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Esophageal atresia (OA) represents one of the commonest and most severe developmental disorders of the foregut, the most proximal segment of the gastrointestinal (GI) tract (esophagus and stomach) in embryological terms. Of intrigue is the common origin from this foregut of two very diverse functional entities, the digestive and respiratory systems. OA appears to result from incomplete separation of the ventral and dorsal parts of the foregut during development, resulting in disruption of esophageal anatomy and frequent association with tracheo-oesophageal fistula. Not surprisingly, and likely inherent to OA, are associated abnormalities in components of the enteric neuromusculature and ultimately loss of esophageal functional integrity. An appreciation of such developmental processes and associated defects has not only enhanced our understanding of the etiopathogenesis underlying such devastating defects but also highlighted the potential of novel corrective therapies. There has been considerable progress in the identification and propagation of neural crest stem cells from the GI tract itself or derived from pluripotent cells. Such cells have been successfully transplanted into models of enteric neuropathy confirming their ability to functionally integrate and replenish missing or defective enteric nerves. Combinatorial approaches in tissue engineering hold significant promise for the generation of organ-specific scaffolds such as the esophagus with current initiatives directed toward their cellularization to facilitate optimal function. This chapter outlines the most current understanding of the molecular embryology underlying foregut development and OA, and also explores the promise of regenerative medicine.

Background Chronic intestinal pseudo-obstruction (CIPO) represents the most severe form of gastrointestinal dysmotility with debilitating and potentially lethal consequences. Symptoms can be non-specific, and result in this condition being diagnosed incorrectly or too late with consequences for morbidity and even mortality. Purpose The present article aims to provide pediatric and adult gastroenterologists with an up to date review about clinical features, diagnosis and therapeutic options for CIPO. Although pediatric and adult CIPO share many clinical aspects distinctive features can be identified. There is no single diagnostic test or pathognomonic finding of CIPO, thus a stepwise approach including radiology, endoscopy, laboratory, manometry, and histopathology should be considered in the diagnostic work-up. Treatment of patients with CIPO is challenging and requires a multidisciplinary effort with participation of appropriately experienced gastroenterologists, pathologists, dieticians, surgeons, psychologists, and other subspecialists based on the presence of comorbidities. Current treatment options invariably involve surgery and specialized nutritional support, especially in children. Medical therapies are mainly aimed to avoid complications such as sepsis or intestinal bacterial overgrowth and, where possible, restore intestinal propulsion. More efficacious therapeutic options are eagerly awaited for such difficult patients.

The esophagus acts as a conduit for the coordinated transport of food from the mouth to the stomach. Developmentally, it can be identified as a distinct structure from 4 weeks of gestation. At birth, it has a length of approximately 8 cm, which doubles in the first years of extrauterine life. Each of the three germ layers (endoderm, ectoderm, and mesoderm) is responsible for esophageal development, and their interactions are crucial for the development of the mucosa, muscular coats, and intrinsic nervous system.

Gastroesophageal reflux (GER) and its associated complications (gastroesophageal reflux disease—GERD) are very common in children with neurological impairment (NI) and correlate with the severity of neurodisability. A number of causative mechanisms underlie GERD in this population, many of which are inherent to the neurodisability and irreversible. Diagnosis is often difficult and compounded by a limited ability of NI children to communicate their symptoms, variable presentation and poor correlation with objective testing. Unfortunately, as a result, management is often misdirected and/or suboptimal. Overall, a high index of suspicion is needed for GERD when managing children with NI. A wide range of treatments are available for managing GER/GERD in this population of children, although the mainstay remains pharmacological therapy, namely, PPIs. A systematic approach is advised starting at simpler ‘conservative’ treatments through dietary manipulation, pharmacotherapy to surgical interventions. At each step there should be careful consideration of the benefits and risks and carers of NI children appropriately counselled about these. There is evidence to suggest that although there is a place for pharmacotherapy, consideration should also be given to diet both in terms of type and method of administration. In this respect there is emerging benefit for the use of post-pyloric feeding even as an alternative to surgery. Surgery, namely, anti-reflux procedures, should be considered the last resort although it appears to have a clear benefit in a highly selective group of NI children especially those with severe disability who have failed medical therapy. Overall, although there have been significant strides into understanding the management of NI children suffering problematic GER, there is a clear need for further robust studies in this challenging group.

Objectives: The presence of extraintestinal manifestations (EIM) in children with gastrointestinal (GI) food allergy (GIFA) is greatly debated. In the present study we assessed the prevalence of EIM in children with GIFA and investigated whether their presence is helpful in the allergy-focused historytaking process. Methods: The medical records of all children with a proven diagnosis of GIFA were reviewed along with those of children diagnosed as having inflammatory bowel disease (IBD) as controls. Data regarding age at onset, age at diagnosis, atopic family history, atopic comorbidities, GI symptoms, and EIM were recorded. Results: Data from 436 children with GIFA and 74 children with IBD were included in the analysis. EIM were documented in 368 children with GIFA, including fatigue (53.0%), allergic shiners (49.1%), mouth ulcers (39.0%), joint pain/hypermobility (35.8%), poor sleep (34.4%), night sweats (34.4%), headache (22.7%), and bed-wetting (17.7%). The proportion of patients with EIM was higher in the GIFA group compared with that in the IBD group (368/436 [84.4%] vs 40/74 [54.1%]; P

