Yoshiaki Ebisawa

Colonic Vascular Conductance Increased by Daikenchuto via Calcitonin Gene-Related Peptide and Receptor-Activity Modifying Protein 1

BACKGROUND Daikencyuto (DKT) is a traditional Japanese medicine (Kampo) and is a mixture of extract powders from dried Japanese pepper, processed ginger, ginseng radix, and maltose powder and has been used as the treatment of paralytic ileus. DKT may increase gastrointestinal motility by an up-regulation of the calcitonin gene-related peptide (CGRP). CGRP is also the most powerful vasoactive substance. In the present study, we investigated whether DKT has any effect on the colonic blood flow in rats. MATERIALS AND METHODS Experiments were performed on fasted anesthetized and artificially ventilated Wistar rats. Systemic mean arterial blood pressure and heart rate were recorded. Red blood cell flux in colonic blood flow was measured using noncontact laser tissue blood flowmetry, and colonic vascular conductance (CVC) was calculated as the ratio of flux to mean arterial blood pressure. We examined four key physiological mechanisms underlying the response using blocker drugs: CGRP1 receptor blocker (CGRP(8-37)), nitric oxide synthase inhibitor, vasoactive intestinal polypeptide (VIP) receptor blocker ([4-Cl-DPhe6, Leu17]-VIP), and substance P receptor blocker (spantide). Reverse transcription-polymerase chain reaction was used for the detection of mRNA of calcitonin receptor-like receptor, receptor-activity modifying protein 1, the component of CGRP 1 receptor and CGRP. After laparotomy, a cannula was inserted into the proximal colon to administer the DKT and to measure CVC at the distal colon. RESULTS Intracolonal administration of DKT (10, 100, and 300 mg/kg) increased CVC (basal CVC, 0.10 mL/mmHg) from the first 15-min observation period (0.14, 0.17, and 0.17 mL/mmHg, respectively) and with peak response at either 45 min (0.17 mL/mmHg by 10 mg/kg), or 75 and 60 min (0.23 and 0.21 mL/mmHg by 100 and 300 mg/kg, respectively). CGRP(8-37) completely abolished the DKT-induced hyperemia, whereas nitric oxide synthase inhibitor partially attenuated the DKT-induced hyperemia. [4-Cl-DPhe6, Leu17]-VIP and spantide did not affect the hyperemia. Japanese pepper significantly increased CVC at 45 min or later, whereas ginseng radix only showed a significant increase at 15 min. Reverse transcription-polymerase chain reaction showed that mRNA for calcitonin receptor-like receptor, receptor-activity modifying protein 1, and CGRP were expressed in rat colon and up-regulated by DKT. CONCLUSIONS The present study demonstrated that DKT increased CVC, which was mainly mediated by CGRP and its receptor components.

A new antimesenteric functional end-to-end handsewn anastomosis: surgical prevention of anastomotic recurrence in Crohn's disease.

BACKGROUND: Recurrence of Crohns disease usually occurs at anastomotic sites. OBJECTIVE: A new anastomosis technique (Kono-S anastomosis) designed to minimize anastomotic restenosis was compared with conventional anastomoses. DESIGN AND SETTINGS: The Kono-S anastomosis technique was first used for Crohns disease in 2003 at the Asahikawa Medical University Hospital. The resection is accomplished by transecting the bowel with a linear cutter so that the mesentery side is located in the center of the stump. Both stumps are sutured to create a supporting column to maintain the diameter and dimension of the anastomosis. Longitudinal enterotomies are made at the antimesenteric sides of the 2 segments of intestine. The side-to-side antimesenteric anastomosis is then performed in transverse fashion. The medical records and follow-up details of all patients undergoing this procedure were reviewed. PATIENTS: From 2003 to 2009, 69 patients with Crohns disease who underwent Kono-S anastomosis (group S) were compared with 73 historical patients with Crohns disease who underwent conventional anastomosis (group C) from 1993 to 2003. MAIN OUTCOME MEASURES: A Kaplan-Meier analysis of the follow-up data on surgical recurrence at the anastomosis was performed. The endoscopic recurrence score at the anastomosis was calculated. RESULTS: The median endoscopic recurrence score in group S was significantly lower than that in group C (2.6 vs 3.4; P = .008). The Kaplan-Meier analysis showed a lesser probability of anastomotic surgical recurrence in the S group at 5 years (0% vs 15%; P = .0013). The absence of postoperative infliximab did not affect the restenosis rate in group S. LIMITATIONS: This study was limited by its historical retrospective nature. CONCLUSION: The Kono-S anastomosis appears to be effective in preventing anastomotic surgical recurrence in Crohns disease.

