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The International Network on Esophageal Atresia (INoEA) stands as a beacon of collaboration in addressing the complexities of this congenital condition on a global scale. The eleven board members, from various countries (USA, Canada, France, Australia, Italy, Sweden, Germany, and The Netherlands) and backgrounds (pediatric gastroenterology, pediatric surgery, pediatric pulmonology, nursing, and parents) met in a face-to-face symposium in Lille in November 2023, to identify challenges and solutions for improving global collaboration of the network. [ABSTRACT FROM AUTHOR]

Simple Summary: The brain senses and regulates all internal bodily processes, including the levels of the sugar molecule glucose in the blood stream (systemic regulation) or in specific organs, such as the gut. The contribution of the vagus nerve to this mechanism, the longest nerve connecting the brain with the rest of the body, has not been well understood. Moreover, it has remained unknown how the activity of the vagus nerve contributes to the inflammatory response as may be seen during infections when the immune system is activated. Here, we mechanically and electrically manipulated the vagus nerve activity, decreasing or increasing it selectively, and measuring the degree of change in the glucose levels and of the inflammatory response systemically and in the gut, an important site of neonatal injury. We reported a surprising dual (hormetic) anti- or pro-inflammatory effect of reduced vagal activity combined with increased levels of glucose dependent on the levels of the infectious agent inducing the inflammatory response. We further discussed the implications for future research and clinical practice. BACKGROUND. Glucosensing elements are widely distributed throughout the body and relay information about circulating glucose levels to the brain via the vagus nerve. However, while anatomical wiring has been established, little is known about the physiological role of the vagus nerve in glucosensing. The contribution of the vagus nerve to inflammation in the fetus is poorly understood. Increased glucose levels and inflammation act synergistically when causing organ injury, but their interplay remains incompletely understood. We hypothesized that vagotomy (Vx) will trigger a rise in systemic glucose levels and this will be enhanced during systemic and organ-specific inflammation. Efferent vagus nerve stimulation (VNS) should reverse this phenotype. METHODS. Near-term fetal sheep (n = 57) were surgically prepared using vascular catheters and ECG electrodes as the control and treatment groups (lipopolysaccharide (LPS), Vx + LPS, Vx + LPS + selective efferent VNS). The experiment was started 72 h postoperatively to allow for post-surgical recovery. Inflammation was induced with LPS bolus intravenously (LPS group, 400 ng/fetus/day for 2 days; n = 23). For the Vx + LPS group (n = 11), a bilateral cervical vagotomy was performed during surgery; of these n = 5 received double the LPS dose, LPS800. The Vx + LPS + efferent VNS group (n = 8) received cervical VNS probes bilaterally distal from Vx in eight animals. Efferent VNS was administered for 20 min on days 1 and 2 +/10 min around the LPS bolus. Fetal arterial blood samples were drawn on each postoperative day of recovery (-72 h, -48 h, and -24 h) as well as at the baseline and seven selected time points (3–54 h) to profile inflammation (ELISA IL-6, pg/mL), insulin (ELISA), blood gas, and metabolism (glucose). At 54 h post-LPS, a necropsy was performed, and the terminal ileum macrophages' CD11c (M1 phenotype) immunofluorescence was quantified to detect inflammation. The results are reported for p < 0.05 and for Spearman R2 > 0.1. The results are presented as the median (IQR). RESULTS. Across the treatment groups, blood gas and cardiovascular changes indicated mild septicemia. At 3 h in the LPS group, IL-6 peaked. That peak was decreased in the Vx + LPS400 group and doubled in the Vx + LPS800 group. The efferent VNS sped up the reduction in the inflammatory response profile over 54 h. The M1 macrophage activity was increased in the LPS and Vx + LPS800 groups only. The glucose and insulin concentrations in the Vx + LPS group were, respectively, 1.3-fold (throughout the experiment) and 2.3-fold higher vs. control (at 3 h). The efferent VNS normalized the glucose concentrations. CONCLUSIONS. The complete withdrawal of vagal innervation resulted in a 72-h delayed onset of a sustained increase in glucose for at least 54 h and intermittent hyperinsulinemia. Under the conditions of moderate fetal inflammation, this was related to higher levels of gut inflammation. The efferent VNS reduced the systemic inflammatory response as well as restored both the concentrations of glucose and the degree of terminal ileum inflammation, but not the insulin concentrations. Supporting our hypothesis, these findings revealed a novel regulatory, hormetic, role of the vagus nerve in the immunometabolic response to endotoxin in near-term fetuses. [ABSTRACT FROM AUTHOR]

