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Background/Aims: Tacrolimus is effective for refractory ulcerative colitis in adults, while data for children is sparse. We aimed to evaluate the effectiveness and safety of tacrolimus for induction and maintenance therapy in Japanese children with ulcer ative colitis. Methods: We retrospectively reviewed the multicenter survey data of 67 patients with ulcerative colitis aged

Endoscopy is a central tool for diagnosing and evaluating paediatric inflammatory bowel diseases (PIBD), but is too invasive to be frequently repeated in young children. Furthermore, it is challenging to distinguish Crohn’s disease (CD) from ulcerative colitis (UC) endoscopically. This study aimed to determine biomarkers useful for the diagnosis of PIBD. Cytokines, chemokines, and growth factors were quantified in the sera of 15 patients with CD or UC, at disease onset prior to treatment, and 26 age-matched controls. Correlation of cytokine levels with the paediatric CD activity index (PCDAI) and the paediatric UC activity index (PUCAI) was analysed. Interleukin (IL)-6, IL-13, IL-7, and vascular endothelial growth factor were higher in the CD group than in the UC group. The receiver operating characteristic curve analysis showed that IL-7 was a putative biomarker for distinguishing CD from UC (area under the curve: 0.94). Granulocyte–macrophage colony-stimulating factor was associated with PCDAI, and an IL-1 receptor antagonist, IL-6, and macrophage inflammatory protein-1β were associated with PUCAI. These findings indicate significant differences in cytokine signatures among patients with new-onset PIBD, which may improve accuracy in diagnosing PIBD.

Summary Background Allied disorders of Hirschsprung's disease (ADHD) have been proposed to be the concept of the functional obstruction of the intestine with the presence of ganglion cells in the terminal rectum. They are classified into two categories based on pathology: (1) abnormal ganglia, including immaturity of ganglia, hypoganglionosis (HG), and intestinal neuronal dysplasia; (2) normal ganglia, including megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS), segmental dilatation (SD), internal anal sphincter achalasia (IASA), and chronic idiopathic intestinal pseudo-obstruction (CIIP). Some of these show poor prognosis, therefore, the establishment of criteria and appropriate treatment strategies is required. Methods The questionnaires were sent to the 161 major institutes of pediatric surgery or gastroenterology in Japan, in order to collect the cases of ADHD during 10 years from 2001 and 2010. Results In total, 355 cases were collected. They included 28 immaturity of ganglia, 130 HG (121 congenital, 9 acquired), 18 intestinal neuronal dysplasia, 33 MMIHS, 43 SD, three IASA, and 100 CIIP. Of the 95 institutes, 69 (72.6%) had their own criteria for ADHD. Criteria were based on clinical symptoms and signs, and conventional pathological examinations. Prognosis was poor in congenital HG, MMIHS, and CIIP, while the others showed good survival rates. Conclusion Almost all Japanese cases of ADHD in the past 10 years were collected. Congenital HG and CIIP showed relatively high incidence, whereas acquired HG and IASA were extremely rare in Japan. The criteria of each disorder were also collected and summarized. Prognosis was poor in congenital HG, MMIHS, and CIIP.

Background and Aim Childhood-onset inflammatory bowel disease (IBD) is characterized by extensive intestinal involvement and rapid early progression. Infliximab (IFX), cyclosporin (CYA), and tacrolimus (FK506) are increasingly used to treat pediatric IBD; however, their long-term effects and adverse events have not been properly investigated in pediatric patients. The aim of this study was to characterize the effects of these biologics and immunomodulators on pediatric IBD patients in Japan. Additionally, we assessed IFX use in pediatric patients with Crohn's disease (CD). Methods A national survey of IFX, adalimumab, CYA, and FK506 use in pediatric IBD patients (

Background Despite the abundance of study evidence for its efficacy and tolerability for the treatment of constipation in other countries, polyethylene glycol 3350 plus electrolytes (PEG3350+E) was not available in Japan until recently. The purpose of this study was to establish the efficacy and safety of PEG3350+E for the treatment of functional constipation in children in Japan. Methods Japanese children aged 2–14 years with a mean spontaneous bowel movement (SBM) frequency of 2 times/week or less for at least 2 months prior to informed consent were enrolled into the study. After a 2‐week screening period, treatment with PEG3350+E was initiated on the day of enrollment and continued for 12 weeks. Change in SBM frequency from screening period week 2 (baseline) to treatment period week 2 was set as the primary endpoint. Secondary endpoints and adverse events were also examined. Results Thirty‐nine patients were enrolled and completed the 12‐week study period. The SBM frequency (mean ± SD) at baseline and treatment period week 2 was 1.00 ± 0.89 and 6.54 ± 4.38, respectively. The change in SBM frequency was 5.54 ± 4.55 (one‐sample t test, P < 0.0001) and remained stable through week 12. Stool consistency was also improved over the entire treatment period. Three mild adverse drug reactions were reported: decreased appetite, abdominal pain, and diarrhea (each in 1 of 39 [2.6%] patients). Conclusion PEG3350+E can be considered as a new treatment option for chronic constipation in children in Japan. Clinical trial registration number: Japic CTI‐163167.

Increased incidence and prevalence of pediatric inflammatory bowel disease (IBD) have been reported in Western countries. Changes in the prevalence of pediatric IBD in Asian countries, however, remain unclear. We evaluated the changes in the prevalence of IBD among Japanese adults and children from 2004 to 2013, by using the Japanese national registry data of patients receiving financial aid. Data from children (ages 0-19 years) were compared with those from young adults (ages 20-39 years). In 2004, age-standardized prevalences of Crohn disease (CD) and ulcerative colitis (UC) among children were 4.2 of 100,000 and 11.0 of 100,000, respectively. The corresponding prevalences among young adults were 41.0 of 100,000 and 89.8 of 100,000, respectively. In 2013, age-standardized prevalences of pediatric CD and UC were 7.2 of 100,000 and 15.0 of 100,000, respectively. During this period, prevalence of pediatric CD increased by 73.8% among children and by 49.0% in young adults. The prevalence of UC increased by 45.0% among children, and by 73.7% among young adults.

