Impaired antimicrobial response and mucosal protection induced by ibuprofen in the immature human intestine.

BACKGROUND: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin (INDO) and ibuprofen (IBU) has been shown to be an effective therapy for the closure of patent ductus arteriosus (PDA). However, this treatment has been associated with an increased risk of developing enteropathies in neonates. Whether the use of IBU is safer than INDO for the immature intestine remains to be elucidated. METHODS: The direct impact of IBU on the human immature intestinal transcriptome was investigated using serum-free organ culture. Differentially expressed genes were analyzed with Ingenuity Pathway Analysis software and compared with those previously reported with INDO. Validation of differentially expressed genes was confirmed by qPCR. RESULTS: We identified several biological processes that were significantly modulated by IBU at similar levels to what had previously been observed with INDO, while the expression of genes involved in "antimicrobial response" and "mucus production" was significantly decreased exclusively by IBU in the immature intestine. CONCLUSIONS: Our findings indicate that IBU has a harmful influence on the immature intestine. In addition to exerting many of the INDO observed deleterious effects, IBU alters pathways regulating microbial colonization and intestinal epithelial defense.

The nitric oxide synthase 2 pathway is targeted by both pro- and anti-inflammatory treatments in the immature human intestine.

BACKGROUND AND AIM: NO synthase 2 (NOS2) was recently identified as one the most overexpressed genes in intestinal samples of premature infants with necrotizing enterocolitis (NEC). NOS2 is widely implicated in the processes of epithelial cell injury/apoptosis and host immune defense but its specific role in inflammation of the immature human intestinal mucosa remains unclear. Interestingly, factors that prevent NEC such as epidermal growth factor (EGF) attenuate the inflammatory response in the mid-gestation human small intestine using serum-free organ culture while drugs that are associated with NEC occurrence such as the non-steroidal anti-inflammatory drug, indomethacin (INDO), exert multiple detrimental effects on the immature human intestine. In this study we investigate the potential role of NOS2 in modulating the gut inflammatory response under protective and stressful conditions by determining the expression profile of NOS2 and its downstream pathways in the immature intestine. METHODS: Gene expression profiles of cultured mid-gestation human intestinal explants were investigated in the absence or presence of a physiological concentration of EGF (50 ng/ml) or 1 µM INDO for 48 h using Illumina whole genome microarrays, Ingenuity Pathway Analysis software and quantitative PCR to investigate the expression of NOS2 and NOS2-pathway related genes. RESULTS: In the immature intestine, NOS2 expression was found to be increased by EGF and repressed by INDO. Bioinformatic analysis identified differentially regulated pathways where NOS2 is known to play an important role including citrulline/arginine metabolism, epithelial cell junctions and oxidative stress. At the individual gene level, we identified many differentially expressed genes of the citrulline/arginine metabolism pathway such as ARG1, ARG2, GLS, OAT and OTC in response to EGF and INDO. Gene expression of tight junction components such as CLDN1, CLDN2, CLDN7 and OCN and of antioxidant markers such as DUOX2, GPX2, SOD2 were also found to be differentially modulated by EGF and INDO. CONCLUSION: These results suggest that the protective effect of EGF and the deleterious influence of INDO on the immature intestine could be mediated via regulation of NOS2. Pathways downstream of NOS2 involved with these effects include metabolism linked to NO production, epithelial barrier permeability and antioxidant expression. These results suggest that NOS2 is a likely regulator of the inflammatory response in the immature human gut and may provide a mechanistic basis for the protective effect of EGF and the deleterious effects of INDO.

Laparoscopic Sac Disconnection and Peritoneal Closure of Pediatric Inguinal Hernia.