Purpose: Anorexia Nervosa (AN) is a serious and potentially lethal mental disorder characterised by a deliberate quest to reduce one's weight. It can have multiple physical and psychological consequences. The clinical presentation of AN can include gastrointestinal symptoms, however, the pathophysiology of these symptoms in the context of AN remains uncertain. It is hypothesised that patients with AN may have an increase in intestinal permeability, which could lead to an increase in faecal calprotectin (fCP), a marker of intestinal inflammation. No relation between AN and elevation of fCP has been previously described in literature. Methods: Eight patients hospitalised for AN have a dosage of fCP. Results: Calprotectine was found to be elevated in 50% of cases, with or without any underlying comorbid gastrointestinal disease. Only the duration of illness tended to be associated with the increase in fCP suggesting a greater alteration as a function related to the time of denutrition. Conclusion: Although these findings provide insights in the potential pathophysiology of gastrointestinal symptoms in AN, further studies that evaluate the factors associated with elevated fCP in patients with AN are needed. Key points: What is already known on this subject? To our knowledge, our study is the first to describe faecal calprotectin (fCP) levels in patients who are malnourished due to anorexia nervosa (AN) and describe the patients' clinical characteristics in order to better explain the gastrointestinal tract implication in AN symptoms. What this study adds? This study's finding of a possible elevation of fCP in patients with AN raises interesting questions on the pathophysiology of AN, and the possibility of an underlying inflammatory process in these patients. Although this is a preliminary study, as the sample size is small, it is therefore important for clinicians to acknowledge that fCP can be elevated in patients with AN without any other disease. The literature remains scarce regarding the relationship between the gastrointestinal tract and AN, although it is a predominant aspect of the symptomatology of the disease. This offers opportunities and strengthen the need for further research on the effects of restriction, renutrition and weight gain on the gastrointestinal tract in patients with AN, and the possible role and use of fCP in this disease. [ABSTRACT FROM AUTHOR]

Introduction : The detailed expression pattern of calretinin immunohistochemistry in the transition zone (TZ) of Hirschsprung disease (HSCR) has not yet been reported. This study aims to examine the value of calretinin immunohistochemistry for more accurately determining the distal and proximal border of the TZ in short segment HSCR. Methods : Specimens of pull-through surgery from 51 patients with short form of HSCR were analyzed on two longitudinal strips using hematoxylin and eosin (H&E) staining and calretinin immunohistochemistry. Results : In all but two patients, the first appearance of calretinin expression was seen on mucosal nerve fibers before the appearance of any ganglion cells, indicating the distal border of the TZ. The maximum distance between the distal border of the TZ and the proximal border of the TZ, defined by ganglion cells in a normal density on H&E stained sections, a strong calretinin expression on mucosal nerve fibers and in >80% of submucosal and myenteric ganglion cells, with no nerve hypertrophy and absence of ganglionitis was 60 mm. Conclusion : The distal border of the TZ is characterized by calretinin positive intramucosal neurites in nearly all of short form of HSCR and not by calretinin expression on ganglion cells. [ABSTRACT FROM AUTHOR]