Background Despite the presence of ganglion cells in the rectum, some patients have symptoms similar to those of Hirschsprung's disease. A consensus has yet to be established regarding the terminology for these diseases. We defined this group of diseases as "allied disorders of Hirschsprung's disease" and compiled these guidelines to facilitate accurate clinician diagnosis and provide appropriate treatment strategies for each disease. Methods These guidelines were developed using the methodologies in the Medical Information Network Distribution System (MINDS). Of seven allied disorders, isolated hypoganglionosis; megacystis-microcolon-intestinal hypoperistalsis syndrome; and chronic idiopathic intestinal pseudo-obstruction were selected as targets of clinical questions (CQ). In a comprehensive search of the Japanese- and English-language articles in PubMed and Ichu-Shi Web, 836 pieces of evidence related to the CQ were extracted from 288 articles; these pieces of evidence were summarized in an evidence table. Results We herein outline the newly established Japanese clinical practice guidelines for allied disorders of Hirschsprung's disease. Given that the target diseases are rare and intractable, most evidence was drawn from case reports and case series. In the CQ, the diagnosis, medication, nutritional support, surgical therapy, and prognosis for each disease are given. We emphasize the importance of full-thickness intestinal biopsy specimens for the histopathological evaluation of enteric ganglia. Considering the practicality of the guidelines, the recommendations for each CQ were created with protracted discussions among specialists. Conclusions Clinical practice recommendations for allied disorders of Hirschprung's disease are given for each CQ, along with an assessment of the current evidence. We hope that the information will be helpful in daily practice and future studies.

Background Inflammatory bowel disease (IBD) – Crohn's disease (CD) and ulcerative colitis (UC) – are chronic inflammatory disorders of the intestine. Patients with IBD are at risk of hospitalization for disease exacerbation or IBD-associated complications. In the pediatric population, however, there are limited data on IBD hospitalizations. We therefore investigated the descriptive epidemiology of hospitalizations relevant to pediatric IBD. Methods The national inpatient claims database in Japan was searched for children (≤18 years old) with a diagnosis of IBD. The study period was 2007–2010. Data on demographic characteristics and descriptive statistics of the hospital course were extracted and analyzed. Results A total of 3559 admissions of 2175 patients met the definition of pediatric IBD: there were 1999 admissions for CD and 1560 admissions for UC. Internists were responsible for patient care in 56.6% of admissions, followed by pediatricians (27.5%). Of 3559 admissions, unscheduled hospitalizations accounted for 79.7%, and 7.6% of hospitalizations were attributable to complications of IBD, including intestinal, extraintestinal and other manifestations. The median age at first admission was 16 years (IQR, 13–17 years), in both the CD and UC groups. Compared with UC patients, CD patients had a higher number of hospitalizations (P < 0.001), but hospital stay was shorter (median: 6 vs 16 days, P < 0.001). There were seven fatal cases of IBD, accounting for 0.32% in the present series, and sepsis was the cause in five. Conclusions This study provides a description of pediatric inpatients with IBD and their hospital course in Japan.

Background Shwachman-Diamond syndrome (SDS) is a rare multisystem disorder associated with exocrine pancreatic insufficiency. The present study reports the results of a nationwide survey and a systematic review on SDS to develop consensus guidelines for intractable diarrhea including SDS. Methods Questionnaires were sent to 616 departments of pediatrics or of pediatric surgery in Japan in a nationwide survey. A second questionnaire was sent to doctors who had treated SDS patients and included questions on clinical information. Additionally, a systematic review was performed using digital literature databases to assess the influence of medical (i.e. non-surgical) treatment on SDS prognosis. Results Answers were received from 529 institutions (85.9%), which included information on 24 patients with SDS (median age, 10.4 years; male, n = 15) treated from January 2005 to December 2014. Although 75% of patients received pancreatic enzyme replacement therapy, there was no significant association between treatment and prognosis. Systematic review identified one clinical practice guideline, two case series, eight case reports and 26 reviews. Patient information from those studies was insufficient for meta-analysis. Conclusions The rarity of SDS makes it difficult to establish evidence-based treatment for SDS. According to the limited information from patients and published reports, medical treatment for malabsorption due to SDS should be performed to improve fat absorption and stool condition, but it is not clear whether this treatment improves the prognosis of malabsorption.

Pediatric ulcerative colitis (UC) sometimes progresses to an intractable condition for medical therapy. The surgical management of UC is challenging because of difficult procedures and frequent infectious complications. The aim of this study was to survey surgical procedures and infectious complications in pediatric patients with UC in Japan and to assess the relationship between preoperatively administered immunosuppressive drugs and postoperative surgical site infection (SSI). A survey of pediatric patients treated from 2000 to 2012 was sent to 683 facilities nationwide. Secondary questionnaires were sent to physicians who followed up patients with UC who had undergone surgery with the aim of assessing the relationships between postoperative SSI and selected preoperative patient characteristics, disease severity, medications, and operative procedures. Data for 136 patients (77 boys and 59 girls) were assessed. Median age at surgery was 14.1 years (range: 2.4-18.9 years). Surgery was performed in one stage in 35 cases, two stages in 57 cases, and three stages in 44 cases. SSI occurred in 36/136 patients (26%). According to multiple logistic regression analysis, there were statistically significant associations between SSI and staged surgery (three/one, OR: 6.7, 95% CI: 2.1-25.5, p = 0.0007; three/two, OR: 3.4, 95% CI: 1.4-8.6, p = 0.0069) and female sex (OR: 2.3, 95% CI: 1.0-5.4, p = 0.0434). Preoperative medications and incidence of SSI were not significantly associated. Preoperative immunosuppressive medication does not affect the incidence of SSI. Three-stage surgery and female sex are independent predictors of development of postoperative SSIs in pediatric patients with UC.

