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Midgut volvulus is associated with intestinal ischemia/reperfusion (IR) injury and can progress to severe intestinal damage. Remote ischemic conditioning (RIC) reduces IR-induced injury in distant organs. The aim of this study was to investigate whether RIC protects the intestine from IR injury. We investigated intestinal IR injury in 3 weeks old SD rats. Animals underwent: (i) sham laparotomy, (ii) intestinal IR injury, (iii) intestinal IR + RIC during ischemia, or (iv) intestinal IR + RIC after reperfusion. Intestinal IR injury was achieved by 45 min occlusion of superior mesenteric artery followed by de-occlusion. RIC was administered via four cycles of 5 min of hind limb ischemia followed by 5 min reperfusion. Animals were sacrificed 24 h after surgery and the ileum was harvested for evaluation. Intestinal injury was present after IR. However, this injury was reduced in both IR + RIC groups. Expression of inflammatory cytokine IL6 was lower in IR + RIC groups compared to IR alone. Carbonyl protein was also significantly lower in IR + RIC compared to IR, indicating lower oxidative stress in both IR + RIC groups. Remote ischemic conditioning attenuated intestinal injury, inflammation, and oxidative stress in experimental intestinal ischemia/reperfusion injury. Remote ischemic conditioning may be useful in children with midgut volvulus to reduce the intestinal injury. Experimental study. Animal experiment.

Background Our previous study identified methicillin-resistant Staphylococcus aureus (MRSA) colonization as an independent risk factor for neonatal surgical site infection. Here we introduce intraoral breast milk application (IBMA) during a fasting state to prevent MRSA colonization. We aimed to evaluate both the risk factors for MRSA colonization and the efficacy of IBMA in neonatal surgical patients. Methods A retrospective review was performed using admission data from 2007 to 2016. Neonatal patients who underwent surgery and were tested periodically for MRSA colonization were evaluated for an association between MRSA colonization and perinatal or perioperative factors. Results The overall incidence of MRSA colonization for the 159 patients enrolled in this study was 16.4%. Univariate analysis showed that MRSA colonization was significantly more frequent in the following patients: those with Down syndrome, those admitted on their day of birth, those in need of fasting immediately after birth, and those not receiving IBMA. Multivariate analysis showed that comorbid Down syndrome was an independent risk factor (hazard ratio: 4.6; 95% confidence interval: 1.2-19.5, P = 0.03) and implementation of IBMA was an independent preventive factor for MRSA colonization (hazard ratio: 0.4; 95% confidence interval: 0.1-0.9, P = 0.04). MRSA-positive patients admitted significantly earlier and stayed longer preoperatively than MRSA-negative patients. Conclusions In neonates undergoing surgery, and patients with Down syndrome, early diagnosis after birth and a long waiting period before operation may be associated with MRSA colonization. Intraoral breast milk application may be beneficial for preventing MRSA colonization.

Ischemia/reperfusion (I/R) is implicated in the pathogenesis of various acute intestinal injuries. Amniotic fluid stem cells (AFSC) are beneficial in experimental intestinal diseases. Tumor necrosis factor-induced protein 6 (TSG-6) has been shown to exert anti-inflammatory effects. We aimed to investigate if AFSC secreted TSG-6 reduces inflammation and rescues intestinal I/R injury. The superior mesenteric artery of 3-week-old rats was occluded for 90 minutes and green fluorescent protein-labeled AFSC or recombinant TSG-6 was injected intravenously upon reperfusion. AFSC distribution was evaluated at 24, 48, and 72 hours after I/R. AFSC and TSG-6 effects on the intestine were assessed 48 hours postsurgery. Intestinal organoids were used to study the effects of TSG-6 after hypoxia-induced epithelial damage. After I/R-induced intestinal injury, AFSC migrated preferentially to the ileum, the primary site of injury, through blood circulation. Engrafted AFSC reduced ileum injury, inflammation, and oxidative stress. These AFSC-mediated beneficial effects were dependent on secretion of TSG-6. Administration of TSG-6 protected against hypoxia-induced epithelial damage in intestinal organoids. Finally, TSG-6 attenuated intestinal damage during I/R by suppressing genes involved in wound and injury pathways. This study indicates that AFSC or TSG-6 have the potential of rescuing the intestine from the damage caused by I/R.

Necrotizing enterocolitis (NEC) is a devastating neonatal disease characterized by acute intestinal injury. Intestinal stem cell (ISC) renewal is required for gut regeneration in response to acute injury. The Wnt/β-catenin pathway is essential for intestinal renewal and ISC maintenance. We found that ISC expression, Wnt activity and intestinal regeneration were all decreased in both mice with experimental NEC and in infants with acute active NEC. Moreover, intestinal organoids derived from NEC-injured intestine of both mice and humans failed to maintain proliferation and presented more differentiation. Administration of Wnt7b reversed these changes and promoted growth of intestinal organoids. Additionally, administration of exogenous Wnt7b rescued intestinal injury, restored ISC, and reestablished intestinal epithelial homeostasis in mice with NEC. Our findings demonstrate that during NEC, Wnt/β-catenin signaling is decreased, ISC activity is impaired, and intestinal regeneration is defective. Administration of Wnt resulted in the maintenance of intestinal epithelial homeostasis and avoidance of NEC intestinal injury. ispartof: Cell Death & Disease vol:10 issue:10 ispartof: location:England status: published

Background The predictive factors for chronic pouchitis after ileal pouch–anal anastomosis (IPAA) in pediatric-onset ulcerative colitis (UC) remain unclear. This study evaluated the predictive factors for chronic pouchitis after IPAA in patients with pediatric UC. Methods The data from 52 patients with pediatric-onset UC who underwent IPAA in Mie University Hospital were retrospectively reviewed. The endoscopy surveillance was performed yearly or at the timing of the symptom. Chronic pouchitis was defined as antibiotic-dependent/-refractory and relapsing cases. Potential predictors of chronic pouchitis were analyzed. Results During the first 5 years after IPAA, pouchitis was identified in 32.7%. Of these patients, 12 (70.6%) developed chronic pouchitis. The predictor of chronic pouchitis was a preoperative history of immunomodulator use before IPAA (p = 0.04). Life table analysis revealed that patients with chronic pouchitis tended to develop pouchitis earlier after IPAA than did patients without chronic pouchitis (p = 0.012). Receiver operating characteristic curve analysis showed that the occurrence of pouchitis within 15 months after IPAA surgery predicted the development of chronic pouchitis (sensitivity, 92%; specificity, 80%). Conclusion In pediatric patients with UC, the predictive factors for chronic pouchitis are immunomodulator use and early occurrence of the first episode of pouchitis within 15 months after IPAA. Level of evidence III