Summary Background The diagnostic corroboration of the relationship between gastro-oesophageal reflux disease (GERD) and chronic cough remains challenging. Aims To compare oesophageal mucosal intercellular space diameter (ISD) in children with GERD, children with gastro-oesophageal reflux (GER)-related cough (GrC) and a control group, and to explore the relationship between baseline impedance levels and dilated ISD in children with GER-related cough. Methods Forty children with GERD, 15 children with GrC and 12 controls prospectively underwent oesophagogastroduodenoscopy (EGD) with oesophageal biopsies taken 2–3 cm above squamocolumnar junction. ISD were quantified using transmission electron microscopy. Impedance-pH monitoring with evaluation of baseline impedance in the most distal impedance channel was performed in both patient groups. Results A significant difference in mean ISD values was found between GrC patients (0.9 ± 0.2 μm) and controls (0.5 ± 0.2 μm, P

Children comprise one-fifth of Europe's population. Promoting child health and development is of key importance for society and its future. This position paper highlights opportunities of investing in gastrointestinal, liver, and nutritional research to promote child health and delineates priorities for research. Investing in child health plays a key role in the promotion of population health, well-being, and disease prevention lifelong, with large health economic benefits. Major opportunities for improving knowledge and translational application arise from recent scientific and technological developments, for example, the long-term impact of early environmental cues interacting with genes. Personalised approaches to therapy and prevention should be enhanced. Deciphering the microbiome and its effects on functions can help in promoting long-term health. Epigenetic research can help to understand how early environmental factors influence later gastrointestinal and hepatic health and disease. A linked nutrition and physical activity strategy can promote health and prevent nutritional deficiencies, inactivity, and chronic noncommunicable diseases, such as diabetes, to ensure optimal health and cognition. Special attention should be devoted to populations with low socioeconomic status, migrant background, and ethnic minorities, and to critical life periods, including pregnancy, lactation, infancy, and childhood. Improved understanding of optimal nutrition and on maintaining gut and liver homeostasis throughout childhood will help prevent chronic diseases in later life.

The vasculature and nervous system share striking similarities in their networked, tree-like architecture and in the way they are super-imposed in mature organs. It has previously been suggested that the intestinal microvasculature network directs the migration of enteric neural crest cells (ENCC) along the gut to promote the formation of the enteric nervous system (ENS). To investigate the inter-relationship of migrating ENCC, ENS formation and gut vascular development we combined fate-mapping of ENCC with immunolabelling and intravascular dye injection to visualise nascent blood vessel networks. We found that the enteric and vascular networks initially had very distinct patterns of development. In the foregut, ENCC migrated through areas devoid of established vascular networks. In vessel-rich areas, such as the midgut and hindgut, the distribution of migrating ENCC did not support the idea that these cells followed a pre-established vascular network. Moreover, when gut vascular development was impaired, either genetically in Vegfa120/120 or Tie2-Cre;Nrp1fl/− mice or using an in vitro Wnt1-Cre;Rosa26Yfp/+ mouse model of ENS development, ENCC still colonised the entire length of the gut, including the terminal hindgut. These results demonstrate that blood vessel networks are not necessary to guide migrating ENCC during ENS development. Conversely, in miRet51 mice, which lack ENS in the hindgut, the vascular network in this region appeared to be normal suggesting that in early development both networks form independently of each other., Highlights • The gut vasculature is thought to direct migrating enteric neural crest cells (ENCC). • We visualised ENCC and the vasculature in the developing gastrointestinal tract. • Enteric and vascular networks initially had little correlation. • ENCC colonised the gut when vascular development was impaired in vivo or in vitro. • Blood vessels are thus not necessary to guide migrating ENCC during ENS formation.

Background & Aims The enteric nervous system (ENS) is the largest branch of the peripheral nervous system, comprising complex networks of neurons and glia, which are present throughout the gastrointestinal tract. Although development of a fully functional ENS is required for gastrointestinal motility, little is known about the ontogeny of ENS function in humans. We studied the development of neuronal subtypes and the emergence of evoked electrical activity in the developing human ENS. Methods Human fetal gut samples (obtained via the MRC-Wellcome Trust Human Developmental Biology Resource–UK) were characterized by immunohistochemistry, calcium imaging, RNA sequencing, and quantitative real-time polymerase chain reaction analyses. Results Human fetal colon samples have dense neuronal networks at the level of the myenteric plexus by embryonic week (EW) 12, with expression of excitatory neurotransmitter and synaptic markers. By contrast, markers of inhibitory neurotransmitters were not observed until EW14. Electrical train stimulation of internodal strands did not evoke activity in the ENS of EW12 or EW14 tissues. However, compound calcium activation was observed at EW16, which was blocked by the addition of 1 μmol/L tetrodotoxin. Expression analyses showed that this activity was coincident with increases in expression of genes encoding proteins involved in neurotransmission and action potential generation. Conclusions In analyses of human fetal intestinal samples, we followed development of neuronal diversity, electrical excitability, and network formation in the ENS. These processes are required to establish the functional enteric circuitry. Further studies could increase our understanding of the pathogenesis of a range of congenital enteric neuropathies.

