Motoi Uchino

Gastroduodenitis associated with ulcerative colitis

BackgroundUlcerative colitis (UC) is regarded as confined to the colorectum; however, there are several case reports showing upper gastrointestinal involvement. The aim of this study was to examine the prevalence and characteristics of gastroduodenitis associated with UC (GDUC).MethodsEsophagogastroduodenoscopy with biopsies was prospectively performed on 250 UC patients (134 men, 116 women; mean age, 42 years; 162 with colectomy, 163 with pancolitis). Criteria for GDUC were created on the basis of endoscopic and histological comparisons with non-UC controls, and the prevalence and characteristics were statistically analyzed.ResultsGDUC was defined endoscopically as friable mucosa (erosive or ulcerative mucosa with contact or spontaneous bleeding), granular mucosa (multiple white spots almost without a red halo), or, conditionally, multiple aphthae (multiple white spots surrounded by a red halo, clinically excluding other disorders such as Crohn’s disease). The prevalence of GDUC was 19/250 (7.6%). The clinical characteristics included more extensive colitis, lower dose of prednisolone, higher prevalence of pouchitis, and longer postoperative period. In our population, the presence of pancolitis and a lower dose of prednisolone were significant risk factors for developing GDUC in multivariate analysis.ConclusionsThe high prevalence of GDUC suggests that the gut inflammatory reaction in UC may not be restricted to the large intestine. Administered steroids might conceal GDUC, and more aggressive UC such as active pancolitis may be related to the development of GDUC.

Safety of One-Stage Restorative Proctocolectomy for Ulcerative Colitis

PURPOSEThe aim of this study was to compare clinical outcomes in patients with ulcerative colitis who underwent restorative proctocolectomy with and without diverting ileostomy.METHODSA series of 245 consecutive patients who underwent ileal pouch anal anastomosis with mucosectomy with an ultrasonically activated scalpel (harmonic scalpel) was studied. Of these patients, 92 patients had a diverting ileostomy and 150 selected patients did not. The decision for or against an ileostomy was made at the end of the operation.RESULTSTwelve patients (8 percent) in the group without ileostomy had pouch-related complications, which necessitated secondary ileostomy in five patients (3.3 percent). Intestinal obstruction developed in 17 patients (11.3 percent) who had no ileostomy and in 12 patients (13.0 percent) who underwent ileostomy. Two of 17 patients who had no ileostomy and 1 of 12 patients with ileostomy required laparotomy with division of adhesions, whereas the remaining patients responded to conservative measures. There were no significant differences in the incidence of postoperative complications after the initial operation between the two groups. In the group with ileostomy, the morbidity rate for ileostomy was 12.1 percent, and that for ileostomy closure was 18.7 percent. The total postoperative complication rate for the group with ileostomy was significant higher than that for the group without ileostomy.CONCLUSIONWe conclude that restorative proctocolectomy with mucosectomy by use of an ultrasonically activated scalpel and without diversion is a superior therapeutic choice for selected patients.

Isoform-specific phosphorylation of metabotropic glutamate receptor 5 by protein kinase C (PKC) blocks Ca2+ oscillation and oscillatory translocation of Ca2+-dependent PKC

Prolonged activation of metabotropic glutamate receptor 5a (mGluR5a) causes synchronized oscillations in intracellular calcium, inositol 1,4,5-trisphosphate production, and protein kinase C (PKC) activation. Additionally, mGluR5 stimulation elicited cyclical translocations of myristoylated alanine-rich protein kinase C substrate, which were opposite to that of γPKC (i.e. from plasma membrane to cytosol) and dependent on PKC activity, indicating that myristoylated alanine-rich protein kinase C substrate is repetitively phosphorylated by oscillating γPKC on the plasma membrane. Mutation of mGluR5 Thr840 to aspartate abolished the oscillation of γPKC, but the mutation to alanine (T840A) did not. Cotransfection of γPKC with βIIPKC, another Ca2+-dependent PKC, resulted in synchronous oscillatory translocation of both classical PKCs. In contrast, cotransfection of δPKC, a Ca2+-independent PKC, abolished the oscillations of both γPKC and inositol 1,4,5-trisphosphate. Regulation of the oscillations was dependent on δPKC kinase activity but not on γPKC. Furthermore, the T840A-mGluR5-mediated oscillations were not blocked by the δPKC overexpression. These results revealed that activation of mGluR5 causes translocation of both γPKC and δPKC to the plasma membrane. δPKC, but not γPKC, phosphorylates mGluR5 Thr840, leading to the blockade of both Ca2+ oscillations and γPKC cycling. This subtype-specific targeting proposes the molecular basis of the multiple functions of PKC.