Background The predictive factors for the development of pouchitis after ileal pouch-anal anastomosis (IPAA) in pediatric-onset ulcerative colitis (UC) have not been well investigated. The present study aimed to determine the predictive factors for the development of pouchitis after IPAA in the pediatric UC population. Methods The data from 54 patients with pediatric-onset UC who underwent IPAA in Mie University Hospital between 2000 and 2017 were retrospectively reviewed. A modified pouchitis disease activity index of ≥5 was defined as pouchitis. Potential preoperative, intraoperative, and postoperative predictors for pouchitis including various demographic and clinical variables were analyzed using Cox regression analysis, Students’ t-tests, Mann–Whitney U tests, and Kaplan–Meier curves. The optimal cutoff value for continuous variables was determined using the receiver operating characteristic curve analysis. Results Pouchitis was identified in 17 (31.5%) patients within 5 y of follow-up. In multivariable analysis, the independent predictors for pouchitis were preoperative cumulative steroid dose of >10,000 mg (P = 0.0056) and >65% neutrophils just before IPAA (P = 0.032). Multivariate analysis revealed that the independent predictors of pouchitis were a total steroid dose of >10,000 mg (P = 0.0002) and a neutrophil percentage of >65% (P = 0.0078). No patient for whom both of these independent predictors were negative developed pouchitis, whereas >40% of patients who had one or both predictors developed pouchitis. Conclusions In pediatric patients with UC, the predictive factors for pouchitis development are a greater cumulative total dose of steroids and a greater percentage of neutrophils before IPAA.

Background Sarcopenia frequently occurs in metastatic cancer patients. Emerging evidence has revealed that various secretory products from metastatic tumours can influence host organs and promote sarcopenia in patients with malignancies. Furthermore, the biological functions of microRNAs in cell‐to‐cell communication by incorporating into neighbouring or distal cells, which have been gradually elucidated in various diseases, including sarcopenia, have been elucidated. Methods We evaluated psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC) using pre‐operative computed tomography imaging in 183 colorectal cancer (CRC) patients. miR‐203 expression levels in CRC tissues and pre‐operative serum were evaluated using quantitative polymerase chain reaction. Functional analysis of miR‐203 overexpression was investigated in human skeletal muscle cells (SkMCs), and cells were analysed for proliferation and apoptosis. Expressions of several putative miR‐203 target genes (CASP3, CASP10, BIRC5, BMI1, BIRC2, and BIRC3) in SKMCs were validated. Results A total of 183 patients (108 men and 75 women) were included. The median age of enrolled patients at diagnosis was 68.0 years (range 35–89 years). High IMAC status significantly correlated with female gender (P = 0.004) and older age (P = 0.0003); however, no other clinicopathological factors correlated with IMAC status in CRC patients. In contrast, decreased PMI significantly correlated with female gender (P = 0.006) and all well‐established disease development factors, including advanced T stage (P = 0.035), presence of venous invasion (P = 0.034), lymphovascular invasion (P = 0.012), lymph node (P = 0.001), distant metastasis (P = 0.002), and advanced Union for International Cancer Control tumour–node–metastasis stage classification (P = 0.0004). Although both high IMAC status and low PMI status significantly correlated with poor overall survival (IMAC: P = 0.0002; PMI: P

Necrotizing enterocolitis (NEC) is one of the most severe gastrointestinal diseases affecting premature infants. It has been shown that NEC is associated with disrupted intestinal barrier and dysregulated endoplasmic reticulum (ER)-stress response. It has also been shown that stem cells derived from amniotic fluid (AFSC) rescued intestinal injury in experimental NEC. Herein, we hypothesized that the beneficial effects of AFSC in the injured intestine are due to the restoration of intestinal barrier function. We evaluated intestinal barrier function using an ex vivo intestinal organoid model of NEC. We found that AFSC restored the expression and localization of tight junction proteins in intestinal organoids, and subsequently decreased epithelial permeability. AFSC rescued tight junction expression by inducing a protective ER stress response that prevents epithelial cell apoptosis in injured intestinal organoids. Finally, we validated these results in our experimental mouse model of NEC and confirmed that AFSC induced sustained ER stress and prevented intestinal apoptosis. This response led to the restoration of tight junction expression and localization, which subsequently reduced intestinal permeability in NEC pups. These findings confirm that intestinal barrier function is disrupted during NEC intestinal injury, and further demonstrate the disruption can be reversed by the administration of AFSC through the activation of the ER stress pathway. This study provides insight into the pathogenesis of NEC and highlights potential therapeutic targets for the treatment of NEC.

Monitoring disease progression is crucial to improve the outcome of necrotizing enterocolitis (NEC). A previous study indicates that intestinal wall flow velocity was reduced in NEC pups from the initial stages of the disease. This study aims to investigate whether splanchnic perfusion via the superior mesenteric artery (SMA) (i) is altered during NEC development and (ii) can be used as a monitoring tool to assess disease progression. NEC was induced in C57BL/6 mice via gavage feeding of formula, hypoxia, and oral lipopolysaccharide, from postnatal day 5 (P5) to P9 (AUP: 32,238). Breastfed littermates served as controls. Doppler ultrasound (U/S) of bowel loops was performed daily. Intestinal wall perfusion was calculated as average flow velocity (mm/s) of multiple abdominal regions. Groups were compared using one-way ANOVA. The SMA flow velocity was not altered during the initial stage of NEC development, but become significantly reduced at P8 when the intestinal disease was more advanced. These changes occurred concomitantly with an increase in heart rate. NEC is associated with intestinal hypo-perfusion at the periphery and flow in the SMA is reduced during the later stages of disease indicating the presence of intestinal epithelium damage. This study contributes to understanding NEC pathophysiology and illustrates the value of Doppler U/S in monitoring disease progression.