Hirschsprung disease (HSCR) is a complex genetic disorder of neural crest development resulting in incomplete formation of the enteric nervous system (ENS). This life-threatening neurocristopathy affects 1/5000 live births, with a currently unexplained male-biased ratio. To address this lack of knowledge, we took advantage of the TashT mutant mouse line, which is the only HSCR model to display a robust male bias. Our prior work revealed that the TashT insertional mutation perturbs a Chr.10 silencer-enriched non-coding region, leading to transcriptional dysregulation of hundreds of genes in neural crest-derived ENS progenitors of both sexes. Here, through sex-stratified transcriptome analyses and targeted overexpression in ENS progenitors, we show that male-biased ENS malformation in TashT embryos is not due to upregulation of Sry–the murine ortholog of a candidate gene for the HSCR male bias in humans–but instead involves upregulation of another Y-linked gene, Ddx3y. This discovery might be clinically relevant since we further found that the DDX3Y protein is also expressed in the ENS of a subset of male HSCR patients. Mechanistically, other data including chromosome conformation captured-based assays and CRISPR/Cas9-mediated deletions suggest that Ddx3y upregulation in male TashT ENS progenitors is due to increased transactivation by p53, which appears especially active in these cells yet without triggering apoptosis. Accordingly, in utero treatment of TashT embryos with the p53 inhibitor pifithrin-α decreased Ddx3y expression and abolished the otherwise more severe ENS defect in TashT males. Our data thus highlight novel pathogenic roles for p53 and DDX3Y during ENS formation in mice, a finding that might help to explain the intriguing male bias of HSCR in humans. Author summary: Hirschsprung disease (HSCR) is a life-threatening birth defect characterized by the lack of enteric neurons in the colon. HSCR is due to many gene defects, which are only partially understood. In particular, the reason why more boys than girls are affected by this condition is currently unknown. Yet, a better understanding of HSCR at the genetic/molecular level would help to develop more efficient therapies compared to current surgical approaches. Here, we identified a potential molecular cascade involving sequential upregulation of p53 and DDX3Y that, when inhibited, can eliminate the male bias in a HSCR mouse model. We found DDX3Y to be also specifically expressed in enteric neurons of a subset of male HSCR patients, suggesting that manipulation of the putative p53-DDX3Y pathway might eventually have therapeutic value in humans as well. [ABSTRACT FROM AUTHOR]

We investigated activation status, cytotoxic potential, and gut homing ability of the peripheral blood Natural Killer (NK) cells in Crohn disease (CD) patients. For this purpose, we compared the expression of different activating and inhibitory receptors (KIR and non-KIR) and integrins on NK cells as well as their recent degranulation history between the patients and age-matched healthy controls. The study was conducted using freshly obtained peripheral blood samples from the study participants. Multiple color flow cytometry was used for these determinations. Our results show that NK cells from treatment-naïve CD patients expressed higher levels of activating KIR as well as other non-KIR activating receptors vis-à-vis healthy controls. They also showed increased frequencies of the cells expressing these receptors. The expression of several KIR and non-KIR inhibitory receptors tended to decrease compared with the cells from healthy donors. NK cells from the patients also expressed increased levels of different gut-homing integrin molecules and showed a history of increased recent degranulation events both constitutively and in response to their in vitro stimulation. Furthermore, treatment of the patients tended to reverse these NK cell changes. Our results demonstrate unequivocally, for the first time, that peripheral blood NK cells in treatment-naïve CD patients are more activated and are more poised to migrate to the gut compared to their counterpart cells from healthy individuals. Moreover, they show that treatment of the patients tends to normalize their NK cells. The results suggest that NK cells are very likely to play a role in the immunopathogenesis of Crohn disease. [ABSTRACT FROM AUTHOR]