The enteric nervous system is vulnerable to a range of congenital and acquired disorders that disrupt the function of its neurons or lead to their loss. The resulting enteric neuropathies are some of the most challenging clinical conditions to manage. Neural stem cells offer the prospect of a cure given their potential ability to replenish missing or dysfunctional neurons. This article discusses diseases that might be targets for stem cell therapies and the barriers that could limit treatment application. We explore various sources of stem cells and the proof of concept for their use. The critical steps that remain to be addressed before these therapies can be used in patients are also discussed. Key milestones include the harvesting of neural stem cells from the human gut and the latest in vivo transplantation studies in animals. The tremendous progress in the field has brought experimental studies exploring the potential of stem cell therapies for the management of enteric neuropathies to the cusp of clinical application.

Achalasia is a rare esophageal motility disorder: its optimal treatment in children is still a matter of debate. Records of children treated for achalasia, over an 18-year period, were reviewed.Forty-eight children (median age at diagnosis 10 years; range 3-17 years) were identified. Twenty-eight patients were initially treated with Heller's myotomy (HM) and 20 with balloon dilatation (BD). At last follow-up (median 3 years; range 1-5.5 years), 43.8% (21/48) of children were symptom free. The number of asymptomatic children was significantly higher among those treated initially with HM compared to BD (HM 15/28, 53.6% BD 6/20, 30%, p 0.05). All children who underwent BD required HM due to symptom recurrence. The median (range) total number of procedures was significantly higher in the BD group (BD 3 (1-7); HM 1 (1-5); p 0.05) with a shorter time to the second intervention (BD 14 months, 95%CI 4-24; HM 58 months, 95%CI 38-79; p 0.05). Of 108 procedures, esophageal perforation occurred in two children after HM (two out of 48 HM procedures in total, 4%) and one child after BD (1/60, 1.7%).Less than half of children with achalasia are symptom free after initial treatment with either BD or HM. HM, however, when performed as first procedure, provided longer symptom-free period and reduced need for subsequent intervention. What is Known: • Balloon dilatation (BD) and Heller's myotomy (HM) are safe and effective treatment options for achalasia. • Controversy, however, exists regarding the most effective initial therapeutic approach. What is New: • HM with or without fundoplication may represent the initial therapeutic approach of choice. • Initial BD may negatively affect the outcome of a subsequent HM.

Gastrointestinal (food) allergy is increasingly prevalent and currently estimated to affect approximately 10 % of all children, with cow’s milk protein the most commonly implicated allergen across the world. The predominant mechanism in GI allergy appears to be delayed-type hypersensitivity with involvement of T cells, mast cells, and eosinophils as key immune cells. Genetic susceptibility together with alterations in gut environment interactions including changes in immune function, exposure to infectious agents, and the microbiome, amongst others, appear to underlie the pathogenesis of allergy in the GI tract. Food allergy is increasingly implicated in common gastrointestinal motility symptoms and disorders such as gastro-esophageal reflux, recurrent abdominal pain, and constipation. In all these, critical neuroimmune interactions generally involving mast cells and eosinophils, power houses of inflammatory mediators and neuro-modulatory factors, functioning in close proximity to GI nerves appear to play a role. This chapter aims to review the putative mechanisms for allergy in motility disorders, including neuro-immune interactions, and review the available evidence for its role in the pathogenesis and treatment of common GI motility disorders.

Chronic intestinal pseudo-obstruction (CIPO) represents the most severe end of the spectrum of gut motility disorders comprising a group of rare, heterogeneous, and disabling disorders of the gastrointestinal (GI) tract characterized by absent or ineffective intestinal peristalsis. Pediatric CIPO results from developmental and pathological processes, which affect, either singly or in combination, the intrinsic or extrinsic intestinal neurons (neuropathy) and/or smooth muscle fibers (myopathy) and/or interstitial cells of Cajal (ICC) (mesenchymopathy). These processes lead to an inability of the small intestine to propel its luminal contents normally, which manifests clinically as continuous or repetitive episodes of intestinal obstruction in the absence of a defined, fixed lumen-occluding lesion, hence the term “pseudo”-obstruction. The diagnosis of CIPO can be challenging and is based on a combination of clinical, radiological, manometric, and histopathologic findings. At the current time, therapeutic strategies are limited and largely supportive, designed to optimize nutrition and reduce the frequency and severity of pseudo-obstructive episodes. Overall management is focused on alleviating symptomatology and complications, preserving function of the GI tract, and improving patients’ quality of life. The therapeutic armamentarium includes pharmacotherapy to address reversible causes, e.g., inflammation, and to stimulate motility where possible, special means of alimentation (enteral, parenteral, and, where tolerated, oral) to provide nutrition while preserving gut function, as well as surgical interventions such as formation of ostomies (i.e., gastrostomy, ileostomy) to allow “venting” and decompression of the gut. A number of novel agents may hold future promise, but at the present time, small bowel transplantation provides the only option for definitive cure with improved outcomes and survival in centers with the relevant expertise.