Incidence and therapeutic outcome of pouchitis for ulcerative colitis in Japanese patients.

Aim: The aim of this study was to examine the cumulative risk of pouchitis following restorative proctocolectomy for UC and FAP in Japanese patients, and to assess the response to medical treatment and its outcome. Patients and Methods: 521 patients with UC and 117 FAP patients underwent proctocolectomy and received a J-shaped IPAA at our department of surgery. We investigated these patients using PDAI for the diagnostic criteria of pouchitis. Results: Pouchitis occurred in only 32 UC patients (6.1%). The cumulative risk of developing pouchitis for a UC patient was 7% at 5 years after and 12% at 10 years after surgery. The medical treatment of acute pouchitis was usually oral metronidazole (250 mg twice daily) for 2 weeks or oral ciprofloxacin (200 mg thrice daily) in patients who could not tolerate metronidazole. Single episodes of pouchitis occurred in 21 patients (65.6%) and chronic or frequent relapses of pouchitis in 11 patients (34.4%). Three patients (9.4%) required re-ileostomy. Two patients (6.3%) required pouch excision. There were no patients with complicated dysplasia. Conclusion: The cumulative risk of pouchitis in Japanese UC patients is lower than that of western countries.

Risk factors for surgical site infection and association with infliximab administration during surgery for Crohn's disease.

BACKGROUND: Preoperative infliximab treatment may influence postoperative infectious complications in patients with Crohn’s disease. OBJECTIVE: The aim of this study was to identify predictors of surgical site infection after surgery for Crohn’s disease and evaluate the effects of preoperative infliximab administration. DESIGN: We performed a prospective surveillance and review of surgical site infections. SETTINGS: This study was conducted in the Surgical Department of Hyogo College of Medicine. PATIENTS: A total of 405 consecutive patients with Crohn’s disease who underwent abdominal surgery between January 2008 and December 2011 were included. MAIN OUTCOME MEASURES: Infection was diagnosed by the infection control team. The possible risk factors were analyzed by using logistic regression analyses to determine their predictive significance. RESULTS: Within the patient population, 20% of patients received infliximab, and 60% had penetrating disease. The median duration from the last infliximab infusion to surgery was 43 days (range, 4–80). The overall incidence of surgical site infection was 27%. The incidence of incisional surgical site infection was 18%, and the organ/space surgical site infection rate was 8%. In the multivariate analysis, proctectomy was the highest risk factor for all surgical site infection (OR, 3.4–11.8; p < 0.01). The administration of preoperative infliximab was not a risk factor for surgical site infection. By contrast, there was a significantly reduced risk of incisional surgical site infection in patients with penetrating disease who received infliximab (OR, 0.1; p < 0.01). LIMITATIONS: This study was a cohort study and not a randomized trial. The data analyses were performed for surgical site infections but not for other infectious complications. CONCLUSIONS: Proctectomy was a high-risk factor for surgical site infection in patients with Crohn’s disease. The administration of preoperative infliximab was not a risk factor for surgical site infection.

Long-term efficacy of infliximab maintenance therapy for perianal Crohn’s disease

