with combined percutaneous transhepatic cholangioscopy and double-balloon endoscopy

Despite advances in biliary stenting in patients with altered gastrointestinal anatomy, it is still a challenging procedure [1]. We present a case where percutaneous transhepatic cholangioscopy (PTCS) was combined with double-balloon endoscopy (DBE) for biliary stenting in a patient with complete obstruction of a choledochojejunostomy. A 71-year-old woman, who had a history of distal cholangiocarcinoma and had undergone pancreaticoduodenectomy 7 years previously, experienced recurrent cholangitis. DBE-assisted balloon dilation had been performed 7 months previously for stricture of the choledochojejunal anastomosis. However, she developed complete obstruction of the anastomosis (▶Fig. 1). A 7.2-Fr percutaneous transhepatic biliary drainage (PTBD) catheter was initially placed, and the fistula tract was dilated up to 12Fr within 4 weeks. DBE-assisted endoscopic retrograde cholangiopancreatography was then attempted. First, the double-balloon endoscope (EI-580BT; Fujifilm, Tokyo, Japan) was advanced to the afferent limb, and a percutaneous transhepatic cholangiogram revealed complete obstruction of the anastomosis. Next, a PTCS scope (BF type P260F; Olympus, Tokyo, Japan) was inserted via the PTBD route. However, a guidewire (0.018-inch, Pathfinder Exchange; Boston Scientific Japan, Tokyo, Japan) through the PTCS scope could not pass the anastomosis (▶Video1). Therefore, we attempted direct precutting (KD-V451M; Olympus) at the anastomosis, using the double-balloon endoscope and guided by transillumination from the percutaneous transhepatic cholangioscope’ (▶Fig. 2, ▶Video1). A small incision was carefully made in order to create a fistula (▶Fig. 3). This was followed by successful passage of the guidewire (0.032-inch, Radifocus Guidewire M; Terumo, Tokyo, Japan) Video 1 Biliary recanalization, using a rendezvous technique with combined percutaneous transhepatic cholangioscopy and double-balloon endoscopy, for a completely obstructed choledochojejunostomy. ▶ Fig. 1 Percutaneous transhepatic cholangiogram showing complete obstruction of the choledochojejunal anastomosis in a patient who had undergone pancreaticoduodenectomy 7 years previously. ▶ Fig. 2 Left panel: The choledochojejunal anastomosis has an appearance similar to an ulcer scar. Right panel: Transillumination from the percutaneous transhepatic cholangioscope guides direct precutting using the double-balloon endoscope. E-Videos