AIM: Implementing international guidelines guarantees high standards of clinical care. A group of experts developed an algorithm to drive the management of common gastrointestinal symptoms in infancyby paediatricians and general practitioners. METHODS: The algorithm started from the evidence-based recommendations of the European Society of Gastroenterology, Hepatology and Nutrition and the European Society of Pediatric Infectious Diseases and an updated review of the literature. We used the structured quantitative method of nominal group technique to reach a consensus. RESULTS: A practical algorithm for the management of infants with acute diarrhoea was designed based on theconsensus reached for each statement. The management of an infant with acute diarrhoeashould include a sequence of actions: 1) a semi-quantitative estimate of infant dehydration through validated clinical scores, 2) rehydration therapy and early re-feedingwith breast milk or regular formula and 3) effective agents to reduce the severity and duration of the diarrhoea. Finally, in children with prolonged diarrhoea, the search for aetiology should include persistent infections or reinfections, cows' milk protein allergy and celiac diseases. Lactose should always be withdrawn. CONCLUSION: This algorithm provides an evidence-based sequence of interventions to optimisethe management of infants with acute diarrhoea. This article is protected by copyright. All rights reserved.

UNLABELLED: Up to 50% of infants present with symptoms of regurgitation, infantile colic and/or constipation during the first 12 months of life. Although they are often classed as functional disorders, there is an overlap with cows' milk allergy. We present practical algorithms for the management of such disorders, based on existing evidence and general consensus, with a particular focus on primary health care. Management consists of early recognition of warning signs of organic disease, parental reassurance and nutritional strategies. CONCLUSION: The proposed algorithms aim to help healthcare providers manage frequent gastrointestinal and cows' milk-related symptoms in infants safely and effectively.

Objectives Enteric neuropathies are severe gastrointestinal disorders with unsatisfactory outcomes. We aimed to investigate the potential of enteric neural stem cell therapy approaches for such disorders by transplanting mouse enteric neural crest cells (ENCCs) into ganglionic and aganglionic mouse gut in vivo and analysing functional integration and long-term safety. Design Neurospheres generated from yellow fluorescent protein (YFP) expressing ENCCs selected from postnatal Wnt1-cre;R26R-YFP/YFP murine gut were transplanted into ganglionic hindgut of wild-type littermates or aganglionic hindgut of Ednrbtm1Ywa mice (lacking functional endothelin receptor type-B). Intestines were then assessed for ENCC integration and differentiation using immunohistochemistry, cell function using calcium imaging, and long-term safety using PCR to detect off-target YFP expression. Results YFP+ ENCCs engrafted, proliferated and differentiated into enteric neurons and glia within recipient ganglionic gut. Transplanted cells and their projections spread along the endogenous myenteric plexus to form branching networks. Electrical point stimulation of endogenous nerve fibres resulted in calcium transients (F/F0 = 1.16±0.01;43 cells, n = 6) in YFP+ transplanted ENCCs (abolished with TTX). Long-term follow-up (24 months) showed transplanted ENCCs did not give rise to tumours or spread to other organs (PCR negative in extraintestinal sites). In aganglionic gut ENCCs similarly spread and differentiated to form neuronal and glial networks with projections closely associated with endogenous neural networks of the transition zone. Conclusions Transplanted ENCCs successfully engrafted into recipient ganglionic and aganglionic gut showing appropriate spread, localisation and, importantly, functional integration without any long-term safety issues. This study provides key support for the development and use of enteric neural stem cell therapies.

Lower threshold and widening indications for paediatric gastrointestinal endoscopy have resulted in a significant increase in the numbers of endoscopic procedures performed in infants. Despite this, knowledge of gastrointestinal mucosal findings in this age group is limited and data on the clinical usefulness of endoscopy are lacking.All of the children younger than 1 year referred to a single tertiary paediatric gastroenterology unit during the period June 1987 to August 2007 who underwent gastrointestinal endoscopy were identified and the clinical indications and histological outcomes were reviewed.A total of 933 gastroesophageal duodenoscopies and 439 colonoscopies were performed in 1024 cases in a total of 823 infants. In order of frequency, clinical indications were diarrhoea (51%), failure to thrive (41.2%), symptoms of reflux (27.1%), and rectal bleeding (8.5%). Mucosal biopsies were insufficient for assessment in only 2.4% of cases. Mucosal histology was normal in 33.8%, whereas histological abnormalities were identified in 63.8%. Specific histological diagnoses included microvillous inclusion disease, autoimmune enteropathy, graft-versus-host disease post-bone marrow transplantation, tufting enteropathy, and disaccharidase deficiency. There was only 1 colonic perforation complicating endoscopy in a total of 889 cases for which relevant information was available (0.1%).In two-thirds of cases, histological abnormalities were detected that influenced management following endoscopic examination and mucosal biopsy in infants. Endoscopy with biopsies is a greatly informative test with low failure and complication rates in the first year of life.

Knowledge of molecular mechanisms that underlie development of the enteric nervous system has greatly expanded in recent decades. Enteric neuropathies related to aberrant genetic development are thus becoming increasingly recognized. There has been no recent review of these often highly morbid disorders. This review highlights advances in knowledge of the molecular pathogenesis of these disorders from a clinical perspective. It includes diseases characterized by an infantile aganglionic Hirschsprung phenotype and those in which structural abnormalities are less pronounced. The implications for diagnosis, screening and possible reparative approaches are presented.