Childhood-onset inflammatory bowel disease (IBD) is characterized by extensive intestinal involvement and rapid early progression. Infliximab (IFX), cyclosporin (CYA), and tacrolimus (FK506) are increasingly used to treat pediatric IBD; however, their long-term effects and adverse events have not been properly investigated in pediatric patients. The aim of this study was to characterize the effects of these biologics and immunomodulators on pediatric IBD patients in Japan. Additionally, we assessed IFX use in pediatric patients with Crohn's disease (CD).A national survey of IFX, adalimumab, CYA, and FK506 use in pediatric IBD patients ( 17 years of age) was sent to 683 facilities in Japan from December 2012 to March 2013. Secondary questionnaires were sent to pediatric and adult practitioners with the aim of assessing the effectiveness and safety of IFX for pediatric CD patients.The response rate for the primary survey was 61.2% (N = 418). Among 871 pediatric CD patients, 284 (31.5%), 24, 4, and 15 received IFX (31.5%), adalimumab, CYA, and FK506, respectively, from 2000 to 2012. According to the secondary survey, extensive colitis (L3, Paris classification) was diagnosed in 69.4% of pediatric CD patients who received IFX. Regarding the effectiveness of IFX in this population, 54.7% (99/181) of patients were in remission, and 42.0% (76/181) were on maintenance therapy. However, 32.0% (58/181) of patients experienced adverse events, and one patient died of septic shock.Infliximab is reasonably safe and effective in pediatric CD patients and should therefore be administered in refractory cases.

We analyzed the database of the Japanese nationwide inflammatory bowel disease (IBD) registry, which was started in 1975, to characterize basic epidemiological and clinical features of childhood IBD, comparing them to those in adults. We analyzed the age of disease onset, disease severity and anatomical distribution in patients that were newly registered between 2003 and 2006 (n = 2,940 for CD and 14,857 for UC). We also analyzed the current age, gender and family history of IBD of all patients filed in 2005, which included patients who were newly registered in 2005 and those who had been registered before 2005 and for whom an annual report had been received in 2005 (total number of subjects: 10,934 for CD and 37,846 for UC). At the time of registration, 10.6% of CD and 5.9% of UC patients were ≤16 years old. In CD, the male to female ratio was 2.6 in adult- and 1.7 in childhood-onset patients (P

Aims: We have evaluated the therapeutic efficacy and safety of pulse steroid therapy for ulcerative colitis (UC) in a Japanese pediatric population by means of a survey. Methods: A questionnaire on UC patients treated with therapy between 2002 and 2006 was sent to 37 members of the Japanese Society for Pediatric Inflammatory Bowel Disease. Results: 21 of 62 cases in 6 of 19 centers registered in this study had been treated with pulse steroid therapy. The success rate of remission induction with this treatment was 55%, and improvement was observed in all cases in which remission was not achieved. There were no reports of any obvious side effects. The most common reason for using pulse steroid therapy was for remission induction in relapsed cases. Over the course of 12 (or fewer) months, the number of cases in which remission was maintained was only 1 in 4. However, the amount of concomitant steroid use had significantly decreased after 1 year. Conclusions: This survey shows that in Japan, pulse steroid therapy is used for a relatively large number of children with UC and is as an effective method of remission induction that has few side effects.

We used [3H] nitrendipine binding to isolated smooth muscle cells and isometric tension studies of muscle strips to characterize the calcium channels from rabbit proximal and distal colon. At 25°C [3H] nitrendipine binding was rapid, saturable, reversible, specific, and linearly proportional to cell number. The affinity of the ligand for its receptor was similar in proximal and distal colon (KD 129 ± 21 pM and 124 ± 17 pM, respectively). In the proximal colon there were 68,000 receptors per cell, compared to 58,000 receptors per cell in the distal colon (p > .1). The Hill coefficient for nitrendipine was close to unity, suggesting binding to a single receptor. Although nitrendipine and nifedipine competitively inhibited [3H]nitrendipine binding, verapamil did not alter [3H] nitrendipine binding, suggesting the presence of at least two discrete, noninteracting sites for the binding of drugs that block calcium channels. In studies with muscle strips nitrendipine competitively inhibited isometric tension stimulated by both bethanechol and high extracellular potassium concentration. There were no significant differences in response from proximal and distal colon. These results suggest that calcium antagonist binding characteristics to calcium channels are similar in proximal and distal colon, and do not explain previously observed differences in the function of muscle in these tissues.

Aim: Previous studies showed that HL-350, a formula thickened with a reduced concentration of locust bean gum, decreased frequent regurgitation in 4-month old infants with reflux. In this study, we investigated the effect of HL-350 in younger infants. Methods: We studied 20 infants less than 2 months old who had three or more episodes of regurgitation or vomiting per day. Ten infants (group A) were fed with HL-350 for the first week, and with control milk, HL-00, for the following week. The other 10 infants (group B) were fed in reverse order. Mothers recorded number of regurgitation episodes, feeding volume and time and number of bowel movements. To evaluate gastric emptying we measured antral cross sectional areas ultrasonographically at various time points after feeding. Results: The median number of regurgitation episodes decreased significantly with feeding of HL-350 (2.3/day) compared to feeding with control milk (5.2/day) (p = 0.00048). No significant difference was evident in feeding volume and time, body weight gain, or gastric emptying rate between HL-350 and control milk. Conclusion: HL-350 decreased the number of regurgitation episodes without affecting gastric emptying delay in very young infants with recurrent vomiting.

Background To assess the usefulness of rectal diameter measurement via ultrasonography as a diagnostic tool for fecal retention in children. Methods One hundred children (median age: 5.0 years), consisting of 80 with functional constipation and 20 without constipation, participated in the study. All patients underwent physical examination that included digital rectal examination. Forty-five children underwent ultrasonography in three differential planes: transection above the symphysis, under the ischial spine, and at the bladder neck. The measurement of the rectal diameter at the transection above the symphysis could most easily detect fecal retention and demonstrated the closest correlations with retention among the three planes. Results Rectal diameter was greater at all measuring points (35.2 vs. 20.9 mm above the symphysis, P < 0.0001; 35.7 vs. 24.0 mm under the ischial spine, P < 0.0001; and 19.4 vs. 8.7 mm at the bladder neck, P < 0.0001) in children with fecal retention than in those with no fecal retention. Comparing between children with functional constipation and those without constipation, children with fecal retention had a greater rectal diameter above the symphysis than in those with no fecal retention (children with functional constipation: 35.3 vs. 20.0 mm, P < 0.0001; children without constipation: 32.6 vs. 14.6 mm, P = 0.0026). The cutoff value for the rectal diameter measured above the symphysis to identify fecal retention was 27 mm, with high sensitivity and specificity (95.5% and 94.1%, respectively). Conclusion Ultrasound rectal diameter measurement can be used to detect fecal retention in children. This article is protected by copyright. All rights reserved.

