Kazuhiko Nakame

The protective and anti-inflammatory effects of glucagon-like peptide-2 in an experimental rat model of necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease, that affects premature infants. Glucagon-like peptide-2 (GLP-2) is an intestinotrophic hormone and reduces the inflammation. We suspected that GLP-2 would have protective and anti-inflammatory effects in an experimental rat model of NEC. NEC was induced in newborn rats by enteral feeding with hyperosmolar formula, asphyxial stress and enteral administration of lipopolysaccharide (LPS). Rats were randomly divided into the following four groups: dam-fed, NEC, NEC+GLP-2(L) given 80 μg/kg/day of GLP-2, and NEC+GLP-2(H) given 800 μg/kg/day of GLP-2. GLP-2 was administered subcutaneously every 6 h before stress. All animals surviving beyond 96 h or any that developed signs of distress were euthanized. The clinical sickness score in the NEC+GLP-2(H) group was significantly lower than that in the NEC group. The NEC score and the survival rate in the NEC+GLP-2(H) group was significantly improved compared with those in the NEC and the NEC+GLP-2(L) groups. Villous height and crypt depth in both the GLP-2 treatment groups were significantly increased compared with those in the NEC group. There were no significant differences in the crypt cell proliferation indices among the groups. Ileal interstitial TNF-α and IL-6 level in the NEC+GLP-2(H) group was decreased to the same levels in the dam-fed group. High dose GLP-2 administration improved the incidence and survival rate for NEC. It also decreased mucosal inflammatory cytokine production. These results support a potential therapeutic role for GLP-2 in the treatment of NEC.

Fetal Ultrasonography to Prevent Irreversible Neurological Sequelae of Neonatal Neuroblastoma

An intra-abdominal mass was observed by fetal ultrasonography at 32 weeks of gestation. The baby was diagnosed as having neuroblastoma at the time of delivery at 39 weeks and its lower extremities were completely paralyzed. The chemotherapy after birth was quite effective to reduce the mass volume but neurological sequelae failed to improve. By carefully monitoring the movement of extremities, it may have been possible to prevent irreversible paralysis by inducing delivery before that state was reached.

Ghrelin and glucagon-like peptide-2 increase immediately following massive small bowel resection

Children with short bowel syndrome face life-threatening complications. Therefore, there is an urgent need for a new therapy to induce effective adaptation of the remnant intestine. Adaptation occurs only during feeding. We focused on preprandial acyl ghrelin and des-acyl ghrelin, and postprandial glucagon-like peptide-2 (GLP-2), which are known to have active orexigenic and trophic actions. This study aims to clarify the secretion trends of these hormones after massive small bowel resection and to obtain basic data for developing a new treatment. Sixty-three growing male rats were used: 3 were designated as controls receiving no operation and 60 were randomized into the 80% small bowel resection (80% SBR) group and the transection and re-anastomosis group. Changes in body weight, food intake, and remnant intestine morphology were also assessed for 15 days after the operation. Acyl ghrelin and des-acyl ghrelin levels increased immediately, equivalently in both operation groups (P=0.09 and 0.70). Interestingly, in 80% SBR animals, des-acyl ghrelin peaked on day 1 and acyl ghrelin peaked on day 4 (P=0.0007 and P=0.049 vs controls). GLP-2 secretion was obvious in 80% SBR animals (P=2.25×10(-6)), which increased immediately and peaked on day 4 (P=0.009 vs. controls). Body weight and food intake in 80% SBR animals recovered to preoperative levels on day 4. Morphological adaptations were evident after day 4. Our results may suggest a management strategy to reinforce these physiological hormone secretion patterns in developing a new therapy for short bowel syndrome.

Long-term outcome of bowel function for 110 consecutive cases of Hirschsprung's disease: Comparison of the abdominal approach with transanal approach more than 30 years in a single institution – is the transanal approach truly beneficial for bowel function?

