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Background GATA6, a transcription factor expressed in cholangiocytes, has been implicated in the response to liver injury. In biliary atresia, a disease characterized by extrahepatic bile duct obstruction, liver expression of GATA6 increases with pathological bile duct expansion and decreases after successful Kasai portoenterostomy. The aim of this study was to garner genetic evidence that GATA6 is involved in ductular formation/expansion. Methods The murine Gata6 gene was conditionally deleted using Alb-cre, a transgene expressed in hepatoblasts (the precursors of hepatocytes and cholangiocytes) and mature hepatocytes. Bile duct ligation (BDL) was used to model biliary obstruction. Results Alb-Cre;Gata6(flox/flox) mice were viable and fertile. Cre-mediated recombination of Gata6 in hepatocytes had little impact on cellular structure or function. GATA6 immunoreactivity was retained in a majority of biliary epithelial cells in adult Alb-Cre;Gata6(flox/flox) mice, implying that surviving cholangiocytes were derived from hepatoblasts that had escaped biallelic Cre-mediated recombination. Although GATA6 immunoreactivity was preserved in cholangiocytes, Alb-cre;Gata6(flox/flox) mice had a demonstrable biliary phenotype. A neutrophil-rich infiltrate surrounded newly formed bile ducts in neonatal Alb-Cre;Gata6(flox/flox) mice. Foci of fibrosis/necrosis, presumed to reflect patchy defects in bile duct formation, were observed in the livers of 37% of adult Alb-cre;Gata6(flox/flox) mice and 0% of controls (p

Anemia and low-grade inflammation are reported to be associated with impaired long-term graft outcome in renal transplant (RTx) recipients. In this study, hemoglobin (Hb) and inflammation marker levels were correlated with measured glomerular filtration rate (GFR) in 128 pediatric RTx recipients over a median follow-up period of 10 years. Serum levels of erythropoietin (EPO), hepcidin-25, high-sensitivity C-reactive protein (CRP) (hsCRP) and interleukin-6 (IL-6) were analyzed by enzyme-linked immunosorbent assays, and GFR was analyzed by Cr-51-EDTA clearance. The median levels of Hb (115 g/L), hsCRP (0.4 mg/L) and IL-6 (1.4 pg/mL) and the median erythrocyte sedimentation rate (ESR; 19 mm/h) remained stable after the first post-operative year. However, approximately half of the patients had a normocytic, normochromic anemia, and one-third had elevated levels of hsCRP (> 1 mg/L) and ESR (> 25 mm/h), indicating continuous low-grade inflammation. Low Hb levels preceded increased fibrosis in protocol biopsies taken at 1.5 and 3 years after transplantation and preceded decreased GFR by several years. Hb levels showed an inverse correlation with EPO levels (r = -0.206, p = 0.038) and ESR (r = -0.369, p

Pediatric intestinal failure (IF) remains to be associated with significant morbidity and mortality, the most frequent underlying etiologies being short bowel syndrome (SBS), and primary motility disorders. Management aims to assure growth and development, while preventing complications and facilitating weaning off parenteral support (PS) by fully utilizing adaptation potential of the remaining gut. Probability of survival and weaning off PS is improved by coordinated multidisciplinary intestinal rehabilitation combining individualized physiological enteral and parenteral nutrition (PN), meticulous central line care and medical management with carefully planned surgical care. Increasing evidence suggests that autologous intestinal reconstruction (AIR) surgery is effective treatment for selected short bowel patients. Bowel lengthening procedures normalize pathological adaptation-associated short bowel dilatation with potential to support intestinal absorption and liver function by various mechanisms. Although reversed small intestinal segment, designed to prolong accelerated intestinal transit, improves absorption in adult SBS, its feasibility in children remains unclear. Controlled bowel obstruction to induce dilatation followed by bowel lengthening aims to gain extra length in patients with the shortest duodenojejunal remnant. Reduced PS requirement limits the extent of complications, improving prognosis and quality of life. The great majority of children with SBS can be weaned from PS while prognosis of intractable primary motility disorders remains poor without intestinal transplantation, which serves as a salvage therapy for life-threatening complications such as liver failure, central vein thrombosis or recurrent bloodstream infections.