Background: A former nationwide survey in Japan on pediatric chronic intestinal pseudo-obstruction (CIPO) determined the most common etiology to be 'idiopathic'. However, currently no appropriate diagnostic criteria for pediatric chronic idiopathic intestinal pseudo-obstruction (CIIP) in children has been defined. The report utilized data mining to identify key clinical features that would qualify statistically CIIP diagnostic criteria. Methods: Sixty-nine cases were reviewed and subject to standard mining association rule. Cases were assigned to three groups: fully dependent on parenteral nutrition (PN) (group A, n = 15), on partial PN or independent from PN, but requiring permanent enterostomy for decompression (group B, n = 37), and all the other (group C, n = 17). Distinctive features related to each group assignment were then extracted from 87 reported clinical features of the CIPO. The statistical operation was performed by an expert in medical informatics using apriori algorithm. Results: Key features of patients in group A and B, thought to be severely intractable cases, were the presence of abdominal distension, intestinal dysmotility, ileus without mechanical obstruction, and the absence of histopathological abnormalities in the intramural ganglion cells. Conclusions: The presence of clinical features of a functional ileus, in the absence of proven histopathological abnormalities, can be used for diagnostic criteria for CIIP covering all the intractable cases in Japanese children. It is highly significant that a normal full-thickness histopathological finding was statistically extracted as one key feature for CIIP in our analysis.

Aim We investigated the effects of milk-based formulas thickened with two different concentrations of locust bean gum on gastric emptying in infants with recurrent regurgitation episodes. Methods Thirty-nine infants with three or more episodes of regurgitation per day but no complications who were fed mainly with infant formula were studied. We first compared gastric emptying in infants fed with formulas thickened with two different concentrations of locust bean gum (HL-350, 0.35 g/100 mL; HL-450, 0.45 g/100 mL) or a regular formula (HL-00). To evaluate gastric emptying, we measured antral cross-sectional areas ultrasonographically at various time points after feeding. Next, to investigate the clinical effect of thickened formulas on regurgitation episodes, 27 infants with episodes were assigned randomly to receive HL-350 and HL-00 or HL-450 and HL-00 for 1 week each. Results Antral cross-sectional areas at 60, 90, 120 and 150 min with HL-450, and at 60 min with HL-350, were greater than with HL-00. The median gastric emptying rate at 120 min with HL-450 (52.8%) was lower than with HL-00 (97.9%; P = 0.0019), while HL-350 (80.3%) and HL-00 did not differ significantly. The mean number of regurgitation episodes was significantly smaller when infants were fed with either HL-350 or HL-450 than with HL-00. Conclusions HL-450, a thickened formula with typical commercially available concentrations of locust bean gum, slowed gastric emptying in infants with gastroesophageal reflux.

This paper shows guidelines for the treatment of Crohn's disease in children by the Working Group of the Japanese Society for Pediatric Gastroenterology, Hepatology and Nutrition (Chair: Yuichiro Yamashiro) and the Japanese Society for Pediatric Inflammatory Bowel Disease (Chair: Akio Kobayashi). The points in which these guidelines differ from those for adult patients are as follows. (i) Total enteral nutrition in the form of an elemental formula is indicated as primary therapy for children with Crohn's disease at onset as well as the active stage. Oral mesalazine is used together. (ii) Total parenteral nutrition (TPN) with oral mesalazine is required for children with serious illness. The use of a corticosteroid should be withheld for at least 1 week after TPN has been started. (iii) When TPN is not considered to be effective, additional corticosteroid is used. Full doses of corticosteroid should be used for at least 2 weeks after clinical improvement has been achieved, and then the dose of the corticosteroid should be tapered carefully. (iv) When surgery is indicated in pediatric patients with stricture or fistula formation and complicated by persistent growth failure despite medical therapy, the optimum time for surgery is thought to be before epiphyseal plates have been closed.

We recorded in vivo colonic motility in rats with a deficiency of interstitial cells of Cajal (ICC) (Ws/Ws rats) and in wild-type rats (+/+ rats), with special reference to the effects of nitric oxide (NO) on colonic motility in both types of rats, in order to ascertain the role of ICC in colonic motility, and the relationship between NO and ICC in regard to colonic motility.Miniature strain-gauge force transducers were sutured on the surface of the ascending and sigmoid colon of Ws/Ws rats and +/+ rats as controls. After 1 week and a fasting period of 24 h, colonic motility in +/+ and Ws/Ws rats was recorded. We also studied the effect of NO on colonic motility in both types of rats, by means of the administration of N-nitro-L-arginine methyl ester (L-NAME) or L-arginine.In +/+ rats, there were contractions with high amplitude and long duration in both the ascending and sigmoid colon. The number, amplitude, and duration of contractions in the ascending colon were 9.9/20 min, 6.1 g, and 22.7 s, respectively. These findings in the sigmoid colon were 5.2/20 min, 5.2 g, and 23.0 s, respectively. The number of contractions in the ascending and sigmoid colon in Ws/Ws rats (2.3 and 1.0/20 min) was significantly lower than that in +/+ rats (P0.05). The number of contractions in the ascending and sigmoid colon in +/+ rats (9.7 and 5.1/20 min before treatment) was significantly increased by L-NAME administration (28.7 and 13.9/40-60 min after treatment; P0.05), but that in Ws/Ws rats was not influenced. The number of contractions in the ascending and sigmoid colon in +/+ rats (10.2 and 5.2/20 min before treatment) was significantly decreased by L-arginine administration (3.6 and 2.1/40-60 min after treatment; P0.05), but that in Ws/Ws rats was not influenced.ICC must be related to the occurrence of a normal number of colonic contractions. NO may be involved in the inhibitory regulation of colonic motility, and the effect of NO on the occurrence of contractions appears to be mediated by ICC.