Necrotizing enterocolitis (NEC) is a devastating disease of premature infants with high mortality rate, indicating the need for precision treatment. NEC is characterized by intestinal inflammation and ischemia, as well derangements in intestinal microcirculation. Remote ischemic conditioning (RIC) has emerged as a promising tool in protecting distant organs against ischemia-induced damage. However, the effectiveness of RIC against NEC is unknown. To address this gap, we aimed to determine the efficacy and mechanism of action of RIC in experimental NEC. NEC was induced in mouse pups between postnatal day (P) 5 and 9. RIC was applied through intermittent occlusion of hind limb blood flow. RIC, when administered in the early stages of disease progression, decreases intestinal injury and prolongs survival. The mechanism of action of RIC involves increasing intestinal perfusion through vasodilation mediated by nitric oxide and hydrogen sulfide. RIC is a viable and non-invasive treatment strategy for NEC., Necrotizing enterocolitis (NEC) is one of the most lethal gastrointestinal emergencies in neonates needing precision treatment. Here the authors show that remote ischemic conditioning is a non-invasive therapeutic method that enhances blood flow in the intestine, reduces damage, and improves NEC outcome.

We aimed to identify predictive factors for the development of chronic pouchitis after ileal pouch-anal anastomosis in patients with ulcerative colitis. Three hundred eighty-seven patients who underwent ileal pouch-anal anastomosis for diagnosis of ulcerative colitis from January 2002 to March 2019 were included in this retrospective analysis. Of 115 patients with pouchitis, 40 patients exhibited acute pouchitis, and 75 patients exhibited chronic pouchitis. Of 75 patients with chronic pouchitis, 11 patients were diagnosed with chronic antibiotic-refractory pouchitis. Multivariate analysis revealed that early pouchitis onset and modified Pouchitis Disease Activity Index score ≥ 7 were independent predictive factors for chronic pouchitis (p = 0.0004 and p = 0.029, respectively). Mean onset of pouchitis after intestinal continuity was significantly earlier in patients with chronic pouchitis than in patients with acute pouchitis (acute pouchitis vs. chronic pouchitis: 3.72 ± 2.98 years vs. 1.85 ± 2.40 years, p < 0.0001). Total modified Pouchitis Disease Activity Index score was significantly higher in patients with chronic pouchitis than in patients with acute pouchitis (acute pouchitis vs. chronic pouchitis: 5.9 ± 1.2 vs. 6.9 ± 1.6, p = 0.0020). Patients with ulcerative colitis were more likely to develop chronic pouchitis if they exhibited early onset or severe disease activity at onset. Evaluation of both factors can aid in early treatment decisions to alleviate chronic pouchitis.

Severe neonatal gastrointestinal diseases such as necrotizing enterocolitis or spontaneous intestinal perforation are potentially lethal conditions which predominantly occur in preterm infants. Cytomegalovirus (CMV), which is known to cause congenital and acquired infections in the newborns, has also been implicated in such severe gastrointestinal diseases in premature infants. However, the pathogenic role of CMV and effect of antiviral therapy in severe gastrointestinal disease in premature neonates is currently unclear. We present an infant, born at 26-weeks' gestation, presented with progressive dyspepsia and abdominal distention after the closure of the symptomatic patent ductus arteriosus at the day of life (DOL) 4, requiring the emergent surgery for ileal perforation at the DOL8. After the surgery, abdominal symptoms persisted and the second emergent surgery was performed for the recurrent ileal perforation at DOL17. Even then the abdominal symptoms prolonged and pathological examination in the affected intestine at the second surgery showed CMV inclusion body. Immunoreactivity for CMV antigen was detected in the specimen at the first surgery on DOL8. Blood and urinary CMV-DNA were detected at DOL28. CMV-DNA was also detected in the dried umbilical cord which was obtained within a week from birth. A 6-week course of intravenous ganciclovir (12 mg/kg/day) was started at DOL34 and then symptoms resolved along with decreasing blood CMV-DNA. Pathological findings characteristic of CMV were not detected in the resection specimen at the ileostomy closure at DOL94. These observations indicate that anti-CMV therapy may be beneficial for some premature infants with severe CMV-associated gastrointestinal diseases and warrants further studies focusing on pathogenic role, diagnosis, treatment and prevention of this underrecognized etiology of severe gastrointestinal diseases particularly in premature neonates.

Necrotizing enterocolitis (NEC) is a devastating intestinal disease primarily affecting preterm neonates and causing high morbidity, high mortality, and huge costs for the family and society. The treatment and the outcome of the disease have not changed in recent decades. Emerging evidence has shown that stimulating the Wnt/β-catenin pathway and enhancing intestinal regeneration are beneficial in experimental NEC, and that they could potentially be used as a novel treatment. Amniotic fluid stem cells (AFSC) and AFSC-derived extracellular vesicles (EV) can be used to improve intestinal injury in experimental NEC. However, the mechanisms by which they affect the Wnt/β-catenin pathway and intestinal regeneration are unknown. In our current study, we demonstrated that AFSC and EV attenuate NEC intestinal injury by activating the Wnt signaling pathway. AFSC and EV stimulate intestinal recovery from NEC by increasing cellular proliferation, reducing inflammation and ultimately regenerating a normal intestinal epithelium. EV administration has a rescuing effect on intestinal injury when given during NEC induction; however, it failed to prevent injury when given prior to NEC induction. AFSC-derived EV administration is thus a potential emergent novel treatment strategy for NEC. ispartof: CELL DEATH & DISEASE vol:11 issue:9 ispartof: location:England status: published

Establishment of evidence-based best practices for preventing surgical site infection (SSI) in neonates is needed. SSI in neonates, especially those with a low birth weight, is potentially life-threatening. We aimed to identify risk factors associated with SSI in neonates. A retrospective review was performed using 2007–2016 admission data from our institution. Neonatal patients who were admitted to the neonatal intensive care unit and underwent surgery were evaluated for a relationship between development of SSI and perinatal or perioperative factors and methicillin-resistant Staphylococcus aureus (MRSA) colonization during hospitalization. One hundred and eighty-one patients were enrolled in this study. Overall SSI incidence was 8.8%. Univariate analysis showed that SSI was significantly more frequent in both patients with contaminated or dirty wound operations and patients with MRSA colonization during hospitalization. Both of these factors were identified as independent risk factors for SSI by multivariate analysis [hazard ratio (HR): 6.1, 95% confidence interval (CI) 2.0–19.9; HR: 3.3, 95% CI 1.1–10.4, respectively]. This study identified contaminated or dirty wound operations and MRSA colonization during hospitalization as risk factors for SSI in neonates. MRSA colonization may be a preventable factor, unlike previously reported risk factors.