Objectives:  Endoscopic follow-up after esophageal atresia (EA) tracheoesophageal fistula (TEF) repair is recommended to detect esophageal histopathological complications. We investigated the prevalence of histopathologically proven esophageal complications (peptic esophagitis, gastric metaplasia, and eosinophilic esophagitis) and assessed the predictors of these complications in children with EA-TEF.Materials and Methods:  This is a prospective longitudinal cohort study performed between September 2005 and December 2014 comprising 77 children with EA-TEF followed-up until February 2017. Univariate analysis was performed using the Wilcoxon's rank-sum test for continuous variables and the Pearson's chi-square test for categorical variables. Multivariable analysis was performed using a Cox regression hazard model. The association between clinical factors and histopathologically proven complications was estimated using a Cox regression hazard model with time until the appearance of complications as the time scale.Results:  All 77 children received proton pump inhibitors (PPIs) (n = 73) or H2 receptor antagonists (H2RA). A total of 252 endoscopies were performed in 73 children (median 2.6/child, range: 1-29). Median age at study completion was 4.9 years (range: 2.3-11.5 years). Histopathologically proven complications occurred in 38 children (52%): peptic esophagitis (n = 32, 44%), eosinophilic esophagitis (n = 15, 21%), and gastric metaplasia (n = 9, 12%). A total of 82% patients were on PPI or H2RA at the time of diagnosis of histological complication. Multivariable Cox regression analysis showed that patients with recurrent anastomotic strictures (>3 dilations) had a higher risk of occurrence of histopathologically proven complications over time (hazard ratio: 3.11, 95% confidence interval [CI]: 1.53-6.34). On univariate analysis, the result of the first endoscopy was not associated with the occurrence of histopathologically proven complications (odds ratio: 0.8, 95% CI: 0.16-3.95).Conclusion:  Histopathologically proven complications with potential long-term consequences occurred in approximately 50% of children after EA-TEF repair. A history of recurrent anastomotic strictures is associated with the occurrence of these complications. The result of the first endoscopy does not predict the histopathological outcome. Children with EA-TEF warrant close and systematic long-term follow-up at specialized multidisciplinary clinics with endoscopic evaluation. [ABSTRACT FROM AUTHOR]

Background: Killer-cell Immunoglobulin-like Receptor (KIR) genes encode receptors, which are mainly expressed on, and control functional activities of, Natural Killer (NK) cells. There exist six distinct activating KIR genes in humans, who differ from one another with respect to the repertoire of these genes. Because activated NK cells can potentially cause tissue destruction, we hypothesized that variation in the inherited activating KIR genes in humans is associated with their innate susceptibility/resistance to developing Crohn disease (CD). Methods: We performed case control studies on three independent Canadian CD patient cohorts (all of the Western European descent): two comprising children (Montreal having 193 cases and 245 controls, and Ottawa having 93 cases and 120 controls) and the third one comprising predominantly adults (Winnipeg having 164 cases and 200 controls). We genotyped cases and controls for activating KIR genes by PCR with gene-specific primers and investigated associations between the genes and cases using unconditional logistic regression. Results: We observed strong associations between all the six KIR genes and CD in Ottawa children, with the strongest risk observed for the KIR2DS1 (p = 1.7 x10-10). Associations between all but the KIR2DS2 were replicated in the Montreal cohort with the strongest association evident for the KIR2DS5 (8.0 x 10−10). Similarly associations between five genes were observed in the adult Winnipeg cohort. In this cohort, strongest associations were evident with the KIR2DS5 (8.75 x 10−8). An overall analysis for all cohorts showed strong associations with four of the genes, with the strongest association evident for the KIR2DS5 (p = 1.35 x 10−17). In the combined analysis for four KIR genes, individuals carrying one or more of the KIR genes were at significantly higher risks for acquiring CD (p = 3.5 x 10−34). Conclusions: Activating KIR genes are associated with risk for developing CD in both children and adults. [ABSTRACT FROM AUTHOR]

Aim: This prospective study evaluated the incidence of functional gastrointestinal disorders (FGIDs) during infancy, on their own or combined with other symptoms.Methods: We asked 273 French paediatricians with a specific interest in FGIDs to provide feedback on 2757 infants aged zero to six months from March 2013 to January 2014. Gastrointestinal health status was assessed by two questionnaires at inclusion and at a four-week follow-up visit. FGIDs were assessed according to the Rome III criteria and quality of life (QoL) was monitored.Results: Combined FGIDs were diagnosed in 2145 (78%) infants: 63% with two disorders and 15% with three or more disorders. The most frequently combined FGIDs were gas/bloating and colic (28%), colic and regurgitation (17.0%) and gas/bloating and regurgitation (8%). Compared to infants with a single FGID, combined FGID were associated with lower body weight (4.63 vs 4.79 kg, p = 0.009), shorter breastfeeding duration (33 vs 43 days, p < 0.001), a decreased QoL score (5.9 vs 6.5, p < 0.001), more frequent drug prescriptions (25% vs 13%, p < 0.001) and significantly greater improvements in QoL scores after four weeks (p = 0.003).Conclusion: Combined FGIDs were extremely common in infants up to six months of age and had a negative impact on breastfeeding, weight gain and QoL. [ABSTRACT FROM AUTHOR]