Background: Most premature infant formulas marketed in Japan have high vitamin D content. Potential for vitamin D intoxication was assessed in premature infants with prolonged feeding of such a premature formula vitamin D content, 2700 IU/L. Methods: Serum vitamin D, calcium and phosphorus, and urinary calcium, were measured in 12 very premature infants fed premature infant formula, regular formula (vitamin D content; 460 IU/L), and/or mother's milk. Results: Concentrations of 25(OH)D in sera associated with sole feeding of premature infant formula (n = 40) were significantly higher than sera corresponding to regular formula or breast milk (n = 25; 175 versus 115 nmol/L, P

Background & Aims : Lipopolysaccharide-induced colonic dysmotility using an in vivo rat model was examined in this study. Methods : Six days prior to the experiment, force transducers were sutured to the proximal colons of the rats. On the day of the experiment, while monitoring colonic contractions, lipopolysaccharide (LPS) (1mg/kg) was given intravenously. Results : LPS injections induced abnormal high amplitude colonic contractions within 15 to 30 min in all the rats tested. After the period of these abnormal waves, motility gradually decreased. These high amplitude contractions were partly suppressed by atropine, a nonspecific cholinergic receptor antagonist. Conclusions : These results indicate that LPS induces a transient increase in colonic motility followed by suppression in conscious rats. This increase might be mediated by cholinergic receptors.

Background & Aims : We retrospectively examined the incidence of duodenal ulcers (DU) among children in Gunma prefecture over the past two decades, from 1980 to 1999, by data from Gunma University Hospital and its subsidiary hospitals, in order to test the hypothesis that the incidence of DU among children in Japan is decreasing.Method : By our own experience and by the interview to doctors in 23 major hospitals in Gunma prefecture. In addition, to study trends in the prevalence of anti-Helicobacter pylori (HP) infection, we measured anti-HP Ig-G antibody in the serum from children who come to the Department of Pediatrics, Gunma University Hospital during the same period with a complaint because of low body height for a growth hormone secretion stimulating test.Result : We identified 48 children with DU in 1980-1989 and 16 children in 1990-1999. The prevalence of HP antibody showed a declining trend from the 1980s to the 1990s, but there was not a statistically significant difference.Conclusions : The incidence of DU among children in Gunma prefecture is declining recently. Further study is needed to determine whether this is due to the decline in HP infection or not.

Granulocytapheresis (GCAP) has produced efficacy in adult patients with ulcerative colitis (UC) by adsorbing activated granulocytes and monocytes/macrophages. We retrospectively investigated efficacy and safety of GCAP in pediatric patients with active UC. Twelve steroid-refractory children (12.2 +/- 3.1 years old) were treated with GCAP, one session/week for 5-10 consecutive weeks. In 8 patients, clinical symptoms improved after two GCAP sessions. Normal body temperature, stool frequency, and disappearance of blood in stool were seen after 24.3 +/- 11.5 days. The endoscopic grade improved from 2.6 +/- 0.3 to 0.4 +/- 0.2. One patient who initially responded, developed bloody diarrhea later and 2 cases remained unchanged. The dose of steroid was tapered during GCAP therapy by 50%. No serious adverse effects were noted. Four of 8 cases relapsed 3.5 +/- 2.2 months after the last GCAP while on maintenance therapy, the other 4 were in remission up to 22.8 +/- 18.1 months. In conclusion, GCAP appears to be effective and well tolerated in children with steroid-refractory UC.

Background: To obtain precise information on the natural course of gastro-esophageal reflux (GER)-related symptoms in Japanese children, we surveyed the prevalence of regurgitation or vomiting and other GER-related symptoms and complications in infants visiting for healthy baby check-ups. Methods: We interviewed the mothers of 921 infants who had visited for baby check-ups at 1, 4, 7 and 12 months after birth, about the number of regurgitation or vomiting episodes per day, other GER-related symptoms, milk volume, feeding interval, and the body position after feeding. Results: Of 1-month-old infants, 47.1% had one or more regurgitation or vomiting episode per day. This proportion decreased to 28.8% at 4 months old and 6.4% at 7 months old. The proportion of infants with three or more episodes of these symptoms per day showed a similar pattern. There was no significant difference in the prevalence of regurgitation or vomiting between breast-fed infants and formula-fed or mixed-feeding infants either at 1 or 4 months of age. There was no significant difference in the bodyweight gain of 3-month-old infants among those with various degrees of regurgitation. There was no significant difference in the frequency of regurgitation or vomiting episodes between infants placed in a vertical position and those placed in a horizontal position after feeding. No infant had a history of chronic coughing, wheezing, bleeding or other serious conditions. Conclusions: Regurgitation is a common symptom in Japanese infants and decreases spontaneously with age. The natural history of GER must be taken into consideration when deciding the treatment.

Background In newborn rats, gastric mucosa is more susceptible to various damaging agents and recovers from injury more quickly than in older animals. To determine whether metabolism of prostaglandins is responsible for this mucosal protective mechanism in developing rats, we studied cyclooxygenase (COX) mRNA expression in the mucosa using quantitative real-time polymerase chain reaction (PRC). Methods Cyclooxygenase-1 and COX-2 mRNA was extracted from the gastric mucosa of rats of various ages and quantitatively analyzed using real-time PCR with dual-labeled fluorogenic probes. The copy numbers of cDNA for COX-1 and COX-2 were standardized to glyceraldehyde-3-phosphate dehydrogenase from the same sample. Results Cyclooxygenase-1 mRNA expression was lowest in 1-week-old rats and highest in 4-week-old rats. Mucosal damage produced by 150 mmol/L HCl and 60% ethyl alcohol did not increase COX-1 mRNA expression in any age group. Cyclooxygenase-2 mRNA expression increased significantly with age. Mucosal injury increased COX-2 mRNA in each age group, especially in 1-week-old rats. Intraperitoneal lipopolysaccharide also increased COX-2 mRNA in both 1- and 4-week old rats. Conclusion The high level of COX-2 mRNA expression in the gastric mucosa of 1-week-old rats may be responsible for the physiologic characteristics of gastric mucosal defenses in this age group.