In neonatal surgical patients requiring an enterostomy, there is no definitive recommendation regarding the ideal enterostomy location: at the edge of the primary incision or at a different incision. We retrospectively reviewed 2005–2017 administration data in our institution. All neonatal patients who underwent contaminated or dirty wound laparotomy and enterostomy construction were evaluated regarding the enterostomy location, occurrence of postoperative incisional surgical-site infection (SSI) at the primary incision, and stoma-related complications. Patients were divided into two groups based on stoma location: at the primary incision (the same incision group: SI group, n = 16) or at another incision (different incision group: DI group, n = 23). We performed 2 jejunostomies, 13 ileostomies, and 1 colostomy in the SI group, and 4 jejunostomies, 18 ileostomies, and 1 colostomy in the DI group. One of 16 patients (6.3%) in the SI group and 2/23 patients (8.7%) in the DI group experienced superficial incisional SSI, with comparable SSI incidence between groups (p = 0.78). Every SSI did not result in stoma-related complications. Although the enterostomy location did not influence the incidence of laparotomy wound infection in this study, prospective studies are mandatory to fully assess the safety of enterostomy construction at the edge of the primary incision.

Purpose Gastroesophageal reflux after surgical repair of esophageal atresia (EA) can be associated with complications, such as esophageal stricture. Recent guidelines recommend prophylactic anti-reflux medication (PARM) after EA repair. However, the effectiveness of PARM is still unclear. The aim of this study was to review evidence surrounding the use of PARM in children operated for EA. Methods We performed a systematic review and meta-analysis. We searched Medline, EMBASE, and the Cochrane Databases from inception until the end of 2016 for comparative studies of PARM versus no PARM (control). Primary outcome was postoperative esophageal stricture. Quality of evidence was assessed using GRADE system. Results We identified four observational studies that focused on esophageal stricture as an outcome. A total of 362 patients were included in meta-analysis. There was no significant difference in esophageal stricture rates between PARM and control (OR = 1.14; 95% CI = 0.61–2.13; p = 0.68; I2 = 38%). The quality of the evidence was very low, due to lack of precision as a consequence of small study sizes. Conclusions Our results indicate that PARM does not reduce the incidence of esophageal stricture after EA repair. Future well-controlled prospective studies are needed to obtain higher quality evidence.

Introduction Management of necrotizing enterocolitis (NEC) consists of cessation of enteral feeding, intravenous antibiotic administration, and supportive treatment. There is no evidence-based recommendation regarding when to restart feeding after a NEC episode. We performed a systematic review and meta-analysis to examine the effect of timing of enteral feeding reinitiation on NEC recurrence. Methods MEDLINE, Embase, Google scholar, and Cochrane databases were searched. Human studies evaluating enteral feeding timing with a primary outcome of NEC recurrence were included. A total of 2,257 titles or abstracts were screened, and 47 full-text articles were analyzed. A systematic review and meta-analysis comparing NEC recurrence and other associated outcomes between early (5 days) initiation of enteral feeding after NEC were performed according to the PRISMA statement. The meta-analysis data were analyzed using RevMan 5.3 to estimate odds ratios (ORs) with 95% confidence intervals (CIs). Results Two retrospective observational studies met the inclusion criteria, comprising 56 cases in which enteral feeding was started early and 35 cases of delayed enteral feeding initiation. There were no randomized controlled trials (RCTs). The recurrence rates of NEC were unchanged between early (5.4%) and delayed (8.6%) enteral feeding groups (pooled OR = 0.61; 95% CI: 0.12–3.16; p = 0.56; I 2 = 0%). Catheter-related sepsis (pooled OR = 0.20; 95% CI: 0.01–3.29; p = 0.26; I 2 = 67%) and post-NEC stricture (pooled OR = 0.28; 95% CI: 0.07–1.18; p = 0.08; I 2 = 23%) rates were not different between early and delayed enteral feeding groups. Conclusion Initiating early enteral feeding, within 5 days of NEC diagnosis, is not associated with adverse outcomes, including NEC recurrence. In addition, catheter-related sepsis and post-NEC stricture rates were unchanged between early and delayed enteral feeding groups after NEC. However, the quality of the evidence from the review of literature is suboptimal. A further RCT is needed to confirm these results.

Background Breast milk administration prevents necrotizing enterocolitis (NEC). However, the mechanism remains unclear. Exosomes are cell-derived vesicles highly present in human milk and regulate intercellular signaling, inflammation, and immune response. We hypothesized that milk-derived exosomes beneficially affect intestinal epithelial cells. Methods Rat milk was collected, and exosomes were isolated using ExoQuick reagent and visualized by Nanoparticle Tracking Analysis. Protein was extracted from encapsulating exosomes, and concentration was measured. 2×10 4 intestinal epithelial cells (IEC-18) were treated for five hours with 0.5-μg/μl exosomes, an equal volume of exosome-free milk, or control solution (PBS). IEC-18 viability was measured using a colorimetric assay (MTT), and gene expression was analyzed by qRT-PCR. Data were compared using one-way ANOVA with Bonferroni post-test. Results Rat milk was collected, and exosome isolation was confirmed. Compared to control, treatment with exosomes significantly increased IEC viability, proliferation, and stem cell activity (all p Conclusions Rat milk-derived exosomes promote IEC viability, enhance proliferation, and stimulate intestinal stem cell activity. These findings provide insight into the mechanism of action of breast milk in the intestines. Exosome administration is a promising prevention method for infants at risk of developing NEC when breastfeeding is not tolerated.