This study aimed to define the controlled outcomes into adulthood for bowel function and lower urinary tract symptoms (LUTS) for males treated for low ARMs with individualized, minimally invasive approaches that preserve the native continence mechanisms as far as possible. This is a single-institution, cross-sectional study. All males treated for low ARMs with cutback anoplasty, incision of anocutaneous membrane or dilatations based on the exact type of each malformation between 1983 and 2006 were invited to answer a detailed questionnaire on bowel function and LUTS. Each patient was matched to three controls representing the normal population. Ethical approval was obtained. Amongst 46 respondents (67 %; median age 12.3 (5–29) years), overall fecal control was comparable to controls (p = NS). All patients had voluntary bowel movements; 98 % of patients and 97 % of controls were socially continent (p = NS); 67 % of patients and 64 % of controls were totally continent (p = NS). Constipation amongst patients (33 vs 3 % in controls; p

Rectopexy is a simple treatment of persisting complete rectal prolapse (RP) or related functional disorders in children. The results of rectopexy have been encouraging with few complications. We describe the postoperative complications and outcome of rectopexy in our institution from 2002 to 2013. Ethical committee accepted the study. Hospital records of 27 successive patients (16 males), median age 7.2 (range 2.8–17) years, who underwent rectopexy (25 laparoscopic, 2 open) were reviewed. Indication for rectopexy included RP (n = 24), solitary rectal ulcer with enterocele (n = 2) and rectocele (n = 1). Nine patients (39 %) were healthy. In the remaining 14 patients, RP was secondary to anorectal malformation (n = 2), bladder exstrophy (n = 1), sacrococcygeal teratoma (n = 1) and myelomeningocele (n = 1) or associated with mental retardation (n = 8) and Asperger’s syndrome (n = 1). Five (18 %) patients had constipation. Unexpected postoperative events and complications were rated by Clavien–Dindo classification (Grades I–V). Seventeen (61 %) patients had postoperative complications (Grade I n = 5, II n = 2 and III n = 7). Readmission was required in 11 (41 %) and reoperation, endoscopy or other surgical procedure in 9 (33 %) patients. Complications included severe faecal obstruction (n = 2), constipation (n = 3), faecal soiling (n = 1) urinary retention (n = 2), enuresis (n = 1), infection (n = 2), residual mucosal prolapse (n = 5), discomfort at defecation (n = 1) and recurrent RP (n = 2). Reoperations included sigmoid resection with re-rectopexy (n = 1), resection of mucosal prolapse (n = 1), suprapubic urinary catheter (n = 2), evacuation of faecal impaction (n = 2), colonoscopy (n = 3), appendicostomy for antegrade continence enema (n = 1). Mental retardation or behavioural disorder increased the risk of postoperative faecal obstruction and constipation RR = 84 (95 % CI 4.3–1600), p = 0.0035. After median follow-up of 4.1 (range 0.6–11) years RP or related condition was cured in 26 patients. Constipation and faecal soiling require management in a total of seven patients. Long-term results of rectopexy were good. Postoperative complications from mild to moderate grade were unexpectedly frequent. Preoperative neurobehavioural disorder and constipation increase the risk of postoperative problems and should be mentioned in patient counselling.

The presence of circulating donor-specific human leukocyte antigen antibodies (HLA-DSA) has been associated with chronic antibody-mediated rejection, leading to progressive graft dysfunction and poor graft survival. The aim of this study was to investigate the incidence and significance of HLA-DSA in paediatric renal transplantation (RTx) patients. A total of 294 post-transplant serum samples from 123 RTx patients were retrospectively analysed for HLA antibodies. Positive samples were further tested for HLA-DSA by a Luminex Single Antigen bead assay. The antibody findings were correlated to measured glomerular filtration rate (GFR) and clinical outcome. HLA antibodies were detected in half of the routine samples (140/294) taken 1 month to 10 years after RTx, and 40% (62/140) of these were HLA-DSA. Overall, one-third (42/123) of the patients had HLA-DSA, which mostly (65%) reacted against class II antigens. Detection of HLA-DSA was not associated with poor GFR at the time of sampling, and no exceptional deterioration of GFR after the HLA-DSA detection was noted in individual patients regardless of the antibody level. The presence of HLA-DSA in the first 2 years posttransplantation was not associated with poorer graft function later on. Detection of HLA antibodies is common in children after RTx, and this finding, as such, does not predict any deterioration of graft function.

