Routine evaluation of vesico-ureteric reflux in children with anorectal malformation does not reduce the rate of urinary tract infection.

OBJECTIVE: Children with anorectal malformations (ARM) have a high rate of renal anomalies and increased risk of urinary tract infection (UTI). We aimed to determine whether using routine Micturating Cystourethrogram (MCUG) to detect VUR is effective in reducing the incidence of UTI or renal scarring in children with ARM. METHODS: A retrospective study of consecutive children diagnosed with ARM in two centres with a minimum of 3 years follow-up was performed, excluding those with cloaca or an MCUG prior to ARM repair. Univariate and multivariate logistic regression analysis was used to determine variables which were associated with VUR, UTI and renal scarring. Associations are described as Odd's Ratio (OR), 95% Confidence Interval. Significance was taken as p<0.05. RESULTS: 344 children were included with a median age of 8 years (IQR 5-11 years). 150 (44%) were female. 89 (26%) had renal anomalies and 101 (29%) had spine anomalies. 148 patients had routine MCUG and VUR was found in 62 (42%) of these children. Univariate analysis did not correlate any of the assessed variables with VUR or renal scarring. However, abnormal renal ultrasound - OR 6.18 (95% CI 2.99-13.07, p 0.0001) was associated with UTI whilst abnormal spine - OR 0.27 (95% CI 0.10-0.62, p 0.009), low ARM - OR 0.30 (CI 0.14-0.63, p 0.006) and intermediate ARM - OR 0.35 (CI 0.17-0.70, p 0.01) were associated with a reduced risk of UTI. On multivariate analysis, only abnormal renal USS retained a significant association with UTI (p<0.0001). CONCLUSIONS: VUR is common in patients with ARM. Children with an abnormal R-USS are at increased risk of UTI. Performing routine MCUG does not reduce the risk of UTI in children with ARM.

APC and AXIN2 Are Promising Biomarker Candidates for the Early Detection of Adenomas and Hyperplastic Polyps.

Aberrant activation of the WNT/CTNNB1 pathway is notorious in colorectal cancer (CRC). Here, we demonstrate that the expression of specific and crucial WNT signaling pathway genes is linked to disease progression in colonic adenomatous (AP) and hyperplastic (HP) polyps in an Iranian patient population. Thus, we highlight potential gene expression profiles as candidate novel biomarkers for the early detection of CRC. From a 12-month study (2016-2017), 44 biopsy samples were collected during colonoscopy from the patients with colorectal polyps and 10 healthy subjects for normalization. Clinical and demographic data were collected in all cases, and mRNA expression of APC, CTNNB1, CDH1, AXIN1, and AXIN2 genes was investigated using real-time polymerase chain reaction (PCR). CTNNB1 and CDH1 expression levels were unaltered in AP and HP subjects, whereas mRNA expression of APC was decreased in AP contrasted with HP subjects, with a significant association between APC downregulation and polyp size. Although AXIN1 showed no changes between AP and HP groups, a significant association between AXIN1 and dysplasia grade was found. Also, significant upregulation of AXIN2 in both AP and HP subjects was detected. In summary, we have shown increased expression of AXIN2 and decreased expression of APC correlating with grade of dysplasia and polyp size. Hence, AXIN2 and APC should be explored as biomarker candidates for early detection of AP and HP polyps in CRC.

Novel TRPM8 antagonist attenuates cold hypersensitivity after peripheral nerve injury in rats.

Abnormal cold sensitivity is a common feature of a range of neuropathies. In the murine somatosensory system, multiple aspects of cold sensitivity are dependent on TRPM8, both short term and in response to peripheral nerve injury. The specialized nature of cold-sensitive afferents and the restricted expression of TRPM8 render it an attractive target for the treatment of cold hypersensitivity. This current study examines the effect of a novel TRPM8 antagonist (M8-An) in naive and spinal nerve-ligated rats through behavioral and in vivo electrophysiological approaches. In vitro, M8-An inhibited icilin-evoked Ca(2+) currents in HEK293 cells stably expressing human TRPM8 with an IC(50) of 10.9 nM. In vivo, systemic M8-An transiently decreased core body temperature. Deep dorsal horn recordings were made in vivo from neurons innervating the hind paw. M8-An inhibited neuronal responses to innocuous and noxious cooling of the receptive field in spinal nerve-ligated rats but not in naive rats. No effect on neuronal responses to mechanical and heat stimulation was observed. In addition, M8-An also attenuated behavioral responses to cold but not mechanical stimulation after nerve ligation without affecting the uninjured contralateral response. The data presented here support a contribution of TRPM8 to the pathophysiology of cold hypersensitivity in this model and highlight the potential of the pharmacological block of TRPM8 in alleviating the associated symptoms.

Autologous intestinal reconstructive surgery to reduce bowel dilatation improves intestinal adaptation in children with short bowel syndrome.