Purpose Oxidative stress has been implicated in the pathogenesis of various neonatal diseases involving the intestine. Hydrogen sulfide (H 2 S) has been shown to protect against oxidative stress. We hypothesized that administration of sodium hydrosulfide (NaHS), an H 2 S donor, to neonatal mice can decrease the intestinal epithelial injury associated with maternal separation (MS). Methods C57BL/6 mice received either intraperitoneal phosphate buffered saline (PBS; n=10) or NaHS (1mg/kg/day; n=10), followed by MS for 3h daily between postnatal day P5 and P9. Control neonatal mice were untreated and were not exposed to MS (n=10). Proximal colon was harvested and analyzed for crypt length, goblet cell number per crypt, oxidative stress and inflammation. Groups were compared using one-way ANOVA with Bonferroni post-test. Results Compared to controls, MS+PBS mice had shorter crypt lengths, fewer goblet cells per crypt, reduced glutathione peroxidase activity, increased expression of thiobarbituric acid reactive substances and inducible nitric oxide synthase mRNA, as well as increased IL-6 , TNFα and myeloperoxidase. Administration of NaHS significantly counteracted these negative effects of MS. Conclusions H 2 S protects the colon from the epithelial damage, oxidative stress and inflammation caused by maternal separation. This study provides insights on the pathogenesis of neonatal bowel diseases and indicates the potential for a pharmacological intervention to rescue the colonic epithelium. Level of evidence n/a – animal and laboratory study.

Administration of hyperosmolar formula is regarded as a risk factor for the development of necrotizing enterocolitis (NEC). However, there are limited number of reports about the relationship between formula osmolality and NEC. The aim of this study is to evaluate the effects of formula concentration in an experimental model of NEC. We studied experimental NEC in C57BL/6 mice. NEC was induced by giving hypoxia, gavage administration of lipopolysaccharide and gavage formula feeding from postnatal day 5–9. We used two types of formula: (1) hyperosmolar formula (HF): 15 g Similac + 75 ml Esbilac (849 mOsm/kg); (2) diluted formula (DF): dilute hyperosmolar formula with an equal amount of water (325 mOsm/kg). Controls were fed by the mother. On postnatal day 9, the ileum was harvested and evaluated for severity of mucosal injury (hematoxylin/eosin staining) and inflammation (PCR for IL6 and TNFα mRNA expression). The incidence of NEC was same in both HF and DF (80%). The intestinal inflammatory response was similar between HF and DF (IL6: p = 0.26, TNFα: p = 0.69). This study indicates the osmolality of enteral formula does not affect incidence of experimental NEC. This experimental study provides new insights into the relationship between formula feeding and NEC.

BACKGROUND The aim of the present study was to investigate the efficacy and safety of double-balloon enteroscopy (DBE) in postoperative pediatric patients. METHODS This was a retrospective analysis of pediatric patients 18 years and younger referred to Mie University Hospital. Twenty procedures in 11 children occurred postoperatively; 29 children (42 procedures) had not undergone surgery. RESULTS Among postoperative patients, five DBE procedures were performed via the oral route, 12 via the anal route, and three via a stomal route. Among nonoperative patients, 14 DBE procedures were performed via the oral route and 28 via the anal route. Four postoperative patients and two nonoperative patients had difficult pleating via the transanal route because of adhesions or thickening of the intestinal wall resulting from inflammation (P = 0.02). Excluding patients with stenosis, the mean length of endoscopic insertion for transanal procedures was significantly shorter among postoperative patients than among nonoperative patients (73.6 cm vs 160.5 cm, P

Major risk factors for necrotizing enterocolitis (NEC) are formula feeding and prematurity; however, their pathogenic mechanisms are unknown. Here, we found that insufficient arginine/nitric oxide synthesis limits blood flow in the intestinal microvasculature, leading to hypoxia, mucosal damage and NEC in the premature intestine after formula feeding. Formula feeding led to increased intestinal hypoxia in pups at postnatal day (P)1 and P5, but not in more mature pups at P9. Accordingly, blood flow in the intestinal microvasculature increased after formula feeding in P9 pups only. mRNA profiling revealed that regulators of arginine/nitric oxide synthesis are at higher levels in endothelial cells of the intestine in P9 than in P1 pups. Importantly, arginine supplementation increased intestinal microvasculature blood flow and prevented NEC, whereas an arginine antagonist exacerbated NEC. Our results suggest that balancing intestinal oxygen demand and supply in the premature intestine by modulating arginine/nitric oxide could be used to prevent NEC. This article has an associated First Person interview with the first author of the paper., Summary: We demonstrate that the immature gut is prone to necrotizing enterocolitis due to limited arginine/nitric oxide synthesis, leading to inadequate microcirculation in response to the challenge imposed by formula feeding.

Necrotizing enterocolitis (NEC) is characterized by intestinal injury and impaired mucin synthesis. We recently showed that breast milk exosomes from rodents promote intestinal cell viability, epithelial proliferation, and stem cell activity, but whether they also affect mucus production is unknown. Therefore, the aim of this study was to investigate the effects of bovine milk-derived exosomes on goblet cell expression in experimental NEC and delineate potential underlying mechanisms of action. Exosomes were isolated from bovine milk by ultracentrifugation and confirmed by Nanoparticle Tracking Analysis and through the detection of exosome membrane markers. To study the effect on mucin production, human colonic LS174T cells were cultured and exposed to exosomes. Compared to control, exosomes promoted goblet cell expression, as demonstrated by increased mucin production and relative expression levels of goblet cell expression markers trefoil factor 3 (TFF3) and mucin 2 (MUC2). In addition, exosome treatment enhanced the expression of glucose-regulated protein 94 (GRP94), the most abundant intraluminal endoplasmic reticulum (ER) chaperone protein that aids in protein synthesis. Furthermore, experimental NEC was induced in mouse pups by hyperosmolar formula feeding, lipopolysaccharide administration and hypoxia exposure on postnatal days 5-9. Milk exosomes were given with each gavage feed. NEC was associated with ileal morphological injury and reduction in MUC2+ goblet cells and GRP94+ cells per villus. Exosome administration to NEC pups prevented these changes. This research highlights the potential novel application of milk-derived exosomes in preventing the development of NEC in high-risk infants when breast milk is not available.

Apart from primary pouchitis, patients with secondary pouchitis caused by surgical complications require surgical management. The use of abdomino-anal salvage surgery to treat secondary pouchitis caused by surgical complications in pediatric patients with ulcerative colitis (UC) has not been reported in detail. A girl was diagnosed with UC at 8 years old. She underwent restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) at 9 years old. She presented at 12 years old because of chronic antibiotic-refractory pouchitis. The fistula and stricture failed to improve despite multiple local salvage surgeries and ileostomy construction. At 15 years old, she underwent redo IPAA. The patient was well at 20 years old with no signs of pouchitis. Early treatment by abdomino-anal salvage surgery might be indicated to improve quality of life in pediatric patients with secondary pouchitis caused by surgical complication unresponsive to defunctioning and local salvage surgery.