Esophageal atresia (EA) affects one in 2,840 newborns, and over half have associated anomalies that typically affect the midline. After EA repair in infancy, gastroesophageal reflux (GER) and esophageal dysmotility and respiratory problems are common. Significant esophageal morbidity associated with EA extends into adulthood. Surgical complications, increasing age, and impaired esophageal motility predict the development of epithelial metaplasia after repair of EA. To date, worldwide, six cases of esophageal cancer have been reported in young adults treated for EA. According to our data, the statistical risk for esophageal cancer is not higher than 500-fold that of the general population. However, the overall cancer incidence among adults with repaired EA does not differ from that of the general population. Adults with repaired EA have had significantly more respiratory symptoms and infections, as well as more asthma and allergies than does the general population. Nearly half the patients have bronchial hyperresponsiveness. Thoracotomy-induced rib fusion and gastroesophageal reflux-associated columnar epithelial metaplasia are the most significant risk factors for the restrictive ventilatory defect that occurs in over half the patients. Over half the patients with repaired EA are likely to develop scoliosis. Risk for scoliosis is 13-fold after repair of EA in relation to that of the general population. Nearly half of the patients have had vertebral anomalies predominating in the cervical spine, and of these, most were vertebral fusions. The natural history of spinal deformities seems, however, rather benign, with spinal surgery rarely indicated.

Botox injection treatment (BIT) is a potentially effective but yet unproven treatment of functional anal outlet obstruction that is caused by non-relaxing internal anal sphincter. We present a single institution experience of BIT from 2005 to 2008.Sixteen patients (11 males), eight with Hirschsprung's disease (HD) (one with total colon aganglionosis, TCA) and eight with internal sphincter achalasia (ISA) were included. Median ages were 3.8 years (0.4-9.3) for HD and 8.1 years (range 1.5-11.4) for ISA. ISA was defined as the absence of rectoanal inhibitory reflex with normal rectal biopsies. Seven HD patients had previous coloanal pull-through (CAPT), and one (TCA) colectomy and ileoanal J-Pouch anastomosis. Two of the ISA patients had undergone internal sphincter myectomy and two had Malone procedure [antegrade colonic enema (ACE)]. Indication for BIT in 16 patients was anal outlet obstruction (n = 11) with soiling and recurring HD-associated enterocolitis (n = 5) and in one patient (HD, TCA) soiling with enterocolitis (n = 1). Before BIT, all patients underwent anorectal manometry, rectal biopsies and barium enema. The effect of BIT was evaluated after 2 months and BIT was repeated if necessary. Effect of BIT was scored as follows: 0 no, 1 little, 2 significant effect and 3 symptoms disappeared.Median follow-up was 19 months (range 3-43). The median number of injections was two per patient (range 1-4) and the median Botox dose was 80 U (range 40-100). Scores of BIT effect were 3 or 2 in five (31%) and 0 or 1 in 11 (69%). After adjunctive treatment modalities (myectomy n = 1, CAPT n = 1, adjusted ACE/laxative treatment), the end result was good or satisfactory in 11 (69%) but remained poor in 5 (31%) patients. Patient age, diagnosis, anorectal resting pressure or findings in barium enema were not correlated with BIT efficiency score (R range -0.06 to 0.39, P = 0.12-0.91).Although successful in some patients, the role of BIT remains undetermined. It is difficult to predict which patients will profit from BIT. Continuing other treatment modalities after BIT may improve the results.

Funnel anus (FA) is a rare and distinct type of anorectal malformation characterized by a skin-lined deep anal funnel, missing transitional epithelium and stenosis secondary to fibrotic internal sphincter. We aimed to characterize associated anomalies, surgical management and outcome of children with FA. The hospital records of 11 consecutive children (7 boys) treated for FA between 1992 and 2006 were screened. The collected data included the type of anorectal malformation, surgical management, associated anomalies, results of diagnostic investigations and outcome. Only one patient was free of any associated malformation. Six patients had a complete Currarino syndrome. Seven patients had a hemisacrum (scimitar) and tethered cord was present in two cases. Six patients underwent excision of a benign presacral teratoma. Anal stenosis associated with FA was managed by serial dilatations. Subsequent resection of the megarectosigmoid secondary to refractory constipation was performed on five occasions. Three patients underwent coloanal pull-through for Hirschsprung's disease (HD). The level of aganglionosis was at the rectosigmoid junction in two cases and low in the rectum in one. One additional patient had hypoganglionosis. Of the three patients with HD two also had Down's syndrome. After median follow-up of 6.5 (0.3-13.5) years four patients have normal bowel function and four suffer from soiling. Two patients with HD and Down's syndrome and one patient with an undefined syndrome are fecally incontinent. Associated anomalies are common and diverse in children with FA. Pelvic MRI, sacral radiography, evaluation of the urinary tract and rectal biopsies are recommended as routine investigations in cases of FA. Surgical care of these patients is demanding and should be confined to dedicated centers.