AIM To assess the long-term efficacy of seton drainage with infliximab maintenance therapy in treatment of stricture for perianal Crohns disease (CD). METHODS Sixty-two patients with perianal CD who required surgical treatment with or without infliximab between September 2000 and April 2010 were identified from our clinics database. The activities of the perianal lesions were evaluated using the modified perianal CD activity index (mPDAI) score. The primary endpoint was a clinical response at 12-15 wk after surgery as a short-term efficacy. Secondary endpoints were recurrence as reflected in the mPDAI score, defined as increased points in every major element. The clinical responses were classified as completely healed (mPDAI = 0), partially improved (mPDAI score decreased more than 4 points), and failure or recurrence (mPDAI score increased or decreased less than 3 points). RESULTS There were 43 males and 19 females, of whom 26 were consecutively treated with infliximab after surgery as maintenance therapy. Complete healing was not seen. Failure was seen in 10/36 (27.8%) patients without infliximab and 4/26 (15.4%) patients with infliximab (P = 0.25). Partial improvement was seen in 26/36 (72.2%) patients without infliximab and 22/26 (88.5%) patients with infliximab (P = 0.25). Short-term improvement was achieved in 48/62 (77.4%) patients. Although the mPDAI score improved significantly with surgery regardless of infliximab, it decreased more from baseline in patients with infliximab (50.0%) than in those without infliximab (28.6%), (P = 0.003). In the long-term, recurrence rates were low regardless of infliximab in patients without anorectal stricture. In patients with anorectal stricture, cumulative recurrence incidences increased gradually and exceeded 40% at 5 years regardless of infliximab. No efficacy of infliximab treatment was found (P = 0.97). Although the cumulative rate of ostomy creation was also low in patients without stricture and high in patients with stricture, no protective efficacy was found with infliximab treatment (P = 0.6 without stricture, P = 0.22 with stricture). CONCLUSION Infliximab treatment was demonstrated to have short-term efficacy for perianal lesions. Long-term benefit with infliximab was not proven, at least in patients with anorectal stricture.

Preoperative oral antibiotics and intravenous antimicrobial prophylaxis reduce the incidence of surgical site infections in patients with ulcerative colitis undergoing IPAA.

BACKGROUND: The usefulness of preoperative oral antibiotics for the prevention of surgical site infection in elective colorectal surgery remains controversial. OBJECTIVE: This study aimed to investigate the effects of oral antimicrobial prophylaxis in addition to intravenous antimicrobial prophylaxis on patients with ulcerative colitis undergoing restorative proctocolectomy. DESIGN: This study was a randomized, nonblinded, single-center clinical trial. SETTING: This study was conducted between July 1, 2006, and April 30, 2009, at Hyogo College of Medicine. PATIENTS: Two hundred patients with ulcerative colitis scheduled to undergo restorative proctocolectomy with IPAA with an open approach were randomly assigned to either group A or B (n = 100). Combined use of preoperative oral antibiotics and intravenous antimicrobial prophylaxis were given to group A, and intravenous antimicrobial prophylaxis alone was given to group B. INTERVENTIONS: Patients in group A received oral antibiotics the day before surgery (500 mg of kanamycin and 500 mg of metronidazole at 2:00 P.M., 3:00 P.M., and 9:00 P.M.), whereas those in group B did not. All patients underwent preoperative mechanical bowel preparation, and intravenous antimicrobial prophylaxis with second-generation cephalosporin was given for 24 hours. MAIN OUTCOME MEASURES: The primary end point of this study was the incidence of overall surgical site infection according to intention-to-treat analysis. RESULTS: The incidence of overall surgical site infection was significantly lower in group A (6/97 patients, 6.1%) than in group B (22/98 patients, 22.4%) (p = 0.0024). In multivariate analysis, the administration of oral antibiotics (OR, 0.178; 95% CI, 0.057–0.552; p = 0.003) and ASA score ≥3 (OR, 5.343; 95% CI, 1.595–17.891; p = 0.007) were independent risk factors for surgical site infection. LIMITATIONS: This study is limited because of its open-label nature. CONCLUSIONS: Combined oral and intravenous antimicrobial prophylaxis in patients with ulcerative colitis undergoing restorative proctocolectomy with IPAA contributed to the prevention of surgical site infection.