OBJECTIVES: Intestinal failure (IF) is a common consequence of neonatal small bowel pathology. In our experience, bowel dilatation is often responsible for the IF state in patients who fail to adapt despite adequate residual bowel length. The aim of the present study was to investigate the role of surgery to reduce bowel dilatation, and thus favour PN independence, for these children. METHODS: Data were collected prospectively for all of the patients referred to our unit for a 7-year period (2004-2011). Eight patients (2 congenital atresia, 2 gastroschisis with atresia, 1 simple gastroschisis, 3 necrotising enterocolitis) with gut dilatation who failed adaptation despite a bowel length >40 cm were identified. Preoperatively, all patients were totally dependent on parenteral nutrition (PN). Patients were managed by longitudinal intestinal lengthening and tailoring (n = 3), serial transverse enteroplasty (n = 2), or tapering enteroplasty (n = 3). RESULTS: Median age at time of surgery was 273 days (103-1059). Mean gut length increased from 51 (35-75) to 73 cm (45-120) following surgery (P = 0.02). Incidence of sepsis (P = 0.01) and peak serum bilirubin levels (P = 0.005) were reduced postoperatively. PN was discontinued after a median of 110 days (35-537) for 7 patients; 1 patient remains on PN 497 days after surgery. CONCLUSIONS: These data indicate that reconstructive surgery to reduce bowel diameter may be an effective technique for treating IF in patients with short bowel syndrome, without sacrificing intestinal length. We suggest that this technique may reduce the need for bowel transplantation in this group of patients.

Atropine sulphate: rescue therapy for pyloric stenosis.

Infantile hypertrophic pyloric stenosis (IHPS) is a common condition which presents with non-bilious vomiting and failure to thrive secondary to gastric outlet obstruction. In the UK, management is by fluid resuscitation followed by pyloromyotomy. Incomplete myotomy complicates 0.3% of cases necessitating further surgery and exposing the patient to further risk. Medical management of IHPS with antimuscarinics to promote pyloric relaxation is a well-described treatment modality that is used as first-line therapy in some countries. The use of this technique is limited by the need for extended hospital admission with parenteral nutrition administration. We describe a case of IHPS complicated by incomplete pyloromyotomy and subsequently managed successfully by atropine sulphate therapy.

Comparison of childhood appendicitis management in the regional paediatric surgery unit and the district general hospital.

BACKGROUND/PURPOSE: Ongoing debate surrounds the future provision of general paediatric surgery. The aim of this study was to compare outcomes for childhood appendicitis managed in a district general hospital (DGH) and a regional paediatric surgical unit (RU). METHODS: Data collected retrospectively for a 2-year period in a DGH were compared with data collected prospectively for 1 year in an RU, where appendicitis management is guided by a care pathway. Children aged 6 to 15 years were included. RESULTS: Four hundred and two patients were included (DGH ,196; RU, 206). There were more cases of gangrenous/perforated appendicitis in the RU (P < .0001). In the DGH, fewer patients received preoperative antibiotics (P < .0001) or underwent preoperative pain scoring (P < .0001). When adjusted for case mix, the relative risk of complications for a child managed at the DGH was 1.76 (95% confidence interval, 1.44-2.16; P < .0001) and that of readmission was 1.76 (95% confidence interval, 1.43-2.16; P < .0001) when compared with the RU. CONCLUSIONS: Patients with appendicitis managed in the DGH had a higher risk of complications and readmission. However, this appears to be related to the use of a care pathway at the RU. Introduction of a care pathway in the DGH may improve outcomes and thus support the ongoing provision of general paediatric surgery.

Human and mouse enteric nervous system neurosphere transplants regulate the function of aganglionic embryonic distal colon.

BACKGROUND & AIMS: Recent advances have raised the possibility of treating enteric nervous system (ENS) disorders with transplanted progenitor cells (ENSPC). Although these cells have been shown to migrate and differentiate after transplantation, no functional effects have been demonstrated. We therefore aimed to investigate whether embryonic mouse and neonatal human ENSPC can regulate the contractility of aganglionic bowel. METHODS: Embryonic mouse and neonatal human ENSPC were grown as neurospheres before transplantation into aganglionic embryonic mouse hindgut explants and culture for 8-12 days. Engraftment and neural differentiation were confirmed using immunofluorescence and transmission electron microscopy. The contraction frequency of transplanted bowel was measured and compared with that of embryonic day 11.5 embryonic ganglionic and aganglionic bowel cultured for the same period. Calcium movement was measured at spatially defined points in bowel wall smooth muscle. Neural modulation of bowel contractility was assessed using tetrodotoxin. RESULTS: Both mouse and human ENSPC migrated and differentiated after neurosphere transplantation. Transmission electron microscopy demonstrated the existence of synapses. Transplantation restored the high contraction frequency of aganglionic bowel to the lower rate of ganglionic bowel. Calcium imaging demonstrated that neurosphere transplantation coordinates intracellular free calcium levels. Both these effects were reversed by the addition of tetrodotoxin, indicating the functional effect of neurosphere-derived neurons. CONCLUSIONS: Neonatal human gut is a source of ENSPC that can be transplanted to restore the contractile properties of aganglionic bowel by a neurally mediated mechanism. This may aid development of a stem cell-based treatment for Hirschsprung's disease.