Severe bacterial infection causes gastrointestinal dysmotility by an unknown mechanism. We investigated the possible involvement of serotonin (5-HT) and nitric oxide (NO) in endotoxin-induced motility disturbance, using an in vivo rat model. Six days prior to the experiment, a force transducer was sutured to the gastric antrum of rats. Lipopolysaccharide induced strong repetitive contractions in the gastric antrum within 2 to 3 min in all rats tested. After 15 min of hypermotility, motility decreased and remained low for more than 60 min. The initial increase in motility was suppressed by atropine, FK1052, or SB204070, whereas it was not affected by granisetron. The subsequent decrease was inhibited by l-NAME and S-methylisothiourea sulfate. These results indicate that in conscious rats, lipopolysaccharide induces a transient increase in gastric motility followed by suppression. The increase might be mediated by 5-HT4 receptors, and the decrease by inducible NOS.

Background/Purpose A nationwide survey was conducted to identify the clinical presentation of pediatric chronic intestinal pseudo-obstruction (CIPO) in Japan. Methods Data were collected via a questionnaire, ensuring patient anonymity, from facilities that treat pediatric gastrointestinal diseases in Japan. Results Ninety-two responses were collected from forty-seven facilities. Sixty-two patients (28 males, 34 females) met formal diagnostic criteria for CIPO. The estimated pediatric prevalence was 3.7 in 1 million individuals. More than half the children (56.5%) developed CIPO in the neonatal period. Full-thickness intestinal specimens were available for histopathology assessment in forty-five patients (72.6%). Forty-one (91.1%) had no pathological abnormalities and were considered to be idiopathic. Patients were treated according to the local protocol of each facility. Forty-one patients (66.1%) had restricted oral intake of ordinary diets, and twenty-nine (46.8%) depended on parenteral nutrition. No therapeutic intervention, including medication and surgery, successfully improved oral food intake or obstructive symptoms. Only three patients (4.8%) died from enteritis or sepsis. Conclusions In Japan, pediatric CIPO is a rare, serious, and intractable disease. The prognosis with respect to survival is good, but unsatisfactory because of the need for prolonged parenteral nutrition and associated potential for restricted quality of life.

Inflammatory bowel disease (IBD) - Crohn's disease (CD) and ulcerative colitis (UC) - are chronic inflammatory disorders of the intestine. Patients with IBD are at risk of hospitalization for disease exacerbation or IBD-associated complications. In the pediatric population, however, there are limited data on IBD hospitalizations. We therefore investigated the descriptive epidemiology of hospitalizations relevant to pediatric IBD.The national inpatient claims database in Japan was searched for children (≤ 18 years old) with a diagnosis of IBD. The study period was 2007-2010. Data on demographic characteristics and descriptive statistics of the hospital course were extracted and analyzed.A total of 3559 admissions of 2175 patients met the definition of pediatric IBD: there were 1999 admissions for CD and 1560 admissions for UC. Internists were responsible for patient care in 56.6% of admissions, followed by pediatricians (27.5%). Of 3559 admissions, unscheduled hospitalizations accounted for 79.7%, and 7.6% of hospitalizations were attributable to complications of IBD, including intestinal, extraintestinal and other manifestations. The median age at first admission was 16 years (IQR, 13-17 years), in both the CD and UC groups. Compared with UC patients, CD patients had a higher number of hospitalizations (P0.001), but hospital stay was shorter (median: 6 vs 16 days, P0.001). There were seven fatal cases of IBD, accounting for 0.32% in the present series, and sepsis was the cause in five.This study provides a description of pediatric inpatients with IBD and their hospital course in Japan.

Background: To clarify the relation between intestinal ischemia-reperfusion (IR) and dysmotility, the authors investigated changes in the motility pattern in the duodenum and jejunum in an in vivo rat model of IR when artery- (and vein-) fed jejunum was clamped transiently. The authors also studied the effect of nitric oxide on the motility changes in this model by means of the administration of L-NAME (N G -nitro-L-arginine methyl ester) or S-methylisothiourea sulfate (SMT). Materials and Methods: A force transducer was sutured onto the serosal side of the duodenum or jejunum. After a 3- to 4-day recovery period, contractions were recorded during periods of preischemia, ischemia (60 minutes), and reperfusion (90 minutes). An intestinal IR was produced by clamping and releasing the mesenteric artery and vein with artery forceps. Results: In the jejunum, there was a prolongation in the duration of contraction and there were decreases in the number of contractions (NC) during the IR. When treated with L-NAME, no decrease in the NC was observed during the 45 to 90 minutes after reperfusion. S-methylisothiourea sulfate did not affect the IR-induced motility changes significantly. In the duodenum, there was a prolongation in the duration of contraction and a decrease in the NC and AC only during the reperfusion. L-NAME or S-methylisothiourea sulfate inhibited the decreases in the NC during the reperfusion. Conclusions: Intestinal IR causes motility changes in the ischemic site during the IR and in the nonischemic site during the reperfusion. The IR-induced motility changes partly depend on nitric oxide production.

We investigated the possible involvement of the upper alimentary tract in vincristine (VCR)-induced dysmotility. Gastric contractions were recorded by a strain-gauge force transducer in conscious rats. Rats were injected with various doses of VCR followed by continuous recording for 12 hr. Additionally, 3-hr recordings to study the later effects were performed one and three days after injection. Gastric motility was dose-dependently increased by VCR. Post- versus preinjection motility index (MI; area under contraction waves) ratios were 0.78+/-0.12 for saline and 1.95+/-0.21 for VCR at 0.75 mg/kg. This increase in MI was completely inhibited by atropine and hexamethonium. MI one day after injection of VCR (0.75 mg/kg) was significantly less than in control (0.32+/-0.10 vs 0.92+/-0.24, respectively). The decrease was reversed by acetylcholine. In conclusion, VCR first increased gastric motility, and this was followed by a gradual decrease in conscious rats. These alterations may involve a presynaptic cholinergic pathway.