Before the closure of an enterostomy, a distal loop contrast radiograph (DLCR) is widely used to disclose pathology which may affect the performance of the procedure. We studied whether DLCR of paediatric patients caused actual alterations in the surgical plan and whether it predicted postoperative complications. Between 1991 and 2006, 105 patients (small bowel enterostomy, SBE; n = 51), (colostomy, CO; n = 54) underwent closure of an enterostomy. All 105 patients had preoperative DLCR. The indications for enterostomy included anorectal malformation (n = 38), neonatal intestinal perforation (n = 25), J-Pouch ileoanal anastomosis (n = 20), anorectal trauma (n = 5), and miscellaneous (n = 17). We recorded sensitivity, specificity, and positive and negative predictive value (PPV and NPV) of DLCR for complications within 6 postoperative weeks. DLCR was considered complete and interpreted as normal in 94 (90%) and abnormal (incomplete n = 3 or pathological n = 8) in 11 (10%) patients. None of the 11 abnormal findings caused cancellation of surgery, but in three (27%) patients it was possible to surgically correct a stricture seen in DLCR. The frequency of surgical complications was 17/105 (16%), SBE (15/51,29%) and CO (2/54, 4%), (P < 0.05). Most common complications (9/17, 53%) were those associated with the intestinal anastomosis. For postoperative complications DLCR had sensitivity, specificity, and PPV and NPV of 47, 97, 73 and 90% (SBE and 47, 97, 88 and 81%), (CO 50, 96, 33 and 98%). The pathology seen in DLCR, however, seldom directly hinted the complications which actually occurred. Abnormal DLCR changed the surgical plan in less than one-fifth of the cases. For surgical complications DLCR had poor sensitivity, good specificity and NPV, and moderate PPV. The pathology suggested by DLCR, however, correlated poorly with the actual complications. Poor sensitivity reflects the high frequency of anastomotic complications, which are practically unpredictable by preoperative radiographs.

Faecal leakage from the catheter conduit can be troublesome and reduces the convenience of use of antegrade continence enema (ACE). We report the results of Deflux injection treatment for leaking ACE conduits in nine patients. From 1994 to the end of 2005, 81 patients underwent a procedure for ACE [appendicostomy with wrap (AW) n = 29, appendicostomy straight (AS) n = 44, Monti-Yang ileal tube (MY) n = 5, lateral caecal flap (LCF) n = 1, caecal tube (CT) n = 1, sigmoid tube (ST) n = 1]. Nine (11%) patients (AW n = 3, AS n = 1, MY n = 3, LCF n = 1, ST n = 1) had persistent stomal leak and underwent Deflux injections of the ACE conduit. With the patients in general anaesthesia, the conduit was visualised with CH10.5 cystoscope. At the junction of the conduit and colon, 0.5-1.0 ml of Deflux was injected submucosally at three sites to create intermingling mounds in order to narrow the conduit. After the injections, a balloon catheter was left in the conduit for 3-7 days. When necessary, the injections were repeated. The result was graded as no improvement, moderate improvement, significant improvement. Nine patients underwent a median of 2 (range 1-4) injections. No major complications occurred. The results after a median follow-up of 22 (range 3-53) months from the first injection were as follows: no improvement (n = 1), moderate improvement (n = 5), significant improvement (n = 3). Repeated injection of the ACE conduit with Deflux is a low invasive method and provides moderate to good results in the majority of the patients who suffer from faecal leakage from conduit.