High-dose regimen to achieve novel target trough concentration in teicoplanin

In the treatment of severe MRSA infections such as endocarditis, more than 20 mg/L of plasma trough concentration (C(min)) is recommended for teicoplanin; however, in the treatment of common MRSA infections, recommended C(min) remains more than 10 mg/L. In this study, we set C(min) as 15-30 mg/L to obtain a favorable clinical outcome in the treatment of common MRSA infections, and investigated the optimal loading regimen that achieved the target C(min) in patients with normal renal function. Seventy-eight patients received the high-dose regimen A (6 mg/kg every 12-h for initial two days) and 60 patients received the high-dose regimen B (the first five loading doses of 10-12 mg/kg at 12-h intervals for initial three days, followed by 6 mg/kg once daily). The mean C(min) on the 4th day was 13.7 ± 5.3 mg/L in regimen A, and 20.0 ± 6.6 mg/L in regimen B (P < 0.001), and the proportion of patients achieving the 15-30 mg/L was 25.6% and 68.3% (P < 0.001). Clinical response at end-of treatment were 66.7% and 85.0% (P = 0.014). The patients of initial C(min) with ≥15 mg/L had tended to be higher clinical response than those with <15 mg/L (80.9% vs 68.6%, P = 0.084). There were no significant differences in the occurrence of adverse effects in regimen A and B (nephrotoxicity; 1.3% vs 3.3%, P = 0.413, hepatotoxicity; 5.1% vs 3.3%, P = 0.608). In conclusion, to obtain C(min) 15-30 mg/L, the first five loading doses of 10-12 mg/kg at 12-h intervals was required in patients with normal renal function.

Topical tacrolimus therapy for antibiotic-refractory pouchitis.

BACKGROUND: Pouchitis is the most common complication after restorative proctocolectomy for ulcerative colitis, and it leads to pouch failure. The administration of oral antibiotics is the main treatment for pouchitis; however, in some cases, antibiotic-refractory pouchitis may develop, which requires further medical therapy. OBJECTIVE: We investigated the applicability of topical tacrolimus for refractory pouchitis. DESIGN: We performed a prospective pilot study. The study protocols were registered with the University Hospital Medical Information Network Clinical Trials Registry, 000006658. SETTING: This study was conducted in the Surgical Department of Hyogo College of Medicine. PATIENTS: Patients with antibiotic-refractory pouchitis were treated for 8 weeks with a tacrolimus enema. MAIN OUTCOME MEASURES: The efficacy was assessed by comparing Pouchitis Disease Activity Index scores. Safety was assessed by measuring whole blood tacrolimus trough levels. RESULTS: Ten patients with refractory pouchitis were enrolled. No severe adverse events occurred. The mean scores decreased from 15.9 ± 0.8 to 7.8 ± 0.8 during 8 weeks of treatment (p < 0.01). Specifically, the clinical symptom, endoscopic finding, and histological finding subscores decreased to 0.8 ± 0.6, 3.9 ± 0.2, and 2.9 ± 0.4. Nine patients recovered from their clinical symptoms, and 3 patients recovered from pouchitis. LIMITATIONS: This small study was neither blinded nor randomized. CONCLUSIONS: This study demonstrates that the use of topical tacrolimus for the treatment of refractory pouchitis is safe and effective in the short term for clinical symptoms. Although complete endoscopic healing was not achieved, this treatment may have early rescue efficacy in the treatment of antibiotic-refractory pouchitis.

Clinical Features and Management of Parastomal Pyoderma Gangrenosum in Inflammatory Bowel Disease

Background: Pyoderma gangrenosum (PG) is often associated with inflammatory bowel disease even after bowel surgery, but it remains an extremely rare pathology. The purpose of this study was to investigate the clinical features and treatment of PG and to consider proper management for peristomal PG. Methods: Demographic data for patients who underwent colorectal surgery with ostomy creation at Hyogo College of Medicine between July 2007 and July 2011 were prospectively collected. The main outcome measures were postoperative occurrence of peristomal PG by type: explosive and rapidly spreading type (type R) and indolent and gradually spreading type (type G). Results: Overall prevalence was 11/738 (1.5%), with type R in 5 patients and type G in 6. Type R and type G were significantly more common in ulcerative colitis and Crohn’s disease, respectively (p = 0.01). Type R developed within 6 days after surgery. Type G developed a mean of 52 days after surgery. Complete healing required a long time in both types, with means of 69 days for type R and 48 days for type G. Conclusion: Although peristomal PG was a rare complication after surgery, differences in the development of PG were observed between ulcerative colitis and Crohn’s disease. Careful observation and knowledge of PG are needed.