今回, 群馬県における第一例目の生体肝移植の成功例を経験したので, ドナーの選定や手術手技を中心に報告する.症例は16歳の男性で, 劇症高アンモニア血症と脳症で発症し, 内科治療により緩解期にあった.Type II citrullinemiaで生体肝移植術目的に小児科より紹介された.ドナーは45歳の父親, 血液型はcompatible, リンパ球クロスマッチは陰性で, 遺伝子診断はType II citrullinemia heterozygoteであった.中肝静脈を含んだ拡大肝左葉グラフトの予測グラフトレシピエント体重比 (GRWR) は0.95%であり, 肝切除率は29%であった.ドナー手術においてグラフト肝に胆管および血管の異常はなく, 肝血行遮断をせずに中肝静脈を含む拡大肝左葉グラフトを採取した.摘出グラフト重量は370gで, GRWRは0.86%であった.手術時間は7時間32分, 出血は516gであった.全肝摘出前に無肝期の門脈圧亢進を防ぐため一時的に門脈下大静脈シャントをおいた.piggyback法でレシピエント中・左肝静脈にドナー肝静脈を再建し, 門脈を再建した.肝動脈は顕微鏡下に再建した.最後にRoux-en Yに胆管空腸吻合を行い, 消化管を連続させた.冷阻血時間は1時間22分, 温阻血時間41分であり, 門脈遮断時間は0分であった.レシピエント肝は脂肪変性を伴う硬変肝で, 全肝重量は1300gであった.レシピエントの手術時間は11時間5分, 出血は1258gであった.患者は術後50日目に退院し, 現在元気に外来通院中である.また, ドナーは術後10日で退院し社会復帰している.

Objective: We investigated the relationships among gastrointestinal sounds, gastrointestinal manometric findings, and small intestinal transit time in healthy fasted humans. Methods: Gastrointestinal sounds acquired with two microphones attached to the upper and lower abdominal walls of healthy subjects were quantified with a computer-aided sound analysis program. Antroduodenal contractions were recorded by manometry. Small intestinal transit time was measured by breath hydrogen testing after intraduodenal administration of lactulose. Results: The sum of the gastrointestinal sound amplitudes (sound index) in both the upper and lower abdomen changed with time, coinciding with the gastric phases of the migrating motor complex. The sound indices in the upper and lower abdomen were 59.0 ± 24.8 and 98.1 ± 21.6 mV/min in phase 1, 95.5 ± 27.9 and 127.4 ± 34.9 mV/min in phase 2, and 132.8 ± 12.4 and 188.5 ± 73.4 mV/min in phase 3, respectively. There were no significant differences among motility phases in terms of the mean duration or frequency of each sound event. Intravenous erythromycin induced phase 3 in the stomach and doubled the sound index. Somatostatin analogue induced phase-3–like clustered contractions in the duodenum, but inhibited antral contractions and decreased the sound index. The small intestinal transit time was shorter and the sound index increased after intravenous metoclopramide, compared with controls. Scopolamine delayed small intestinal transit time and decreased the sound index. Conclusions: This study is the first to document the relationships between gastrointestinal sounds and the migrating motor complex. The chronological relation between antral motility and gastrointestinal sounds, and the dissimilar effects of erythromycin and somatostatin, suggest that antral contractions increase gastrointestinal sounds, perhaps by supplying gas into the intestine.

Previous studies have suggested that the mechanisms involved in gastric mucosal protection in newborn rats are different from those in adult rats. The aim of this study was to derermine whether nitric oxide (NO) has protective effects against ethanol-induced gastric mucosal damage in newborn rats. In 1-week-old rats, (1) pretreatment with N G -nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, increased gastric mucosal damage induced by 35% ethanol dose-dependently (0.3 - 30 mg/kg), (2) concurrent administration of 300 mg/kg L-arginine (L-Arg) inhibited the L-NAME induced-increase in damage completely, and (3) pretreatment with low dose L-Arg (30 mg/kg) decreased the mucosal damage induced by 60% ethanol. We concluded that endogeneous NO is involuved in the protective mechanism of the gastric mucosa in neonatal rats.

Objective: Plasma soluble thrombomodulin level reflects endothelial damage. The plasma thrombomodulin level at birth is increased in asphyxiated full-term infants. There is no report of plasma thrombomodulin level in premature infants. To determine the thrombomodulin level in premature infants and whether it might reflect endothelial damage, we examined the plasma thrombomodulin level in very low birthweight (VLBW) infants at birth. Methods: Forty-five VLBW infants, of whom 14 had perinatal asphyxia complications, were recruited. As a control, 50 full-term infants without complications were also studied. Plasma thrombomodulin concentration, pH, base deficit, serum creatinine and D-dimer concentration, platelet count and fibrinogen concentration were measured within 1 hour after birth. Results: There were significant differences in plasma pH, creatinine concentration, platelet count, antithrombin III activity and D-dimer concentration between VLBW infants and full-term infants. Plasma thrombomodulin concentration (39.0 (16.6-93.7) vs 27.0 (16.6-39.1) μg/L, p < 0.0001) and plasma thrombomodulin-to-serum creatinine ratio (0.82(0.19-2.65 ) vs 0.47(0.24-0.70) μg/μmol,p < 0.0001) were significantly higher in VLBW infants than those in full-term infants. By univariate analyses for all neonates, there were significant relations between plasma thrombomodulin concentration and gestational age, birthweight, plasma pH, creatinine concentration, platelet count and antithrombin III activity. A stepwise multiple linear regression model using the above variables as dependent factors showed only birthweight contributed significantly to plasma thrombomodulin concentration (plasma thrombomodulin concentration (μg/l) = 45.677-0.006 (birthweight; g), r 2 = 0.323, p < 0.0001, n = 94). Plasma thrombomodulin concentration and plasma thrombomodulin-to -serum creatinine ratio in VLBW infants with asphyxia were higher than in those without asphyxia, but not significantly different (43.2 ± 17.7 vs 38.3 ± 8.5 μg/l and 0.92 ± 0.60 vs 0.83 ± 0.37 μg/μmol). Conclusion: Plasma thrombomodulin level in VLBW infants shows a high value at birth, and we consider the main factor responsible for this elevation may be endothelial damage or low clearance rate of thrombomodulin, which may be related to early gestational age. Endothelium, neonate, thrombomodulin, very low birthweight.