Aluminum potassium sulfate and tannic acid (ALTA) injection as the mainstay of treatment for internal hemorrhoids

PurposeAluminum potassium sulfate and tannic acid (ALTA) induce noninvasive sclerosis and the involution of hemorrhoids by initiating an inflammatory reaction. We assessed the mid-term outcome after ALTA sclerotherapy for symptomatic hemorrhoids.MethodsBetween May 2006 and July 2009, 1210 patients with grade III or IV hemorrhoids underwent surgery at Kunimoto Hospital. Our treatment strategy for internal hemorrhoids is first establishing whether ALTA therapy is possible for the type of hemorrhoid, and then performing either ALTA therapy or alternatively, ligation and excision (LE) for those types unsuitable for ALTA therapy.ResultsA total of 448 patients were treated with ALTA therapy alone (Group A), 706 patients were treated with a combination of ALTA and LE therapy (Group B), and 56 patients were treated with LE alone (Group C). The overall recurrence rates were 3.6% (16/448) and 0.3% (2/706) in Groups A and B, respectively. There was no recurrence in Group C. Rectal ulcers developed at the injection site in four (0.9%) patients from Group A, but they healed within a few months with conservative therapy.ConclusionALTA sclerotherapy is a simple and safe treatment for symptomatic hemorrhoids, with few complications.

Direct evidence that induced nitric oxide production in hepatocytes prevents liver damage during lipopolysaccharide tolerance in rats

BACKGROUND The role of nitric oxide (NO) in lipopolysaccharide (LPS) tolerance in the liver has been investigated in a number of previous studies, but it is still not clear whether NO is cytotoxic or cytoprotective. The aims of this study were to investigate whether low-dose LPS (LLPS)-induced hepatic production of NO is beneficial and to clarify the origins of cytoprotective NO-producing cells in the liver during LPS tolerance. MATERIALS AND METHODS Male Wistar rats received saline or LLPS intraperitoneally (i.p.; 0.01-1000 microg/kg) followed by a high dose of LPS (HLPS, 5 mg/kg) at various time intervals (4-16 h). NG-nitro-L-arginine methyl ester (L-NAME) was used to investigate the effects of inhibition of NOS. 4,5-Diaminofluorescein (DAF-2) was used to identify NO-producing cells in isolated liver cells in vitro. At various time points (4-16 h) after saline or LLPS (1 microg/kg, i.p.) injection, hepatocytes and Kupffer cells were isolated, incubated in 7 microm DAF-2 diacetate, and perfused with Krebs solution. Illumination at 495 nm revealed DAF-fluorescence (515 nm) in isolated cells under confocal laser fluorescence microscopy. The NO production in hepatocytes and Kupffer cells was assessed by the number of labeled cells per 1000 cells or per 100 cells, respectively. RESULTS Pretreatment with LLPS (0.1-100 microg/kg) resulted in a significant reduction (maximal at 8 h) of the HLPS-induced liver damage. L-NAME abolished the LLPS-induced protection. The NO production in hepatocytes was significantly increased and reached a maximum of 84% of all cells 8 h after LLPS administration. By contrast, the NO production in Kupffer cells remained constant at 95%, even following preinjection of LLPS. CONCLUSION LLPS-induced NO in hepatocytes, but not in Kupffer cells, exhibits cytoprotective effects on HLPS-induced liver damage, suggesting that NO has a beneficial role in the induction of the early phase of LPS tolerance.

Cetuximab-induced hypomagnesaemia aggravates peripheral sensory neurotoxicity caused by oxaliplatin

Calcium and magnesium replacement is effective in reducing oxaliplatin-induced neurotoxicity. However, cetuximab treatment has been associated with severe hypomagnesaemia. Therefore, we retrospectively investigated whether cetuximab-induced hypomagnesaemia exacerbated oxaliplatin-induced neurotoxicity. Six patients with metastatic colorectal cancer who were previously treated with oxaliplatin-fluorouracil combination therapy were administered cetuximab in combination with irinotecan alone or irinotecan and fluorouracil as a second-line treatment. All patients had normal magnesium levels before receiving cetuximab. The Common Terminology Criteria for Adverse Events version 3.0 was used to evaluate the grade of neurotoxicity, hypomagnesaemia, hypocalcaemia, and hypokalemia every week. All six patients had grade 1 or higher hypomagnesaemia after starting cetuximab therapy. The serum calcium and potassium levels were within the normal range at the onset of hypomagnesaemia. Oxaliplatin-induced neurotoxicity occurred in all patients at the beginning of cetuximab therapy, with grade 1 neurotoxicity in five patients and grade 2 in one patient. After cetuximab administration, the neurotoxicity worsened in all six patients, and three progressed to grade 3. Among the three patients with grade 3 neurotoxicity, two required a dose reduction and one had to discontinue cetuximab therapy. A discontinuation or dose reduction in cetuximab therapy was associated with exacerbated oxaliplatin-induced neurotoxicity due to cetuximab-induced hypomagnesaemia in half of patients who had previously received oxaliplatin. Therefore, when administering cetuximab after oxaliplatin therapy, we suggest serially evaluating serum magnesium levels and neurotoxicity.

