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.
•Routine MCUG and the subsequent finding of VUR are not associated with increased rates of UTI compared to those who do not have routine MCUG.•Abnormal renal ultrasound is associated with ...UTI.•Routine MCUG is not recommended to detect VUR in patients with anorectal malformations as the detection and treatment does not alter the rate of UTI.
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.
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.
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).
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.
Mutations in SNCA, the gene encoding α-synuclein (αSyn), cause familial Parkinson's disease (PD) and aberrant αSyn is a key pathological hallmark of idiopathic PD. This α-synucleinopathy leads to ...mitochondrial dysfunction, which may drive dopaminergic neurodegeneration. PARKIN and PINK1, mutated in autosomal recessive PD, regulate the preferential autophagic clearance of dysfunctional mitochondria ("mitophagy") by inducing ubiquitylation of mitochondrial proteins, a process counteracted by deubiquitylation via USP30. Here we show that loss of USP30 in Usp30 knockout mice protects against behavioral deficits and leads to increased mitophagy, decreased phospho-S129 αSyn, and attenuation of SN dopaminergic neuronal loss induced by αSyn. These observations were recapitulated with a potent, selective, brain-penetrant USP30 inhibitor, MTX115325, with good drug-like properties. These data strongly support further study of USP30 inhibition as a potential disease-modifying therapy for PD.
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.
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).
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.
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.
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.
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 inhibitors of
d-amino acid oxidase (DAO) were discovered. In vivo data for compound
1 showed central and peripheral DAO inhibition and increased peripheral
d-serine levels.
The ‘NMDA ...hypofunction hypothesis of schizophrenia’ can be tested in a number of ways. DAO is the enzyme primarily responsible for the metabolism of
d-serine, a co-agonist for the NMDA receptor. We identified novel DAO inhibitors, in particular, acid
1, which demonstrated moderate potency for DAO in vitro and ex vivo, and raised plasma
d-serine levels after dosing ip to rats. In parallel, analogues were prepared to survey the SARs of
1.
Abstract 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.
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.
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