Within the embryonic lung, intrinsic nerve ganglia, which innervate airway smooth muscle, are required for normal lung development and function. We studied the development of neural crest-derived intrinsic neurons within the embryonic mouse lung by crossing Wnt1-Cre mice with R26R-EYFP reporter mice to generate double transgenic mice that express yellow fluorescent protein (YFP) in all neural crest cells (NCCs) and their derivatives. In addition to utilizing conventional immunohistochemistry on frozen lung sections, the complex organization of lung innervation was visualized in three dimensions by combining the genetic labelling of NCCs with optical projection tomography, a novel imaging technique that is particularly useful for the 3D examination of developing organs within embryos. YFP-positive NCCs migrated into the mouse lung from the oesophagus region at embryonic day 10.5. These cells subsequently accumulated around the bronchi and epithelial tubules of the lung and, as shown by 3D lung reconstructions with optical projection tomography imaging, formed an extensive, branching network in association with the developing airways. YFP-positive cells also colonized lung maintained in organotypic culture, and responded in a chemoattractive manner to the proto-oncogene, rearranged during transfection (RET) ligand, glial-cell-line-derived neurotrophic factor (GDNF), suggesting that the RET signalling pathway is involved in neuronal development within the lung. However, when the lungs of Ret(-/-) and Gfrα1(-/-) embryos, deficient in the RET receptor and GDNF family receptor α 1 (GFRα1) co-receptor respectively, were examined, no major differences in the extent of lung innervation were observed. Our findings demonstrate that intrinsic neurons of the mouse lung are derived from NCCs and that, although implicated in the development of these cells, the role of the RET signalling pathway requires further investigation.

Collagen is an abundant protein found in the extracellular matrix of many tissues. Due to its biocompatibility, it is a potentially ideal biomaterial for many tissue engineering applications. However, harvested collagen often requires restructuring into a three-dimensional matrix to facilitate applications such as implantation into poorly accessible tissue cavities. The aim of the current study was to produce a conformable collagen-based scaffold material capable of supporting tissue regeneration for use in wound repair applications. Microporous collagen spheres were prepared using a thermally induced phase separation (TIPS) technique and their biocompatibility was assessed. The collagen spheres were successfully cross-linked with glutaraldehyde vapour, rendering them mechanically more stable. When cultured with myofibroblasts the collagen spheres stimulated a prolonged significant increase in secretion of the angiogenic growth factor, vascular endothelial growth factor (VEGF), compared with cells alone. Control polycaprolactone (PCL) spheres failed to stimulate a similar prolonged increase in VEGF secretion. An enhanced angiogenic effect was also seen in vivo using the chick embryo chorioallantoic membrane assay, where a significant increase in the number of blood vessels converging towards collagen spheres was observed compared with control PCL spheres. The results from this study indicate that microporous collagen spheres produced using TIPS are biologically active and could offer a novel conformable scaffold for tissue regeneration in poorly accessible wounds.

Enteric neuropathies comprise a vast and disparate array of congenital and acquired disorders of the enteric nervous system (ENS), reflecting both the complexity of its neuronal composition and the many interactions that modulate its function. Although present therapeutic strategies, largely limited to surgery and the provision of artificial nutrition, have transformed the early survival and life of sufferers, levels of morbidity and mortality remain unacceptably high. This highlights the need to develop new treatments for enteric neuropathies. In the last decade, the tremendous advances in molecular biology and genetics have significantly enhanced our understanding of ENS development and function. Coupled with equivalent progress in the fields of pharmacology and stem-cell biology, this has led to the identification of novel tools and targets for therapy, which either aim to optimise the function of the intrinsic ENS or replace/replenish components of an inadequate or dysfunctional ENS. This article reviews current work on a number of these interventions with a particular focus on the use of ENS stem cells as potential therapeutic tools for enteric neuropathies.

Chronic intestinal pseudo-obstruction (CIPO) comprises a group of rare, heterogeneous, and disabling disorders of the gastrointestinal (GI) tract characterized by absent or ineffective intestinal peristalsis. CIPO in children results from a spectrum of developmental and pathological processes that affect, singly or in combination, the intrinsic or extrinsic intestinal nerves (neuropathy) and/or smooth muscle fibers (myopathy) and/or interstitial cells of Cajal (ICC) (mesenchymopathy). Ultimately, this leads to an inability of the small bowel to propel its luminal contents, which manifests clinically with repetitive episodes or continuous signs and symptoms of intestinal obstruction in the absence of a defined, fixed lumen-occluding lesion, hence the term “pseudo”-obstruction. The diagnosis of CIPO remains challenging and should be based on a combination of clinical, radiological, manometric, and histopathologic findings. Current therapeutic strategies are limited and mainly supportive, aimed at maintaining the patient’s optimal nutritional status and reducing the frequency and severity of the pseudo-obstructive episodes. The latter in turn should limit symptoms and complications, preserve function of the GI tract, and improve overall quality of life. This can be achieved with appropriate pharmacotherapy, enteral, and parenteral nutrition (including oral nutrition if tolerated) along with formation of ostomies (i.e., gastrostomy, ileostomy) to allow “venting” and decompression of the gut. A number of novel agents may hold promise but at the present time, small bowel transplantation provides the only option for definitive cure with improved outcomes and survival in centers with the relevant expertise.