BACKGROUND We compared the long-term outcomes of the bowel function (BF) in Hirschsprungs disease (HD) patients who underwent transanal endorectal pull-through (TA) with those who underwent the Soave-Denda (SD) procedure. METHODS Patient data were collected from 1984 to 2015 from 110 HD patients who underwent definitive diagnosis and operation. The follow-up data were analyzed retrospectively. BF was evaluated according to the evacuation score (ES) of the Japan Society of Anorectal Malformation Study Group at 3, 5, 7, 9, and 11years of age. RESULTS The operative procedures performed were as follows: SD: 71 (64.5%), TA: 38 (34.5%), and Duhamel: 1 (1.0%). We compared SD with TA. The ES improved chronologically after both procedures, and patients achieved satisfactory results at least 10years after operation. There was no significant difference in the total ES at all ages. The incontinence and frequency of bowel movement scores of TA patients were significantly lower than those of SD patients at several points. CONCLUSION TA is simple, less invasive, and adaptive for neonates and small infants. However, regarding the bowel function, TA is not always superior to SD. The surgical technique of TA must be improved according to a detailed understanding of the anatomy. LEVEL OF EVIDENCE Retrospective study - level III.

Ghrelin improves intestinal mucosal atrophy during parenteral nutrition: An experimental study

BACKGROUND/PURPOSE Total parenteral nutrition (TPN) has been reported to be associated with mucosal atrophy of the small intestine. Ghrelin has hormonal, orexigenic, and metabolic activities. We investigated whether ghrelin improved intestinal mucosal atrophy using a TPN-supported rat model. METHODS Rats underwent jugular vein catheterization and were divided into four groups: TPN alone (TPN), TPN plus low-dose ghrelin (TPNLG), TPN plus high-dose ghrelin (TPNHG), and oral feeding with normal chow (OF). Ghrelin was administered continuously at dosages of 10 or 50 μg/kg/day. On day 6 rats were euthanized, and the small intestine was harvested and divided into the jejunum and ileum. Then the villus height (VH) and crypt depth (CD) were evaluated. RESULTS The jejunal and ileal VH and CD in the TPN group were significantly decreased compared with those in the OF group. TPNHG improved only VH of the jejunum. TPNLG improved VH and CD of the jejunum and CD of the ileum. The improvement of TPNLG was significantly stronger than that in CD of the jejunum and ileum. CONCLUSIONS TPN was more strongly associated with mucosal atrophy in the jejunum than in the ileum. Low-dose intravenous administration of ghrelin improved TPN-associated intestinal mucosal atrophy more effectively than high-dose administration.

Long-term follow-up for anicteric survival with native liver after redo Kasai: a first report

PURPOSE We present a first report of the long-term follow-up of biliary atresia (BA) patients who became anicteric with the native liver (ANL; total bilirubin <1.5mg/dL) after redo-Kasai. METHODS Forty-six redo-Kasai cases (1984-2015) were the subjects for this study. ANL ratios were determined using the Kaplan-Meier estimate. RESULTS BA type was I (n=3), II (n=1), and III (n=42). Mean ages (initial/redo) at Kasai were 60.3/231.9days, respectively. Jaundice persisted after the initial Kasai in 24/46 cases while 22 had recurrence of jaundice after initially becoming anicteric. After redo, 5/24 of the persistent jaundice cases and 14/22 of the initially anicteric cases became anicteric (p<.05). Of these 19, 7 (one type I, six type III) are currently ANL while the remaining 12 had LTx or died. Morbidity/Complications documented in the 7 post-redo ANL cases after a mean follow-up of 16.7years (range: 10.0-31.1) included 4 episodes of cholangitis, 3 episodes of portal hypertension, 4 episodes of esophageal varices, 3 episodes of splenomegaly, one splenectomy, and 4 episodes of thrombocytopenia. CONCLUSIONS Ours is the first long-term follow-up study of redo-Kasai cases. We found that the ANL ratio after redo-Kasai was low at 7/46 (15.2%) and that ANL were prone to multiple morbidity. LEVEL OF EVIDENCE Retrospective comparative study, level III.