Background: Laparoscopic sac disconnection and peritoneal closure represents an alternative to open pediatric hernia repair. We performed a retrospective review of our data to evaluate this alternative method. Materials and Methods: With REB approval, a retrospective chart review of all patients who underwent laparoscopic indirect inguinal hernia repair between June 2013 and July 2016 was conducted. Primary outcome was the recurrence rate. Secondary outcomes included length of surgery, postoperative hydrocele, and perioperative complications. Data were extracted from EPIC Hyperspace onto a standardized data extraction form. Results: A total of 243 patients were included, of which 82% were males. Age ranged from 1 month to 17 years of age. A total of 322 defects were repaired. Eighty (32%) had contralateral patent processus vaginalis. Twelve (4%) patients presented with incarceration and three (1.2%) had a direct inguinal hernia defect. Recurrence rate was 0.6% (n = 2). There were no intraoperative complications. Operative time was an average of 40 and 54 minutes for unilateral and bilateral repairs, respectively. No testicular ascents, testicular atrophy, vas deferens injury, postoperative hydroceles, and wound infections were reported. Conclusion: Laparoscopic sac disconnection and peritoneal closure of pediatric inguinal hernia is a safe, feasible method with one of the lowest reported recurrence rate among the other laparoscopic methods.

Nail-fold excision for the treatment of ingrown toenail in children.

OBJECTIVE: To evaluate the effectiveness of the nail-fold excision procedure in children. STUDY DESIGN: Prospectively collected data on patients less than 18 years of age who underwent a nail-fold excision for symptomatic ingrown toenail were analyzed. Patients were seen in 2 centers and data collected included demographics, site of ingrown toenail, complications (including recurrence), patient satisfaction, and duration of follow-up. RESULTS: Overall, 67 procedures were performed on 50 patients between June 2009 and July 2011 at the 2 institutions. The mean age was 14 years (range, 9-18 years) and 30 were male patients. No recurrences were seen after a follow-up for a median of 14 months (range 6-28 months). Patients were very satisfied with the cosmetic outcomes. Six minor complications occurred, including 3 patients with bleeding requiring dressing change, 2 with excessive granulation tissue, and 1 with nail growth abnormality. CONCLUSIONS: The nail-fold excision technique is highly effective in the pediatric population, with no recurrence, excellent cosmesis, and very high patient satisfaction.

Diverticular disease in a pediatric patient with Crohn's disease mimicking a perforated post-appendectomy appendiceal stump.

We present the finding of a diverticulum in the colonic wall of the cecum, arising in the context of ileocecal stricture in a child with Crohn disease mimicking a post-appendectomy perforated appendiceal stump. To our knowledge, a non-Meckel diverticulum in a pediatric patient with Crohn disease has not yet been reported and we examine the mechanics behind it. According to the Laplace Law, the pressure inside a container with curved walls is inversely proportional to its radius. A diverticulum forms at the point of maximum stricture and at the locus of least resistance (weakness) in the bowel wall due to the inflammatory bowel disease. The long-time interval between diagnosis of ileocecal stricture and surgery (9 months) is important to allow the formation of this diverticulum. Continued follow-up in adulthood is warranted due to an increased risk of intestinal diverticular disease and neoplasms in patients with Crohn disease.

The effectiveness of nail excision versus Vandenbos procedure for the surgical management of ingrown toenails in children: A retrospective chart review.

BACKGROUND: Ingrown toenail commonly occurs in patients who have experienced trauma or long-term compression to their toes. There exist two common methods of surgical management - wedge resection and Vandenbos procedure. We compared the recurrence rate of these two methods in pediatric patients. METHODS: We conducted a retrospective study reviewing patients who presented to our institution with ingrown toenail between 2009 and 2015. Patients who received any surgical treatment outside of our institution or were over 18 years of age were excluded. RESULTS: There were 523 patients seen at our institution with ingrown toenail. Of these patients, 482 had sufficient data available to be included in this study, with a total of 929 ingrown toenails. Out of these, 333 were managed conservatively while the remaining 596 required surgical intervention; 373 had wedge resection performed and the other 223 had Vandenbos procedure. Our analysis determined that 78 total complications arose in the wedge resection group (21%) while 32 total complications arose in the Vandenbos group (14%; p = 0.0949). Wedge resections had a significantly higher recurrence rate than Vandenbos procedures (41 (11%) vs 5 (2%), p = 0.0001). CONCLUSION: Surgical complications are comparable between wedge resections and Vandenbos procedure. Vandenbos procedure offers a significantly lower recurrence rate than wedge resection. LEVEL OF EVIDENCE: Level III.

Laparoscopic approach to ovarian mass in children and adolescents: already a standard in therapy.