Background The choice of infant formula is thought to play an important role on gastric emptying (GE) in a variety of gastrointestinal disorders. It is known that many ingredients impact on GE, including the type of protein and level of hydrolysis. In clinical practice, feeds are often recommended due to putative improved GE related to the type of protein and level of hydrolysis, however whether this is scientifically justified still needs to be established. A systematic review comparing the impact of protein type and hydrolysis on GE in children was therefore performed. Methods The Patient, Intervention, Comparison and Outcome system was used. A structured literature search was performed using the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines, searching PubMed, Cochrane databases and Google Scholar from 1990 to 2014. We only included articles published in full text English language using specific search terms, including both scintigraphy and C13-octanoic acid breath test. Results We identified 126 publications of which 20 were eligible for inclusion but only 8 were included. Studies reviewed GE in both healthy children as well as those with neurodevelopmental delay and reflux. Two studies investigating GE of breast milk versus formula indicated a faster GE for breast milk. Four studies found that feeds containing whole whey in varying amounts emptied faster than predominant whole casein feeds and one study found no difference in GE. Five studies investigated a mix of whole versus hydrolysed protein and found conflicting results related to study population and hydrolysis. Conclusions Breast milk has a faster GE than formula milk. Although there seems to be a trend towards whey feeds emptying faster, different methodologies, feed compositions and patient groups makes it difficult to draw firm conclusions. Future studies should be performed with comparable feeds in populations where increased GE may be of clinical benefit.

We evaluated the effect of bowel preparation on colonic transit time (CTT) measured by the radio-opaque marker test in children with constipation. All children underwent 2 radio-opaque marker-CTT tests, both in cleansed and uncleansed bowel state. Our findings confirm that the state of colonic fecal filling may significantly influence CTT.

Objectives: The aim of the study was to review published evidence and the opinion of practising clinicians on the prevalence and long-term health consequences of functional gastrointestinal symptoms in infants younger than 12 months. Methods: PubMed was searched from inception to November 2014 to find articles reporting the prevalence and long-term health outcomes of infantile colic, regurgitation, functional constipation, functional diarrhoea, and dyschezia in infants younger than

OBJECTIVES: This European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) position statement provides a comprehensive guide for health care providers to manage percutaneous endoscopic gastrostomy tubes in a safe, effective, and appropriate way.METHODS: Relevant literature from searches of PubMed, CINAHL, and recent guidelines was reviewed. In the absence of evidence, recommendations reflect the expert opinion of the authors. Final consensus was obtained by multiple e-mail exchange and during 3 face-to-face meetings of the gastroenterology committee of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.RESULTS: Endoscopically placed gastrostomy devices are essential in the management of children with feeding and nutritional problems. The article focuses on practical issues such as indications and contraindications.CONCLUSIONS: The decision to place an endoscopic gastrostomy has to be made by an appropriate multidisciplinary team, which then provides active follow-up and care for the child and the device.

The neurons and glia that comprise the enteric nervous system (ENS), the intrinsic innervation of the gastrointestinal tract, are derived from vagal and sacral regions of the neural crest. In order to form the ENS, neural crest-derived precursors undergo a number of processes including survival, migration and proliferation, prior to differentiation into neuronal subtypes, some of which form functional connections with the gut smooth muscle. Investigation of the developmental processes that underlie ENS formation has progressed dramatically in recent years, in no small part due to the attention of scientists from a range of disciplines on the genesis of Hirschsprung's disease (aganglionic megacolon), the major congenital abnormality of the ENS. This review summarizes recent advances in the field of early ENS ontogeny and focuses on: (i) the spatiotemporal migratory pathways followed by vagal and sacral neural crest-derived ENS precursors, including recent in vivo imaging of migrating crest cells within the gut, (ii) the roles of the RET and EDNRB signalling pathways and how these pathways interact to control ENS development, and (iii) how perpendicular migrations of neural crest cells within the gut lead to the formation of the myenteric and submucosal plexi located between the smooth muscle layers of the gut wall.

The transcriptional regulator SOX10 and the signalling molecule endothelin 3 have important roles in the development of the mammalian enteric nervous system (ENS). Using a clonal cell culture system, we show that SOX10 inhibits overt neuronal and glial differentiation of multilineage ENS progenitor cells(EPCs), without interfering with their neurogenic commitment. We also demonstrate that endothelin 3 inhibits reversibly the commitment and differentiation of EPCs along the neurogenic and gliogenic lineages,suggesting a role for this factor in the maintenance of multilineage ENS progenitors. Consistent with such a role, the proportion of Sox10-expressing progenitors in the total population of enteric neural crest cells is reduced in the gut of endothelin 3-deficient embryos. This reduction may be related to the requirement of endothelin signalling for the proliferation of ENS progenitors. The dependence of ENS progenitors on endothelin 3 is more pronounced at the migratory front of enteric neural crest cells, which is associated with relatively high levels of endothelin 3 mRNA. Our findings indicate that SOX10 and endothelin 3 have a crucial role in the maintenance of multilineage enteric nervous system progenitors.