Neutrophil extracellular traps (NETs) promote cancer metastasis in preclinical models following massive exogenous inflammatory stimuli. It remains unknown whether cancer hosts under physiologic conditions experience NETosis and consequent metastasis. Here we show that plasma redox imbalance caused by albumin oxidation promotes inflammation-independent NETosis. Albumin is the major source of free thiol that maintains redox balance. Oxidation of albumin-derived free thiol is sufficient to trigger NETosis via accumulation of reactive oxygen species within neutrophils. The resultant NETs are found predominantly within lungs where they contribute to the colonization of circulating tumor cells leading to pulmonary metastases. These effects are abrogated by pharmacologic inhibition of NET formation. Moreover, albumin oxidation is associated with pulmonary metastasis in a cohort of head and neck cancer patients. These results implicate plasma redox balance as an endogenous and physiologic regulator of NETosis and pulmonary cancer metastasis, providing new therapeutic and diagnostic opportunities for combatting cancer progression., Neutrophil extracellular traps (NETs) are known to promote metastasis in mouse models. Here the authors show plasma redox imbalance caused by albumin oxidation to induce inflammation-independent NETosis and lung metastasis, and albumin oxidation and reduced plasma free thiol to be associated with lung metastasis in a cohort of head and neck cancer patients.

Necrotizing enterocolitis (NEC) is a disease known to cause injury to multiple organs including the liver. Liver regeneration is essential for the recovery after NEC-induced liver injury. Our aim was to investigate hepatic proliferation and progenitor cell marker expression in experimental NEC.Following ethical approval (#32238), NEC was induced in mice by hypoxia, gavage feeding of hyperosmolar formula, and lipopolysaccharide. Breastfed pups were used as control. We analyzed serum ALT level, liver inflammatory cytokines, liver proliferation markers, and progenitor cell marker expression. Comparison was made between NEC and controls.Serum ALT level was higher in NEC (p0.05). The mRNA expression of inflammatory cytokines in the liver was also higher in NEC (IL6: p0.05, TNF-α: p0.01). Conversely, mRNA expression of proliferation markers in the liver was lower in NEC (Ki67; p0.01, PCNA: p0.01). LGR5 expression was also significantly decreased in NEC as demonstrated by mRNA (p0.05) and protein (p0.01) levels.Inflammatory injury was present in the liver during experimental NEC. Proliferation and LGR5 expression were impaired in the NEC liver. Modulation of progenitor cell expressing LGR5 may result in stimulation of liver regeneration in NEC-induced liver injury and improved clinical outcome.Level IV.

The processes by which the intra-abdominal organ circulatory system develops in the embryo and during organogenesis are unclear. Previous studies have used fixed tissues to study the development of abdominal organ vasculature in the embryo; however, the intravital circulation of intra-abdominal organs in rodent fetal development has not been studied. This protocol describes a system that uses two-photon laser-scanning microscopy (TPLSM) for real-time observation and quantification of normal and pathologic live fetal intra-abdominal dynamics while the fetus is still connected to the mother via the umbilical cord.

Background Prebiotics are non-digestible food ingredients that enhance the growth of certain microbes within the gut microbiota. Prebiotic consumption generates immune-modulatory effects that are traditionally thought to reflect microbial interactions within the gut. However, recent evidence suggests they may also impart direct microbe-independent effects on the host, though the mechanisms of which are currently unclear. Methods Kinome arrays were used to profile the host intestinal signaling responses to prebiotic exposures in the absence of microbes. Identified pathways were functionally validated in Caco-2Bbe1 intestinal cell line and in vivo model of murine endotoxemia. Results We found that prebiotics directly regulate host mucosal signaling to alter response to bacterial infection. Intestinal epithelial cells (IECs) exposed to prebiotics are hyporesponsive to pathogen-induced mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) activations, and have a kinome profile distinct from non-treated cells pertaining to multiple innate immune signaling pathways. Consistent with this finding, mice orally gavaged with prebiotics showed dampened inflammatory response to lipopolysaccharide (LPS) without alterations in the gut microbiota. Conclusions These findings provide molecular mechanisms of direct host-prebiotic interactions to support prebiotics as potent modulators of host inflammation. Electronic supplementary material The online version of this article (10.1186/s40168-017-0357-4) contains supplementary material, which is available to authorized users.

We describe here a child with angiodysplasia of the small intestine, diagnosed by double-balloon endoscopy (DBE), who was treated with transumbilical single-incision laparoscopic surgery (T-SILS). A 9-year-old boy presented to another hospital with intermittent fresh melena of a duration of 5 months and 4 days. Anoscopy and gastric mucosal membrane scintigraphy were unsuccessful diagnostically, and he was referred to our hospital for further examination and treatment. Under general anesthesia, we performed DBE by an anal route, with the ileum assessed for a distance of about 150 cm from the ileocecal valve. Although no bleeding lesion was found in the colon, a flat elevated venous lake approximately 20 mm in size was observed 20 cm from the ileocecal valve, suggesting angiodysplasia of the small intestine. A tattoo was made under DBE, and wedge resection by T-SILS was performed 1 month later under general anesthesia. The excised specimen appeared as a flat, elevated venous lake approximately 20 mm in size. Histopathologic analysis revealed several dilated and distorted veins within the submucosa of the small intestine. The patient was diagnosed with angiodysplasia of the small intestine. His postoperative course was uneventful, and he remained free of recurrent gastrointestinal bleeding 18 months after the operation. This is the first case report showing the diagnosis, localization, and tattooing of an obscure gastrointestinal bleeding lesion of the small intestine by preoperative DBE and removal of the lesion by subsequent T-SILS in children.