Ghrelin stimulates intestinal adaptation following massive small bowel resection in parenterally fed rats

Background: Since short bowel syndrome (SBS) patients face life‐threatening conditions, the development of therapeutic strategies to induce intestinal adaptation has been investigated. Ghrelin, a ligand of growth hormone (GH) secretagogue‐receptor that stimulates the release of GH and insulin like growth factor‐1 (IGF‐1), has several pleiotropic effects. We investigated whether ghrelin induces intestinal adaptation in parenterally fed rats with SBS. Methods: Sprague‐Dawley rats underwent venous catheterization and were divided into 3 groups: those receiving 90% small bowel resection while leaving the proximal jejunum and distal ileum (90% SBR) with TPN (SBS/TPN group), those receiving 90% SBR with TPN+ghrelin (SBS/TPN/ghrelin group), and those receiving sham operation and fed chow (sham group). Ghrelin was administered intravenously at 10&mgr;g/kg/day. On Day 13, the rats were euthanized and the small intestine harvested, and the histology and crypt cell proliferation rates (CCPR), apoptosis, and nutrient transporter protein levels were analyzed and the plasma hormones were measured. Results: The villus height and crypt depth of the ileum in the SBS/TPN/ghrelin group were significantly higher than in the SBS/TPN group. The CCPR of the jejunum and the ileum significantly increased by the administration of ghrelin; however, the apoptosis rates did not significantly differ between the SBS/TPN and SBS/TPN/ghrelin groups. Significant differences did not exist in the plasma IGF‐1 and nutrient transporter protein levels among three groups. Conclusions: The intravenous administration of ghrelin stimulated the morphological intestinal adaptation of the ileum to a greater degree than the jejunum due to the direct effect of ghrelin. HIGHLIGHTSVillus height and crypt depth of the ileum were increased by ghrelin.Crypt cell proliferation rates of the small intestine were increased by ghrelin.Plasma IGF‐1 concentrations were not altered with or without ghrelin.The nutrient transporter protein levels were not changed with or without ghrelin.

The bowel function and quality of life of Hirschsprung disease patients who have reached 18 years of age or older – the long-term outcomes after undergoing the transabdominal soave procedure

BACKGROUND/PURPOSE Hirschsprung disease (HD) is considered curable, but the postoperative bowel function is not always satisfactory. In this study, we evaluated the general condition, bowel function, and social performance in adults who were older than 17years of age who had undergone definitive operations in childhood. METHOD From 1984 to 2016, 110 patients with HD underwent definitive surgery at our institute. Sixty-three patients who had undergone the transabdominal Soave procedure reached 18years of age. Their present status and symptoms, anorectal function, genitourinary function, and social performance were evaluated during the clinical follow-up via a questionnaire survey. RESULT The mean age of the questionnaire respondents was 25.0 (19-37) years. The bowel function was mostly good. However, 56% of patients had abdominal pain more than once a week. Regarding evacuation symptoms, incontinence and soiling occurred in 18.7%. Among the respondents 33.3% were married, and 60% of those who were married had children. The respondents had achieved success in their education and professional careers. CONCLUSION The bowel function of most patients was satisfactory, although some had chronic abdominal symptoms. Pediatric surgeons should continue trying to achieve complete bowel function after definitive surgery of HD. TYPE OF STUDY Prospective Cohort Study. LEVEL OF EVIDENCE Level III.

Oral diatrizoate acid for meconium‐related ileus in extremely preterm infants

Intestinal disorders are common in very low‐birthweight infants. The purpose of this study was to evaluate the impact of prophylactic oral Gastrografin® (diatrizoate acid) on meconium‐related ileus (MRI) in extremely preterm infants.

Rare case of ectopic pancreas presenting with persistent umbilical discharge

1 Girard N, Brunel H, Dory-Lautrec P, Chabrol B. Neuroimaging differential diagnoses to abusive head trauma. Pediatr. Radiol. 2016; 46: 603–14. 2 Sieswerda-Hoogendoorn T, Boos S, Spivack B, Bilo RA, van Rijn RR. Abusive head trauma: part II: radiological aspects. Eur. J. Pediatr. 2012; 171: 617–23. 3 Suh DY, Davis PC, Hopkins KL, Fajman NN, Mapstone TB. Nonaccidental pediatric head injury: diffusion-weighted imaging findings. Neurosurgery 2001; 49: 309–18; discussion 318–20. 4 Orman G, Wagner MW, Seeburg D et al. Pediatric skull fracture diagnosis: should 3D CT reconstructions be added as routine imaging? J. Neurosurg. Pediatr. 2015; 16: 426–31. 5 Bin SS, Schutzman SA, Greenes DS. Validation of a clinical score to predict skull fracture in head-injured infants. Pediatr. Emerg. Care 2010; 26: 633–9.