Despite much progress in the understanding of pathogenesis and of management, diarrhoeal illnesses remain one of the most important causes of global childhood mortality and morbidity. Infections account for most illnesses, with pathogens employing ingenious mechanisms to establish disease. In the developed world, an upsurge in immune-mediated gut disorders might have resulted from a disruption of normal bacterial-epithelial cross-talk and impaired maturation of the gut's immune system. Oral rehydration therapies are the mainstay of management of gastroenteritis, and their composition continues to improve. Malnutrition remains the major adverse prognostic indicator for diarrhoea-related mortality, emphasising the importance of nutrition in early management. Drugs are of little use, except for specific indications although new agents that target mechanisms of secretory diarrhoea show promise, as do probiotics. However, preventive strategies on a global scale might ultimately hold the greatest potential to reduce the burden of diarrhoeal disease. These strategies include vaccines and, most importantly, policies to address persisting inequalities between the developed and developing worlds with respect to nutrition, sanitation, and access to safe drinking water.

Cultures of dissociated foetal and postnatal mouse gut gave rise to neurosphere-like bodies, which contained large numbers of mature neurons and glial cells. In addition to differentiated cells, neurosphere-like bodies included proliferating progenitors which, when cultured at clonal densities,gave rise to colonies containing many of the neuronal subtypes and glial cells present in the mammalian enteric nervous system. These progenitors were also capable of colonising wild-type and aganglionic gut in organ culture and had the potential to generate differentiated progeny that localised within the intrinsic ganglionic plexus. Similar progenitors were also derived from the normoganglionic small intestine of mice with colonic aganglionosis. Our findings establish the feasibility of expanding and isolating early progenitors of the enteric nervous system based on their ability to form distinct neurogenic and gliogenic structures in culture. Furthermore, these experiments provide the rationale for the development of novel approaches to the treatment of congenital megacolon (Hirschsprung's disease) based on the colonisation of the aganglionic gut with progenitors derived from normoganglionic bowel segments.

Gastro-esophageal reflux (GER) is common in infants and children and has a varied clinical presentation: from infants with innocent regurgitation to infants and children with severe esophageal and extra-esophageal complications that define pathological gastro-esophageal reflux disease (GERD). Although the pathophysiology is similar to that of adults, symptoms of GERD in infants and children are often distinct from classic ones such as heartburn. The passage of gastric contents into the esophagus is a normal phenomenon occurring many times a day both in adults and children, but, in infants, several factors contribute to exacerbate this phenomenon, including a liquid milk-based diet, recumbent position and both structural and functional immaturity of the gastro-esophageal junction. This article focuses on the presentation, diagnosis and treatment of GERD that occurs in infants and children, based on available and current guidelines.

This position statement summarises a view of academia regarding standards for clinical research in collaboration with commercial enterprises, focussing on trials in pregnant women, breast-feeding women, and children. It is based on a review of the available literature and an expert workshop cosponsored by the Early Nutrition Academy and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Clinical research collaborations between academic investigators and commercial enterprises are encouraged by universities, public funding agencies, and governmental organisations. One reason is a pressing need to obtain evidence on the effects, safety, and benefits of drugs and other commercial products and services. The credibility and value of results obtained through public–private research collaborations have, however, been questioned because many examples of inappropriate research practice have become known. Clinical research in pregnant and breast-feeding women, and in infants and children, raises sensitive scientific, ethical, and societal questions and requires the application of particularly high standards. Here we provide recommendations for the conduct of public–private research collaborations in these populations. In the interest of all stakeholders, these recommendations should contribute to more reliable, credible, and acceptable results of commercially sponsored trials and to reducing the existing credibility gap.

Background Aprepitant (Emend, Merck Sharp & Dohme Ltd, Haarlem, the Netherlands), a neurokinin-1 receptor antagonist, prevents vomiting in a range of conditions. No data are available on its use in children with cyclical vomiting syndrome (CVS). Aim We investigated the efficacy of aprepitant as prophylactic treatment or acute intervention in CVS children refractory to conventional therapies. Methods Forty-one children (median age: 8 years) fulfilling NASPGHAN criteria treated acutely (RegA) or prophylactically (RegP) with aprepitant were retrospectively reviewed. Primary outcome was the clinical response (decrease in frequency and intensity of CVS episodes). Secondary outcomes were: number of CVS episodes/year, number of hospital admissions/year, CVS episode duration, number of vomits/h, symptom-free interval length (days), and school attendance percentage. The follow-up period was 18-60 months. Results Sixteen children received RegP and 25 RegA. One child on RegP stopped treatment due to severe migraine. At 12-months on intention-to-treat analysis, 13 children on RegP (81%) achieved either complete (3/16, 19%) or partial (10/16, 62%) clinical response. On RegA, 19 children (76%) had either complete (3/25, 12%) or partial (16/25, 64%) response (P = 0.8 vs. RegP). In both RegP and RegA, there was a significant decrease in CVS episodes/year, hospital admission number/year, CVS episode length, number of vomits/h, as well as an increase in symptom-free interval duration and school attendance percentage. Side effects were reported only in RegP (5/16, 31%) including hiccough (3/16, 19%), asthenia/fatigue (2/16, 12.5%), increased appetite (2/16, 12.5%), mild headache (1/16, 6%) and severe migraine (1/16, 6%). Conclusion Aprepitant appears effective for both acute and prophylactic management of paediatric cyclical vomiting syndrome refractory to conventional therapies.