Introduction: The Bristol Stool Form Scale (BSS) which consists of 7 photographs of different stool forms allows assessment of stool consistency (scale 1 for hard lumps to scale 7 for watery stools), in an objective manner in adults. The BSS is also sometimes used to characterise the stools of infants and young children. Despite its use, there is general agreement among paediatric gastroenterologists that the BSS is not adequate to be used in infants and young children who wear diapers; thus, a new scale specifically designed for this population is needed. Our aim is to develop a paediatric stool scale, the Brussels Infant and Toddler Stool Scale ('BITSS'), and to evaluate the interobserver agreement of stool assessment with the BITSS between the patient's parent and healthcare providers (physicians and nurses). Methods and analysis: This study has two phases. In the first phase, 11 key-opinion leaders in the field of paediatric gastroenterology representing different areas of the world selected seven coloured photographs of infants and/or young children wearing diapers to match the original descriptors of the BSS. The selected photographs were used to create a new scale in which the drawings of stools of the BSS were replaced by infant/toddlers stool photographs. In phase II, we aim at demonstrating that parents, nurses and primary healthcare physicians interpret the stool-pictures of the BITSS with a high degree of consensus and that the agreement is independent of whether it is a parent or a healthcare provider. Interobserver variability of stool assessment with the BITSS between the patient's parent and healthcare providers will be assessed. Ethics and dissemination: The study will be approved by the Ethics Committee of the participating centres. The findings of this study will be submitted to a peer-reviewed journal. Abstracts will be submitted to national and international conferences. [ABSTRACT FROM AUTHOR]

In Montreal, Quebec, 31% of the population is born outside Canada. Yet, only 9% of patient consultations for symptoms associated with functional gastrointestinal disorders (FGIDs) are from immigrants at the Paediatric Gastroenterology Clinic at Sainte-Justine's University Hospital Centre. This discrepancy inspired a multidisciplinary exploratory study (anthropological and paediatric) to examine the sociological, interpretative and pragmatic aspects of immigrant and non-immigrant patients and family life with FGIDs. This paper examines the discrepancy between immigrant and non-immigrant paediatric patients with FGIDs and presents the different pathways to care utilised by families. Semistructured interviews were carried out between November 2008 and June 2009, with children and their parents. In total, 38 families were recruited: with 27 families (including a child experiencing abdominal pain, his/her siblings, mother and/or father as well as any other significant individual living in the family home) from the community and 11 from the paediatric gastroenterology clinic. A comparative analysis between the immigrant and non-immigrant groups focused on perceptions, meanings and actions taken to relieve/alleviate symptoms. Immigrant and nonimmigrant families alternate and combine different therapeutic environments: home, alternative healing therapies and medical paths to care. Our analysis suggests that culture (as a set of values, beliefs and ways of being), as well as social interactions within family life and the clinic, shape pathways to care. The analysis highlights the centrality of receptiveness -- and more widely the social dimensions -- of all medical encounters. Treatment disparities between immigrant and non-immigrant families in pathways to care help us to understand these patients' social world and the intricate relationships between values and social milieux, between culture, practices of symptom management and rationales guiding diverse therapeutic actions. [ABSTRACT FROM AUTHOR]

This paper examines how children and families of diverse ethnic backgrounds perceive, understand and treat symptoms related to functional gastrointestinal disorders (FGIDs). It is questioned how different ways of dealing with medical uncertainty (symptoms, diagnosis) may influence treatment pathways. Semi-structured interviews were conducted with 43 children of 38 family groups of immigrant and non-immigrant backgrounds. The analysis takes into account (a) the perceived symptoms; (b) the meaning attributed to them; and (c) the actions taken to relieve them. The social and cultural contexts that permeate these symptoms, meanings and actions were also examined. It is found that, in light of diagnostic and therapeutic uncertainty, non-immigrant families are more likely to consult health professionals. Immigrant families more readily rely upon home remedies, family support and, for some, religious beliefs to temper the uncertainty linked to abdominal pain. Furthermore, non-immigrant children lead a greater quest for legitimacy of their pain at home while most immigrant families place stomach aches in the range of normality. Intracultural variations nuance these findings, as well as family dynamics. It is concluded that different courses of action and family dynamics reveal that uncertainty is dealt with in multiple ways. Family support, the network, and trust in a child's expression of distress are key elements in order to tolerate uncertainty. Lastly, the medical encounter is described as a space permeated with relational uncertainty given the different registers of expression inherent within a cosmopolitan milieu. Narrative practices being an essential dynamic of this encounter, it is questioned whether families’ voices are equally heard in these clinical spaces. [ABSTRACT FROM PUBLISHER]