INTRODUCTION: Functional cysts, ovarian torsion, and benign neoplasms are the most common ovarian masses among young adolescents. The laparoscopic approach to giant ovarian cysts in the pediatric population maybe difficult due the limited working space and the high risk of spillage. In this paper, we evaluate the role of laparoscopic surgery in the treatment of adnexal disease occurring in young girls. MATERIALS AND METHODS: With the approval of the institutional review board, a retrospective chart review(2007-2003) of patients with adnexal disease was conducted. RESULTS: Overall, 12 patients were evaluated with preoperative imaging, sonography, and magnetic resonance imaging (MRI) scan and laboratory values. None resulted in malignant histology. All resections of ovarian cysts were performed laparoscopically. The outcome was uneventful in all patients. CONCLUSIONS: Treatment is indicated if the diagnosis is in question, the cyst persists, in the case of ovarian torsion,or if the patient is symptomatic. Laparoscopy is becoming the favored approach by most pediatric surgeons for the treatment of ovarian cysts. All surgical procedures for ovarian cysts should spare functional ovary as much as is technically possible. Simple cysts can be fenestrated, but complex or functional cysts should be excised, with the preservation of the remaining ovary by careful dissection. The laparoscopic approach for adnexal masses can be performed in an acceptable manner, with comparable results to an open approach, plus the cosmetic advantages of minimally invasive surgery, which is an important aspect for the treated patients.

Contemporary Microbiology and Antimicrobial Treatment of Complicated Appendicitis: The Value of a Short-term Study.

BACKGROUND: Antimicrobial stewardship interventions to curtail the use of third-generation cephalosporins and antipseudomonal penicillins for the treatment of complicated appendicitis in children are challenging given the tendency to treat complicated disease with broad-spectrum antimicrobials. Reasons for this are unclear, but there is a paucity of contemporary microbiologic data associated with the child presenting with either acute perforated or gangrenous appendicitis. This study aimed to justify the appropriateness of an empiric regimen consisting of ampicillin, tobramycin/gentamicin plus metronidazole and to analyze duration of postoperative therapy. METHODS: We conducted a retrospective cohort study from February 1, 2017, to October 31, 2018, in children who underwent appendectomy or interventional radiologic drainage for primary complicated appendicitis. The primary outcome was the proportion of patients who had a pathogen isolated from peritoneal fluid culture that was not susceptible to the recommended empiric therapy. The secondary outcomes were the total duration of antimicrobial therapy and the proportion of patients with a postoperative infectious complication within 30 days after intervention. RESULTS: Of 425 children with primary acute appendicitis, 158 (37%) had complicated appendicitis at presentation. Culture was performed in 53 (40%) of the 133 who underwent a surgical or interventional radiologic intervention. The group with peritoneal cultures was more likely to present with longer symptom duration before admission [3 (interquartile range, 2-5) vs 2 (interquartile range, 1-2) days; P < 0.001] and with purulent peritonitis [47% (25/53) vs 13% (10/80); P < 0.001]. The most common pathogens isolated were anaerobes (81%), Escherichia coli (74%) and Streptococcus anginosus group (62%). Only 4% of isolated bacteria were resistant to empiric therapy. Postoperative infectious complications were documented in 23 (17%) patients and were not associated with the presence of a resistant pathogen or the choice of antimicrobial agents but with more severe disease and higher C-reactive protein values (303 vs 83 mg/L; P=0.03) at presentation. CONCLUSIONS: In a cohort of previously healthy children presenting with complicated appendicitis requiring surgical drainage, the most common bacteria from peritoneal cultures continue to be S. anginosus, aminoglycoside-susceptible Gram-negative bacilli and anaerobes. In an attempt to reduce extended-spectrum cephalosporin use, these data were useful in supporting the use of metronidazole with ampicillin and an aminoglycoside, rather than third-generation cephalosporins.

Vacuum bell treatment of pectus excavatum: An early North American experience.