Distal Hemorrhoidectomy With ALTA Injection: A New Method for Hemorrhoid Surgery

Aluminum potassium sulfate and tannic acid injection (ALTA) is a useful and less-invasive treatment for internal hemorrhoids. However, it is not a treatment option for external hemorrhoidal diseases, including mixed hemorrhoids. Distal hemorrhoidectomy with ALTA injection involves surgical resection of external piles, followed by injection therapy on internal piles. We report technical details and the short-term results of this procedure in patients with mixed hemorrhoids. Seventy-two patients with mixed hemorrhoids treated between 2010 and 2011 were included. The main outcome measures were the short-term response and complication rates. At 28 days after surgery, the disappearance rate of prolapse was 100%. Three patients (4%) had postoperative complications, all minor in nature. No prolapse recurrence was observed within a median follow-up period of 6 months. Distal hemorrhoidectomy with ALTA injection appears to be a promising treatment option for patients with mixed hemorrhoids.

Efficacy of Lubiprostone in Chronic Constipation: Clinical and WorkProductivity Outcomes

Objective: Chronic constipation is a common health problem that significantly affects the quality of life of patients and results in high economic burden. This clinical study was performed to assess the efficacy of lubiprostone in the treatment of chronic constipation using a validated constipation scoring system and the work productivity and activity impairment questionnaire. Methods: We prospectively enrolled 35 patients who received lubiprostone. All the patients had chronic constipation as defined by the Rome III criteria. The patients were treated orally with a 24-μg lubiprostone capsule twice a day. Changes in the scores before and 2 weeks after the beginning of administration were recorded and analyzed. Results: Of the 35 patients, 28 completed the study and were included in the efficacy analysis. The total constipation scoring system score was significantly improved from 11.3 ± 4.8 at baseline to 8.0 ± 4.0 after 2 weeks. Although the work activity subscale did not show a significant improvement, such an improvement was statistically significant in the case of non-work-related activities. Conclusion: Our results demonstrate that lubiprostone is effective in improving many chronic constipationrelated symptoms as well as the quality of life in patients with chronic constipation.

Obscure gastrointestinal bleeding occurring 50 years after an appendectomy

A 69-year-old male, with a history of an appendectomy 50 years previously, presented to hospital due to refractory dizziness and bloody stool. A routine blood test revealed that he had severe anaemia. Upper and lower endoscopy revealed no evidence of bleeding in the oesophagus, stomach, duodenum, terminal ileum or colorectum. He was diagnosed as having obscure gastrointestinal bleeding.1 Capsule endoscopy (CE) was performed and dark-bluish areas with whitish villi were detected in the jejunum (figure 1). Subsequently, double-balloon endoscopy (DBE) was performed orally and multiple dark-bluish areas coated with whitish villi were found at the distal jejunum (figure 2A), and white debris also oozed from …

The role of human intestinal paneth cells expressing toll-like receptors in innate host defense

Background&Aim: Small intestinal Paneth cells contnbute to mucosal innate immunity by sensing bactena and secreting microbicidaI peptides, particularly a-defensins (Nature Immunol l: 113, 2000). Our aims were to investigate the expression and function of Toll-like receptor (TLR)s and related molecules in crypts of human small intestine. Methods: Ileal mucosa were obtained from surgical specimens resected from patients with colon cancer with normal ileum under informed consent. Intact crypts were isolated by standard EDTA dissociation, and further collagenase dissociation was conducted to prepare crypt single cell s0spensions. RT-PCR experiments were performed on individual crypts or isolated Paneth cells to assay for TLRI-10, CD14, MD2 and MyD88 mRNAs. Specific TLRs were immunocolocalized in isolated crypts and in Paneth cells with a-defensin HD5 using anti-TLR-2 and TLR-4 antibodies and confocal microscopic analysis. Isolated intact crypts were exposed to I x l03 S. typhimurium CFU/crypt to induce Paneth cell secretion. Secretions were assayed for bactericidal activity against defensin sensitive S. typhimurium phoPand for HD5 secretion by western blot analysis. Inhibition assay was performed using anti-TLR2 neutralizing antibody in the secretion assay system Results: TLR1-8, TLR10, CD14 and MyD88, but not M02 mRNAs were detected in single isolated crypts and isolated Paneth cells. TLR2 and ]-LR4 expression was restricted to Paneth cells in the isolated crypts. TLR4 staining in single Paneth cells was localized at the membrane surface and also near secretory granules, aDefensin secretion by Paneth cells in response to bacteria was inhibited by TLR2 antibody pre-treatment as judged by the diminished bactencidal activity and reduced secretion of HD5 in western blots. Conclusion: Paneth cells in human small intestinal crypts express Toll-like receptors that appear to be implicated in ex vivo responses to bacterial exposure.