Background: Hirschsprung disease (HSCR) is the most common identifiable developmental disorder of the enteric nervous system (ENS), characterized by a failure of its formation in a variable segment of distal bowel. Currently available surgical therapies for HSCR, although lifesaving, are associated with an unsatisfactory long-term prognosis for many, highlighting the need for newer curative therapies. On the basis of our understanding of ENS development, I potential therapeutic tool relates to the cells that gave rise to the ENS during embryogenesis. Data from initial animal studies suggested that such "ENS stem cells" persist within postnatal gut, from which they can be harvested and used to replenish absent nerves within experimental models of gut aganglionosis. More recently, it has been shown that ENS stem cells can also be isolated from human postnatal gut. The early human studies, however, used full-thickness gut tissue obtained at surgery to generate ENS stem cells, which in clinical terms poses practical problems. In an effort to directly address such obstacles our latest research has shown that ENS stem cells can also be harvested from gut mucosal biopsies obtained at routine endoscopy. Such gut mucosal ENS stem cells are capable of appropriately and fully colonizing aganglionic gut tissue, including from HSCR, to generate components of a mature and functional ENS.Conclusions: Current evidence suggests that transplantation of ENS stem cells, sourced from easily accessible postnatal gut, could be a viable alternative treatment for HSCR and ultimately for a number of other congenital or acquired ENS disorders. JPGN 48:S92-S94, 2009.

Background & Aims: Intractable ulcerating enterocolitis of infancy (IE) is an uncommon, autosomal-recessive, and devastating inflammatory bowel disorder that arises as a consequence of a poorly defined underlying immunologic disorder. Infants with IE suffer from recurrent severe oro-anal disease and an enterocolitis that is unresponsive to conventional immunosuppressive therapy and requires early pancolectomy to control the severity of the disease. Despite such aggressive treatment these individuals remain at high risk of Epstein–Barr virus–driven lymphomatous proliferations, including non-Hodgkin's lymphoma. The underlying genetic basis for this disease remains undefined. This report aims to describe the use of bone marrow transplantation as a treatment for this condition. Methods: This was a case series report. Results: We describe the successful treatment of IE by allogeneic bone marrow transplantation in 2 brothers, now aged 7 and 11 years, one of whom had developed an Epstein–Barr virus–related monomorphous B-lymphocyte lymphoproliferative disorder. This treatment has resulted in prolonged clinical remission in both boys and abrogated the need for aggressive immunosuppression. Conclusions: Bone marrow transplantation can be used for the treatment of intractable ulcerating enterocolitis of infancy, which may support a role in other intractable inflammatory bowel conditions in the pediatric population.

INTRODUCTION AND AIM: Diagnosis of aerophagia is based on clinical symptoms and described in Rome III Criteria. The aim of this study was to estimate the normal and pathological values for air swallows measured with pH-impedance in children. MATERIAL AND METHODS: We analysed features of air swallowing in pH-impedance for patients hospitalized in the Great Ormond Street Hospital in 2008-2014, with the clinical symptoms of aerophagia, who have met the Rome III Criteria. Children with pH-impedance performed due to other gastrointestinal conditions (GORD, Abdominal pain, food allergy and asthma) and had normal studies comprised the control group. The exclusion criteria were: neurological, metabolic or genetic disorders, previous oesophageal surgery including fundoplication, connective tissue disorders and studies lasting less than 16 hours in durationAll studies were re analysed manually, meals were excluded from analysis. Total number of air swallows (in upright and recumbent position); mixed swallows, gastric belching and supragastric belching were counted. The results were presented as total number of episodes and as median number of episodes per hour. RESULTS: Impedance recording of 10 patients (7 males) with clinical aerophagia and control group of10 children (7 males) were analysed. Mean age of patients was 10 years (4.5-13.5) and 7 years in control group (4.5-17 years). Mean (±SD) recording time for patients 21.3 hrs (±2.3) for control 21.2 hrs (±1.2).Total number of liquid reflux (mean ± SD) for patients 46.9 (±22.6), control 27.6 (±15.4) p = 0.028. The median of total air swallows per hour was 30.35 (IQR: 22.6 to 43.50) in patients with aerophagia and 7.33 (IQR: 5.43 to 9.9) in control group. There were significant differences in total number of air swallows, as well as in supragastric belches between the groups (p = 0.0001 and p = 0.001, respectively). Both, air swallows and gastric belches were significantly more often observed in boys (median for boys 20.92 and 1.06; for girls 7.20 and 0.34; p = 0.02 and p = 0.006, respectively). CONCLUSIONS: pH-impedance is an important diagnostic tool in the measurement of gas and fluid movement in the oesophagus. Hereby we showed suitability of pH-impedance in the assessment of children with clinically diagnosed aerophagia.