PURPOSE: Conservative treatment of pectus excavatum with a vacuum bell device may be an attractive alternative to surgical repair. We describe an early North American experience with this device. METHODS: Prospectively maintained chest wall clinic registries from two institutions were reviewed to identify pectus excavatum patients ≤21 years treated with the vacuum bell from 2013 to 2017. Multivariate linear regression was used to compare mean improvements in deformity-depth and Haller Index between groups of patients based on age and usage metrics (hours/day and days/week). RESULTS: Thirty-one patients with a median age of 14 years received treatment with the device. Mean follow-up duration was 18 months. Median depth and Haller Index at treatment onset were 2.3 cm and 3.9, respectively. Improvements in deformity-depth were superior with device usage >2 h/day (p < 0.01) and daily use (p < 0.01). After adjusting for compliance, younger age of treatment onset was associated with greater improvement in Haller Index but not deformity depth. CONCLUSION: Our prospective early North American experience found the vacuum bell to be a potential alternative to surgical treatment for pectus excavatum. Longer usage periods in a daily frequency are associated with best results. TYPE OF STUDY: Treatment study; case series with no comparison group. LEVEL OF EVIDENCE: Level IV.

Thoracoscopic treatment of a neonatal traumatic pneumatocele.

Traumatic pneumatoceles appear rarely after pulmonary parenchymal or bronchial disruption. Treatment is usually expectant with intervention reserved for complications, such as infection, expansion, or cardiopulmonary deterioration. A 17-day-old female was transferred to our NICU with a left-sided pneumatocele resulting from an intraparenchymal chest tube insertion. She was born at 30 weeks gestation and required a chest tube insertion for severe hydrops fetalis with respiratory failure and associated chylothoraces. An acute deterioration following several weeks of clinical improvement was unsuccessfully treated with radiologically guided drainage. In this paper, we describe the thoracoscopic management of this case.

Laparoscopic-assisted colostomy in children.

INTRODUCTION: Colostomy morbidity has been reported to be as high as 50%. Laparoscopic-assisted colostomy (LAC) is associated with decreased colostomy complication. LAC is recommended for stoma formation in adults but has not been previously reported in children. In this paper, we report on our initial experience with LAC in children. MATERIALS AND METHODS: Using a two- to four-port (3.5-mm) technique, LAC was performed in a female with an imperforate anus and 2 male patients with complicated Hirschsprung's disease (HD), respectively. Data collected included operative time, time to recover bowel function, and morbidity. Close follow-up was done until stoma closure. RESULTS: The operative time was 144 minutes in the HD patients (including concomitant laparoscopic biopsies and a leveling colostomy) and 40 minutes in the imperforate anus patient. Median time to passage of both flatus and stool was 40 hours (range, 24-48). Time to commence feeds postop was 40 hours (range, 24-48). The median time of follow-up was 3 months (range, 2-9) until the stoma was taken down. No complications have occurred to date. CONCLUSIONS: LAC is safe and easily performed in neonates and infants. It facilitates accurate stoma placement and orientation. It allows additional bowel mobilization, especially in HD. In accordance with the adult experience, LAC seems to obviate stoma-related complications. Encouraged by our initial low morbidity rate, a prospective evaluation of this technique is planned.

A less intensive bracing protocol for pectus carinatum.

OBJECTIVES: Despite the widespread use of bracing to correct Pectus carinatum (PC) there is no consensus in the number of hours per day patients are instructed to wear the brace. In our practice, we use a less rigorous protocol of 8-12h/day. We sought to evaluate our results and those in the literature to determine whether more intensive usage is necessary. STUDY DESIGN: We reviewed the outcomes of patients with PC treated at our institution between 2012 and 2015. We searched MEDLINE, EMBASE and Web of Science for studies describing the use of bracing to correct PC. RESULTS: Seventy-five patients presented with PC at our institution. Among those who were offered bracing and had adequate follow-up (n=32), the success rate (full correction or improvement) was 90.6%. The compliance rate was 93.8%. Fifteen studies met our inclusion criteria. Our pooled data combining our results with those of other published data showed that less intensive brace usage (<12h/day), when compared to more intensive usage (≥12h/day), is associated with higher patient compliance (89.6% vs. 81.1%) with a similar time to correction (7.3 vs 7.1months) and success rate (85.3% vs. 83.5%). CONCLUSIONS: Implementing a less intensive bracing protocol for PC is successful, efficient and improves compliance. TYPE OF STUDY: Clinical Research. LEVELS OF EVIDENCE: Oxford Centre for Evidence-Based Medicine Level-of-Evidence rating: Level IV.

Gene expression profiling in necrotizing enterocolitis reveals pathways common to those reported in Crohn's disease.