To determine whether dilated bowel proximal to obstruction associated with duodenal atresia and stenosis is related to feeding problems after a surgical correction of obstruction, the authors reviewed retrospectively the degree of bowel dilatation and disturbed transit as well as other clinical features in 18 duodenal atresia and 12 duodenal stenosis patients. A multivariate analysis was conducted to determine the possible correlation among them. The authors also evaluated the physiological function of the dilated bowel in duodenal atresia and stenosis patients (n = 8) by manometry of dilated bowel. The results were as follows. (1) In multivariate analysis, using the degree of disturbed transit as a dependent variable and using other clinical features as independent variables, the presence of postoperative complication and the existence of bowel dilatation 2 weeks after the operation were risk factors for disturbed transit. (2) One or two episodes of phase 3 were found in six of eight measured patients during the recorded period. The most distinctive manometric finding was the low contraction amplitude of both phase 2 and phase 3. These results indicate that dilated bowel was related to disturbed transit during the postoperative period, and that the low contraction amplitude of the dilated bowel was the main pathophysiological feature. The tapering or plication of dilated bowel might be indicated in patients with a markedly dilated bowel.

小児の粘膜脱症候群の1例を経験した.本症について, 自験例と本邦における15歳以下の粘膜脱症候群の報告例について, その臨床像, 診断, 内視鏡所見, 治療, 予後等について集計した.症例は, 9歳7ヶ月の男児で, 主訴は, 起床時の下着の汚れと血便.既往歴では, 腸管膜嚢腫, 気管支喘息を認めた.現病歴は, 起床時, 下着に血液の付着を繰り返し認めたため, 内視鏡検査を施行, 直腸内に, びらん・発赤・潰瘍がみられ, 同部の生検による病理組織像では, 間質の鬱血, 円形細胞の浸潤に加え線維増生や, 筋線維の粘膜固有層への増生を認めた.これらの所見と, 臨床症状から粘膜脱症候群と診断した.本例と本邦での粘膜脱症候群の15歳以下の小児の報告例をまとめると, 年齢は5歳から15歳で, 平均年齢12.3歳であった.性別では, 男児33例, 女児10例で男児に多い傾向が見られた.主訴・主要症状では, 38例中37例に血便, 出血を認めた.しかし, 実際に粘膜脱を認めた例は38例中10例であった.病変の内視鏡所見は, 全体の約69%, 29例が隆起型で, 潰瘍型は9例, 平坦型は1例, 混合型は3例のみであった.病変部位では, 42例中41例が直腸内であり, S状結腸例は1例であった.また, 直腸内病変は前壁17例, 全周性8例, 側壁4例, 後壁3例で, 多発例は3例であった.治療や予後では, 生活習慣, 排便習慣の改善指導を中心とした内科的治療を行った例が9例で, 治癒または改善を認めたものが4例, 不変, 再発例が2例であった.一方, 外科的治療を選択した例は25例であり, 治癒または改善を認めたものが16例, 不変, 再発例が2例であった.以上より, 本邦の小児の粘膜脱症候群は, 男児に, 10歳以上の年長者に多く, 内視鏡学的には, 隆起型が多い傾向がみられた.しかし, 本症例のように, 10歳以下で発症し, 内視鏡病変が潰瘍型である例でも粘膜脱症候群の可能性があるため, 下部消化管の出血, 血便の鑑別疾患として本疾患は重要であり, そうした症例には, 排便習慣などを確かめることが必要であると思われた.

To determine whether vascular endothelial damage occurs in neonates with asphyxia, we examined the plasma thrombomodulin level at birth in infants with and without asphyxia. The plasma thrombomodulin concentration in 11 asphyxiated infants was significantly elevated compared with that in 48 infants without asphyxia (38.1 vs 27.0 micrograms/l, p < 0.0001). The plasma thrombomodulin-to-serum creatinine ratio was also significantly elevated (0.62 vs 0.48 microgram/mumol, p = 0.0005). The plasma thrombomodulin concentration and the plasma thrombomodulin-to-serum creatinine ratio in infants without asphyxia did not differ between the two types of delivery: normal vaginal delivery and elective caesarean section. Stepwise regression analysis showed the serum D-dimer concentration, plasma pH and serum creatinine concentration were significant independent variables for plasma thrombomodulin concentration, whereas base deficit, platelet count, fibrinogen concentrations and antithrombin III activity were not. Our data suggest that vascular endothelial damage might occur in asphyxiated infants.

We studied the effects of a mild irritant, 10% ethanol, and sofalcone on the gastric mucosal defense mechanisms in newborn rats, comparing the effects to those seen in adult rats. The results indicate

We encountered a gastric bezoar that had developed in a 9-year-old girl treated with sodium alginate (Alloid G) for acute gastritis associated with systemic lupus erythematosus. A hard mass palpated in the left upper abdomen proved, upon gastric endoscopy, to be an intragastric foreign body. Sodium alginate was detected in an analysis of a sample from this bezoar. In an in vitro simulation, sodium alginate solidified when mixed with the patient's other medicines. The bezoar caused no complications, and disappeared spontaneously after discontinuation of the medications. This case indicates that this sodium alginate preparation, Alloid G, can be a cause of pharmacobezoar.

We report pneumatosis cystoides intestinalis in a 10-month-old girl who developed bloody diarrhea following chemotherapy for leukemia. The diagnosis was made only by colonic endoscopic ultrasonography, whereas the abdominal plain radiogram and computed tomography failed to elucidate the diagnosis. She was successfully treated with hyperbaric oxygen therapy. Wider application of endoscopic ultrasonography may lead to the more frequent detection of pneumatosis cystoides intestinalis, currently a rare disorder.