Background Gastroesophageal reflux disease (GERD) in infants is among the most common reason for physician consultation worldwide. A traditional Japanese medicine, rikkunshito (RKT), is effective for GERD in adult and pediatric patients. The aim of this study was to evaluate the efficacy and safety of RKT in infants with GERD. Methods Fifty-four infants were referred to between July 2004 and December 2012 for evaluation and treatment of GERD. All infants had failure to thrive. We excluded nine patients with cow's milk protein allergy, neurological impairment or surgical indications. We retrospectively reviewed the clinical records of 45 infants with GERD. Twenty-nine infants were treated with RKT (TJ-43; 0.3 g/kg/day; RKT group), and 16 infants were treated with mosapride citrate at 0.5 mg/kg/day (mosapride group). The primary endpoint was RKT-induced relief of clinical symptoms and bodyweight gain in infants with GERD. Results After 3 months of treatment, the frequency of vomiting per day was significantly lower in the RKT group than in the mosapride group (P = 0.0146) and the weight Z-score was significantly higher in the RKT group than in the mosapride group (RKT group, −2.5 ± 1.5 vs mosapride group, −5.0 ± 2.0; P = 0.0386). No adverse effects were noted in either group. Conclusions RKT may be safe and effective for relief of GER symptoms and for bodyweight gain in infants with GERD.

Contrast lymphangiography is a useful technique to determine the site of lymphatic leakage in the patient with chylous ascites. Conventional lymphangiography with lipid-soluble contrast material carries the disadvantage of complications, such as oil emboli and lymphedema. The authors report a successful case of computed tomography (CT)-lymphangiography with direct injection of water-soluble contrast medium into a lower limb lymphatic vessel to determine the site of lymphatic leakage in a pediatric patient with refractory primary chylous ascites. The patient subsequently underwent laparoscopic ligation of the leaking site and recovered well. This novel technique offers superior potential for preoperative assessment and the planning of laparoscopic repair.

The aims of this study were to review our therapy and outcome for meconium peritonitis (MP) patients, and to clarify predictors of postoperative morbidity and mortality. We retrospectively reviewed a total 15 patients with MP who received surgical intervention at our institute from December 1990 to November 2012. Diagnosis of MP was confirmed by operative findings. We analyzed the relationship between outcome and patients' factors including patients' characteristics, prenatal diagnosis, type of MP, general condition, and surgical procedure. There was no relationship between outcome and the following factors: gender, gestational age, body weight at birth, delivery type, Apgar score, prenatal diagnosis, types and causes of MP, and surgical procedure. However, the preoperative presence of circulation deficiency and serum CRP values were statistically significant predictors of outcome in our MP patients. Prenatal diagnosis is essential for the first step of perinatal therapy for MP. Surgical strategy should be selected according to the information of prenatal diagnosis. Early surgical procedures to reduce systemic and abdominal inflammation just after birth may improve the outcome of severe MP cases.

In sepsis, circulating free DNA (cf-DNA) is increased, and is a marker of severity and prognosis of septic patients. This study aimed to evaluate cf-DNA in a dextran sodium sulfate-induced colitis mouse model, and its clinical implications.Dynamic pathology of the cecum wall in the DSS-induced colitis mouse model was analyzed using multiphoton microscopy (MPM). Plasma cf-DNA concentrations in colitis mouse were quantified using PicoGreen dsDNA Assay Kit. Plasma cf-DNA was also measured in 123 human ulcerative colitis (UC) patients [mean age: 35.9 years (3-75 years) with 20 pediatric patients] to assess its relationships with clinical severity and Matt's grade.Real-time images of cf-DNA were detected in the colitis model. The amount of labeled cf-DNA in the circulation of the colitis mice group was significantly higher compared with that in the control group (P0.05). In human UC blood samples, plasma cf-DNA concentrations in UC patients were significantly positively correlated with the clinical severity of UC and Matt's grade (P0.05, P0.05, respectively).Using MPM, we observed and analyzed real-time images of cf-DNA in a colitis mouse model. Plasma cf-DNA is a potential non-invasive blood marker for reflecting clinical severity and mucosal damage in UC patients.

The aims of this study were to reveal how using the antibiotics recommended by the 2010 Surgical Infection Society (SIS) and Infectious Disease Society of America (IDSA) guidelines can affect the therapeutic outcomes. We reviewed the cases of 53 patients with a postoperative intra-abdominal abscess without anastomotic leakage after gastrointestinal surgery who underwent image-guided percutaneous abscess drainage (PAD) and concomitant antibiotic therapy. The type of antibiotic initially administered was determined based on the surgeon’s judgment. A persistent abscess was defined as one or more PAD procedures resulting in complete resolution after 21 or more days. The recommended antibiotics were defined according to 2010 SIS/IDSA guidelines. All 53 patients had complete resolution without the need for surgery. The results of a multivariable analysis revealed that a C-reactive protein level ≥12 mg/dL and non-recommended antibiotics were significant risk factors for a persistent abscess (P = 0.042 and 0.013, respectively). With regard to a fever lasting more than 48 h, there was a significant difference between the recommended (45.1 %) and non-recommended (72.7 %) antibiotic groups (P = 0.046). Using the recommended antibiotics may shorten the time to defervescence and reduce the risk of a persistent abscess in patients undergoing PAD for a postoperative abscess after gastrointestinal surgery.

Bladder rupture in a fetus is a rare occurrence. We report the first neonatal case of laparoscopic repair for prenatally diagnosed bladder rupture. A male neonate, who had presented with megacystis, bilateral hydronephrosis and hydroureters since 27 weeks-of-gestation, was delivered by emergency cesarean section because of sudden collapse of the bladder with massive ascites at 37 weeks-of-gestation. The diagnosis of bladder rupture was made by retrograde urethrocystography. Laparoscopic repair was carried out subsequent to urethral catheterization. Intraoperatively, laceration from the left side of the bladder dome to the posterior wall was observed. This tear was successfully repaired using a two-layer interrupted suture without any postoperative complications. Laparoscopic repair could be the treatment of choice for bladder rupture, because it has the advantage of closure of the perforated site more certainly than bladder decompression alone, and with better cosmesis than open repair.