BACKGROUND: Necrotizing enterocolitis (NEC) is the most frequent life-threatening gastrointestinal disease experienced by premature infants in neonatal intensive care units. The challenge for neonatologists is to detect early clinical manifestations of NEC. One strategy would be to identify specific markers that could be used as early diagnostic tools to identify preterm infants most at risk of developing NEC or in the event of a diagnostic dilemma of suspected disease. As a first step in this direction, we sought to determine the specific gene expression profile of NEC. METHODS: Deep sequencing (RNA-Seq) was used to establish the gene expression profiles in ileal samples obtained from preterm infants diagnosed with NEC and non-NEC conditions. Data were analyzed with Ingenuity Pathway Analysis and ToppCluster softwares. RESULTS: Data analysis indicated that the most significant functional pathways over-represented in NEC neonates were associated with immune functions, such as altered T and B cell signaling, B cell development, and the role of pattern recognition receptors for bacteria and viruses. Among the genes that were strongly modulated in neonates with NEC, we observed a significant degree of similarity when compared with those reported in Crohn's disease, a chronic inflammatory bowel disease. CONCLUSIONS: Gene expression profile analysis revealed a predominantly altered immune response in the intestine of NEC neonates. Moreover, comparative analysis between NEC and Crohn's disease gene expression repertoires revealed a surprisingly high degree of similarity between these two conditions suggesting a new avenue for identifying NEC biomarkers.

Alimentary tract duplications in newborns and children: diagnostic aspects and the role of laparoscopic treatment.

Alimentary tract duplications are rare congenital lesions normally diagnosed in newborns and children that can occur anywhere from the mouth to the anus and have a reported incidence of approximately 1 in 4500 life births. Symptoms and clinical presentation vary greatly. The presentation varies according to age and location. The treatment finally is surgical; total resection when possible should be the aim of the intervention. In pediatric surgery minimally invasive surgical procedures became more and more important over the last decades. In consequence the operative procedure on alimentary tract duplications changed in this manner. We review on case reports and clinical reports on minimally invasive surgery in the treatment of alimentary tract duplications, determine the importance of minimally invasive techniques in the treatment of this rare entity and rule out that further studies in the field should be performed.

A unique presentation of a standard type C esophageal atresia in a very low-birth-weight neonate.

Neonates with esophageal atresia and tracheoesophageal fistula usually present with inability to swallow immediately after birth often associated with respiratory distress. This is an unusual presentation of a very low-birth-weight neonate with a type C tracheoesophageal fistula that was fed for the first 4 days of life through an unintentional tracheogastric tube without incident.

Growth-associated Protein-43 (GAP-43) Expression In Ganglionic and Aganglionic Colon.

Abstract Objectives: Because of its specificity for nerve fibers of the enteric nervous system, calretinin is an effective adjunctive marker in the assessment for Hirchsprung disease. Growth associated protein (GAP-43) has been shown to be expressed in nerve fibers within the intestinal lamina propria. No prior report compares GAP-43 expression in ganglionic versus aganglionic intestine. Methods: Six consecutive Hirschsprung endorectal pull through specimens were retrieved from our archives. In addition 3 controls were selected from colonic resections for reasons other than Hirschsprung Disease. Immunoperoxidase for GAP-43 was carried out on the ganglionic and aganglionic segments of all cases and controls. Submucosal ganglion soma positivity and nerve fiber positivity within the lamina propria were graded on a subjective scale of 1-3 that incorporated both strength and density. Data: GAP-43 strongly stained submucosal ganglion cells and nerve fibers within the lamina propria in 6/6 of the ganglionic segments and 3/3 of the normally innervated controls . GAP-43 did not show any ganglion cell body positivity within the aganglionic segments; however, all 6 aganglionic segment lamina propria were positive for nerve fiber staining. There was a small subjective increase in the amount of nerve fiber positivity for GAP-43 in ganglionic segments and controls versus aganglionic segments. Conclusion: GAP-43 marks mucosal nerve fibers in ganglionic intestine but also aganglionic intestine and thus is less useful than calretinin as a marker for Hirschsprung Disease. The abundant mucosal nerves highlighted by GAP-43 requires further characterization.