It is not what you do, it is the way that you do it: impact of a care pathway for appendicitis.

BACKGROUND/PURPOSE: Appendicitis is the most common surgical emergency in children. However, management varies widely. The aim of this study was to assess the impact of introducing a care pathway on the management of childhood appendicitis. METHODS: Data were collected prospectively for 3 successive cohorts: All patients operated for suspected appendicitis were included. The pathway was modified after interim analysis of group B data. P < .05 was significant. RESULTS: Six hundred patients were included. When compared with group A, group C patients were more likely to receive preoperative antibiotics (P < .0001), undergo formal pain assessment (P < .0001), and be operated before midnight (P = .025). There was a significant decrease in readmission rates from 10.0% to 4.2% (P = .023) despite an increase in cases of gangrenous and perforated appendicitis (P = .010). CONCLUSIONS: The introduction of a care pathway resulted in improved compliance with antibiotic regimens, more frequent pain assessment, and fewer post-midnight operations. Postappendicectomy readmission rates were reduced despite an increase in disease severity. This was achieved by critical reevaluation of outcomes and pathway redesign where appropriate.

Behavioral and neurochemical alterations in mice deficient in anaplastic lymphoma kinase suggest therapeutic potential for psychiatric indications.

The receptor tyrosine kinase product of the anaplastic lymphoma kinase (ALK) gene has been implicated in oncogenesis as a product of several chromosomal translocations, although its endogeneous role in the hematopoietic and neural systems has remained poorly understood. We describe that the generation of animals homozygous for a deletion of the ALK tyrosine kinase domain leads to alterations in adult brain function. Evaluation of adult ALK homozygotes (HOs) revealed an age-dependent increase in basal hippocampal progenitor proliferation and alterations in behavioral tests consistent with a role for this receptor in the adult brain. ALK HO animals displayed an increased struggle time in the tail suspension test and the Porsolt swim test and enhanced performance in a novel object-recognition test. Neurochemical analysis demonstrates an increase in basal dopaminergic signalling selectively within the frontal cortex. Altogether, these results suggest that ALK functions in the adult brain to regulate the function of the frontal cortex and hippocampus and identifies ALK as a new target for psychiatric indications, such as schizophrenia and depression, with an underlying deregulated monoaminergic signalling.

Characterisation and transplantation of enteric nervous system progenitor cells.

AIMS: Enteric nervous system (ENS) progenitor cells have been postulated to be an appropriate source of cells for the treatment of Hirschsprung's disease. In order for this to be successful, the techniques previously used for the isolation of rodent ENS progenitor cells need to be adapted for postnatal human tissue. In this paper, we describe a method suitable for the preparation of both mouse and human postnatal ENS progenitor cells and assess their transplantation potential. METHOD: Single cell suspensions were isolated from 11.5 days post-coitum embryonic mouse caecum and postnatal human myenteric plexus. These cells were cultured under non-adherent conditions to generate neurospheres which were implanted into aganglionic embryonic mouse hindgut explants. Cell proliferation, migration and differentiation were observed using immunofluorescence microscopy. RESULTS: Neurospheres generated from both mouse and human tissues contained proliferating neural crest-derived cells that could be expanded in tissue culture to generate both glial cells and neurons. When implanted into aganglionic murine gut, cells migrated from the neurospheres using pathways appropriate for cells derived from the neural crest, and differentiated to become glia and neurons expressing neuronal phenotypic markers characteristic of the ENS including nitric oxide synthase and vasoactive intestinal polypeptide. CONCLUSION: We have developed a technique for the isolation and expansion of ENS progenitor cells from human neonates. These cells have the ability to differentiate into neurons and glia when transplanted into aganglionic gut, this demonstration being a necessary first step for their autologous transplantation in the treatment of Hirschsprung's disease.

Novel use of skin substitute as rescue therapy in complicated giant exomphalos.

Giant exomphalos can be successfully managed using conservative or surgical techniques. However, if treatment is complicated by sepsis, early skin cover of the defect becomes necessary. Options include split skin grafting, but in the presence of ongoing infection the risk of graft failure is high and limited skin is available for regrafting. We describe the novel use of a skin substitute (Integra Artificial Skin, Integra Life Sciences Corporation, Plainsboro, NJ) as an alternative to primary grafting in the management of infected giant exomphalos.

Topography, stem cell behaviour, and organogenesis.

The fundamental problem of development is to explain how the progeny of a single cell, the fertilised egg, differentiates to form all the tissues of the body in the right place at the right time. It has only been during the last couple of years that the mechanisms and molecules mediating interactions between cells and tissues have begun to be delineated. This article reviews some of these recent studies. Sequences of topographically defined cellular interactions lead not only to the development of the body but also to the obvious and remarkable inference that the body more or less automatically builds itself.