Aim The Duhamel pull-through and transanal endorectal pull-through (TEPT) are commonly used for the treatment of Hirschsprung's disease (HD). To date, there has been no meta-analysis evaluating postoperative outcomes following Duhamel pull-through and TEPT. The purpose of this meta-analysis was to compare patient outcome after Duhamel pull-through and TEPT for HD. Materials and Methods Original articles published between 1998 and 2016 were identified using the MEDLINE database. Studies comparing Duhamel pull-through and TEPT were included. Outcomes evaluated included incidence of postoperative constipation, incontinence/soiling, enterocolitis, anastomotic stricture, and leak. We analyzed dichotomous variables by estimating odds ratios (OR) with 95% confidence intervals (CI) and continuous variables using the weighted mean difference with 95% CI. The meta-analysis was done using RevMan 5.3. Result There were no randomized controlled trials. Seven observational clinical studies were included, comprising 260 cases of Duhamel pull-through and 170 cases of TEPT. Anastomotic stricture (OR = 0.10; 95%CI 0.02–0.48; p = 0.004) was lower following Duhamel pull-through than TEPT. There were no significant differences in the incidence of postoperative incontinence/soiling and anastomotic leak. After TEPT, postoperative constipation seems to be lower and enterocolitis higher compared with those after Duhamel pull-through; however, these differences are not significant when the follow-up period is equal between groups. Conclusion The Duhamel pull-through seems to be associated with lower incidence of anastomotic stricture compared with TEPT. The effects of the two analyzed operative techniques on constipation and enterocolitis remain unclear. The quality of evidence supporting the above findings is suboptimal, indicating the need for prospective studies.

Anorectal malformation (ARM) is associated with a tethered spinal cord (TSC). Long-term functional outcome of untethering surgery for TSC in patients with ARM has not been well evaluated. Patients aged 7 years and older who underwent repair of ARM and spinal magnetic resonance imaging from January 1995 to December 2008 were reviewed retrospectively. Untethering surgery was performed in all patients who were diagnosed with TSC, regardless of the presence or of neurological symptoms. Clinical symptoms reflecting anorectal, urinary, and lower limb function were compared between patients complicated with TSC (TSC group, n = 17) and those without TSC (non-TSC group, n = 14). The median age at functional evaluation was 11.7 and 12.9 years in the TSC and non-TSC groups, respectively (p = 0.52). Untethering surgery for TSC was performed at a median age of 1.3 years. Preoperative urinary and lower limb dysfunction, except for vesicoureteral reflux in the TSC group in one patient, was improved after surgical detethering. Current anorectal function was comparable between the groups. Long-term functional outcome in patients with ARM and TSC undergoing untethering surgery is equivalent to that in those without TSC. Prophylactic surgical detethering for patients with ARM and TSC can be a treatment of choice to maximize neurological functional outcome.

Maternal separation (MS) in neonates can lead to intestinal injury. MS in neonatal mice disrupts mucosal morphology, induces colonic inflammation and increases trans-cellular permeability. Several studies indicate that intestinal epithelial stem cells are capable of initiating gut repair in a variety of injury models but have not been reported in MS. The pathophysiology of MS-induced gut injury and subsequent repair remains unclear, but communication between the brain and gut contribute to MS-induced colonic injury. Corticotropin-releasing hormone (CRH) is one of the mediators involved in the brain–gut axis response to MS-induced damage. We investigated the roles of the CRH receptors, CRHR1 and CRHR2, in MS-induced intestinal injury and subsequent repair. To distinguish their specific roles in mucosal injury, we selectively blocked CRHR1 and CRHR2 with pharmacological antagonists. Our results show that in response to MS, CRHR1 mediates gut injury by promoting intestinal inflammation, increasing gut permeability, altering intestinal morphology, and modulating the intestinal microbiota. In contrast, CRHR2 activates intestinal stem cells and is important for gut repair. Thus, selectively blocking CRHR1 and promoting CRHR2 activity could prevent the development of intestinal injuries and enhance repair in the neonatal period when there is increased risk of intestinal injury such as necrotizing enterocolitis.

Purpose The aim of this study is to assess gastric emptying in experimental necrotizing enterocolitis (NEC) and its diagnostic significance using non-invasive ultrasound imaging. Methods Fourteen neonatal mice (C57BL/6) were randomized into two groups: NEC [n=10] and control [n=4]. NEC was induced by gavage feeding of hyperosmolar formula, hypoxia, and lipopolysaccharide between postnatal day 5 (P5) and 9 (P9). Stomach volume was measured using a 40-MHz ultrasound transducer on P5 and P9. Gastric residual volume was calculated in control mice from two measurements at 4h interval and in NEC mice from two measurements immediately after gavage feeding and 4h post-fasting. The distal ileum was harvested for histology and quantitative PCR analysis on P9. Results On P9, NEC mice had a greater gastric residual volume compared to control (p=0.002) indicating delay in gastric emptying. Positive correlations were found between gastric residual volume and both IL-6 mRNA expression level and histological bowel damage (p=0.035, p=0.012, respectively). Conclusions During experimental NEC there is a delay in stomach emptying which is related to the severity of the disease. Ultrasound assessment of gastric emptying is a new non-invasive imaging modality that could be used to predict the severity of NEC.

Background Histological segmental distribution of ulcerative colitis (UC) may represent an early finding of newly diagnosed UC, especially in pediatric patients; a sign of Crohn's disease; or a predictor of refractory UC. However, its significance remains unknown. This study was performed to compare the final pathologic findings in resected total colon and rectum specimens between pediatric and adult patients with refractory UC who underwent proctocolectomy and clarify the significance of segmental distribution in pediatric patients with UC. Methods Ninety patients with medically refractory UC (14 with childhood-onset UC and 76 with adult-onset UC) who underwent a two-staged operation comprising total proctocolectomy and ileal J-pouch anal anastomosis in the first stage were included in this study. We retrospectively reviewed all patients' medical records and performed a histological evaluation of the resected total colon using Geboes' grading system for histological inflammation activity of UC and factors of Tanaka's criteria for refractory UC. Results Histological segmental distribution was more frequently observed in the resected colon at surgery in pediatric (64%) than in adult patients (21%) with refractory UC. The administration of immunomodulators or anti-TNF-α antibody within 30 days before surgery was more frequently performed in adults than in children. Patients with refractory UC with a segmental distribution had a statistically significant relationship with shorter duration before surgery (P = 0.0009), male gender (P = 0.0342), and higher activity of disease inflammation in rectum (P = 0.0399). Multivariate analysis revealed the statistically significant relationship between segmental distribution and disease duration before surgery ≤ 6 years (P = 0.0031). Conclusions Endoscopists should perform biopsies of both normal and abnormal mucosa throughout the total colon and follow changes in the pathological pattern because segmental distribution is an important predictor of prognosis.