Interstitial cell of Cajal loss correlates with the degree of inflammation in the human appendix and reverses after inflammation.

BACKGROUND: Normal gut motility relies on the complex interaction between the interstitial cell of Cajal (ICC) and the enteric nerve networks. Inflammation of the gastrointestinal tract adversely affects both ICC and enteric nerves. We aimed to determine the distribution of ICC and nerve networks in patients with appendicitis. METHODS: Specimens from controls and patients with appendicitis were examined with immunohistochemistry (c-Kit for ICC, beta III tubulin [Tuj-1] and neuronal nitric oxide synthase [histochemical diaphorase] for nitrergic neurons) and electron microscopy (EM). Data were quantified using image analysis. RESULTS: We found a profound decrease in c-Kit immunoreactivity (c-Kit IR) in the advanced inflammatory stages of appendicitis, which correlated with the severity of inflammation. Electron microscopy confirmed ultrastructural injury in both ICC and nerve fiber networks during acute inflammation. After the inflammation resolved, interval appendices displayed a recovery in ICC c-Kit IR to control levels and normal ultrastructure. The neuronal network also displayed ultrastructural recovery; however, neuronal nitric oxide synthase activity did not recover. CONCLUSIONS: Severe inflammation results in significant ultrastructural damage of nerves and ICC networks in appendicitis. The loss of c-Kit IR is likely due to impaired ICC cytophysiology because ICC was still present under EM. After resolution of acute inflammation, ICC recovers their normal ultrastructure and c-Kit IR.

Laparoscopic manoeuvre for orchidopexy in high intra-abdominal testes when cremasteric artery is present.

OBJECTIVE: We report a case of high intra-abdominal testes (HIT) associated with the presence of the cremasteric artery (CA). The aim was to correlate the normal anatomy of the CA with the clinical finding in our patient and discuss its surgical implication. METHODS: Left primary laparoscopic testicular descent by the Prentiss manoeuvre was performed in a 2 year-old boy with bilateral HIT. Cadaveric dissection was carried out focusing on the anatomical origin of the CA. Data obtained from cadavers and the clinical findings were analyzed. RESULTS: During laparoscopic orchiopexy a left HIT was found in the presence of the CA. Primary tension-free orchiopexy was achieved preserving the CA. Our cadaver study revealed that the CA arose more frequently (68%) from the medial aspect of the inferior epigastric artery. CONCLUSION: In the presence of HIT, surgeons should be aware of the CA as part of the testicular collateral circulation. Acquaintance with the normal anatomy of the CA is important to determine the most appropriate laparoscopic manoeuvre in orchiopexy when this artery is present. We believe that the Prentiss manoeuvre avoids compression and strangulation of the CA around the epigastric vessels while allowing testicular placement in the scrotum.

Colonic dysmotility in postsurgical patients with Hirschsprung's disease. Potential significance of abnormalities in the interstitial cells of Cajal and the enteric nervous system.

PURPOSE: Normal gut muscular function depends on the coordinated activity of both the enteric nervous system (ENS) and the interstitial cells of Cajal (ICC). Hirschsprung's disease (HD) has long been considered a purely neuronal deficit but recent data point to abnormalities in ICC in the proximal ganglionated HD colon. We examined the labeling of ICC and neuronal cells in the proximal ganglionated colon in patients with HD to determine whether abnormalities of ICC and ENS might be associated with a poor clinical outcome. METHODS: Tissue from 11 patients with HD was studied using immunohistochemistry for ICC and neuronal identification in comparison to control tissue from patients without HD. Image data were evaluated quantitatively and interpreted relative to clinical outcome. RESULTS: Interstitial cells of Cajal in the ganglionated colon of the HD group did not differ from the control group, but nerve cells/fibers were decreased 40%. Paired decreases in both nerve fibers and ICC in individual patients were associated with normal bowel function. Poor postoperative outcome was observed in a patient with normal innervation but with a profound decrease in ICC in the ganglionated colon. CONCLUSIONS: Nerve fibers are decreased in the proximal ganglionated colon in patients with HD without associated gut dysmotility. Poor clinical outcome was noted only in a patient with normal innervation and markedly decreased ICC. Collection of data from a much larger number of patients with poor clinical outcome will be necessary to determine the significance of this imbalance of ICC and innervation.