The repair of choice for persistent rectal prolapse (PRP) in children is disputed. Laparoscopic suture rectopexy (LSRP) is effective in adults, but its usefulness in pediatric PRP is unknown. We compared LSRP with posterosagittal rectopexy (PSRP). Sixteen children, with a median age of 6.5 years (range, 0.8–16.8) and duration of symptoms of 2.8 years (range, 0.5–10.2), underwent surgery for PRP. Eight (1991–2000) had PSRP, and eight (2002–2005) had LSRP. Three patients with LSRP were healthy; the others had mental retardation and epilepsy (n = 1), cerebral palsy (n = 1), Aspeger’s syndrome (n = 1), meningomyelocele (n = 1), and bladder extrophy (n = 1). Preoperative cologram (n = 6), sigmoideoscopy (n = 3), and anorectal manometry (n = 2) were normal in patients with LSRP. In LSRP, the rectum was mobilized and sutured to the sacral periosteum. Median operation time for LSRP was 80 min (range, 62–90) and for PSRP 40 min (range, 25–70) (p < 0.05); median hospital time was 6 days (range, 3–8) for LSRP and 6 days (range, 3–9) for PSRP (not significant). Six patients with LSRP had a median follow-up of 13 months (range, 4–24). None have had recurrences, and two patients (33%) require laxatives. Of the patients with PSRP, two (25%) had recurrence and underwent abdominal rectopexy with sigmoid resection. Medium-term results indicate that LSPR is effective in pediatric PRP. Constipation is the only postoperative problem in a significant proportion of patients.

We investigated the effects of jejunoileal denervation with or without ischemia–reperfusion on mucosal characteristics and small intestinal structure. Growing pigs underwent sham laparotomy, jejunal transection, or extrinsic jejunoileal denervation with or without in situ ischemia–reperfusion. Small intestinal morphology, crypt cell proliferation, enterocyte ultrastructure, and disaccharidase activities were analyzed from jejunum and ileum after eight weeks. Immunohistological analysis of the ileum showed no staining of catecholaminergic neurons after extrinsic denervation. Neural isolation of the jejunoileum with or without ischemia–reperfusion injury reduced weight gain and villous enterocyte density in the ileum, abolished the proximodistal gradient of sucrase activity, and increased mucosal thickness, villus height, and villus surface area in the ileum. However, gross jejunoileal morphology, crypt cell proliferation, and enterocyte ultrastructure remained unchanged. In conclusion, jejunoileal denervation in growing pigs selectively modulates constitutional mucosal characteristics in the ileum, presumably due to altered enterocyte turnover, without a decrease in small intestinal absorptive surface area. These changes are independent of short ischemia and subsequent reperfusion.

This study investigates the effects of ilealautotransplantation on morphology, crypt cellproliferation, and brush border disaccharidases of theremaining jejunoileum and colon in growing pigs with 75% proximal small bowel resection. Resection wasperformed on 30 pigs, of which 15 underwent anautotransplantation of the remaining ileum. Theautotransplanted pigs showed reduced weight gain andremnant ileal length when compared to the resectedcontrols. In the autotransplanted pigs, small boweldiameter and weight, mucosal weight and protein content,villus height and surface area, crypt depth, and the number of proliferating crypt cells werereduced similarly both in the intact jejunum and in theautotransplanted ileal remnant. Autotransplantation alsodecreased the number of proliferative crypt cells of the colon. Specific activities of maltaseand sucrase tended to increase in the autotransplantedileal remnant, whereas the total enzyme activitiesdecreased. These results suggest that ilealautotransplantation disturbs postresectional adaptation of theremaining gut.

The aim of this study was to evaluate possible changes in the neuropeptide innervation pattern of the remaining porcine ileum following 75% proximal resection of the small intestine. Three-month-old piglets were operated on and two months postoperatively full-thickness specimens of the proximal part of the distal ileum wall were taken. Age-matched 3- and 5-month-old unoperated piglets were used as controls. The number and intensity of VIP-, galanin-, enkephalin-, substance P-, and somatostatin-containing nerve fibers were estimated in sections processed for immunofluorescence microscopy and subjected to quantitative scoring. The VIP-, galanin-, and enkephalin-immunoreactive fibers of the circular muscle layer and villi were also quantitated by computer-assisted morphometry. The number and intensity of VIP-immunoreactive fibers in the mucosa and circular muscle layer markedly decreased after resection as compared to 3-month-old and 5-month-old controls (P < 0.05). The galanin immunoreactivity index decreased significantly after resection in the circular muscle layer as compared to both control groups (P < 0.05). The increase in the number of enkephalin-immunoreactive nerve fibers that normally occurred from 3 to 5 months of age was inhibited by the resection. We were not able to see any differences in somatostatin or substance P immunoreactivity between the groups. The results suggest that massive resection induces significant changes in the neuropeptide-containing innervation of the remaining small intestine. These findings are compatible with altered motor activity and mucosa function in the remain intestine.