Acute diarrhoea is a leading cause of child mortality in developing countries. Principal pathogens include Escherichia coli, rotaviruses, and noroviruses. 90% of diarrhoeal deaths are attributable to inadequate sanitation. Acute diarrhoea is the second leading cause of overall childhood mortality and accounts for 18% of deaths among children under five. In 2004 an estimated 1.5 million children died from diarrhoea, with 80% of deaths occurring before the age of two. Treatment goals are to prevent dehydration and nutritional damage and to reduce duration and severity of diarrhoeal episodes. The recommended therapeutic regimen is to provide oral rehydration solutions (ORS) and to continue feeding. Although ORS effectively mitigates dehydration, it has no effect on the duration, severity, or frequency of diarrhoeal episodes. Adjuvant therapy with micronutrients, probiotics, or antidiarrhoeal agents may thus be useful. The WHO recommends the use of zinc tablets in association with ORS. The ESPGHAN/ESPID treatment guidelines consider the use of racecadotril, diosmectite, or probiotics as possible adjunctive therapy to ORS. Only racecadotril and diosmectite reduce stool output, but no treatment has yet been shown to reduce hospitalisation rate or mortality. Appropriate management with validated treatments may help reduce the health and economic burden of acute diarrhoea in children worldwide. [ABSTRACT FROM AUTHOR]

Background/Aims Functional gastrointestinal disorders (FGID) affect 15%-20% of the general pediatric and adult population. Animal models suggest that a neonatal stress such as invasive procedures and maternal separation could be responsible for visceral hypersensitivity and FGID. We tested the hypothesis that congenital esophageal atresia (EA), a condition corrected during the neonatal period and associated with multiple stresses, is a clinically significant risk factor for the development of FGID later in life. We postulated that, to be clinically significant, the effect of neonatal stress on the incidence of FGID should be as strong as that of enteric infections in the development of irritable bowel syndrome in children. Methods Subjects with EA and healthy controls were enrolled in this multicenter cohort study. Gastrointestinal symptoms were assessed by a questionnaire and FGID was diagnosed using the Rome III criteria. Results Fifty-three children (25 girls; median age, 12 years) with EA were compared to 72 age- and sex-matched controls. Although 11 children with EA (21%) had a FGID diagnosis versus 8 controls (11%), this difference was not significant (?² = 2.20, P > 0.05). In subjects with EA, the presence of associated malformations, the occurrence of complications during the first month, and the length of hospital stay > 30 days did not influence the incidence of FGID. Chronic abdominal pain was present in 38% of subjects with EA versus 25% of controls (P > 0.05). Conclusions Neonatal stress secondary to surgical correction of EA is not a clinically significant risk factor for the development of FGID in childhood. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The use of intravenous pantoprazole, a proton pump inhibitor, has been increasing in the paediatric intensive care unit. • Despite this increased use, data on the disposition of intravenous pantoprazole in paediatric intensive care patients are very scarce. WHAT THIS STUDY ADDS • Our population approach has determined the pharmacokinetic parameters of intravenous pantoprazole in paediatric intensive care patients and the relative importance of factors influencing its disposition. • Pantoprazole clearance was significantly influenced by developmental changes and by the presence of systemic inflammatory syndrome, hepatic dysfunction and CYP2C19 inhibitors. AIMS To characterize the pharmacokinetics of intravenous pantoprazole in a paediatric intensive care population and to determine the influence of demographic factors, systemic inflammatory response syndrome (SIRS), hepatic dysfunction and concomitantly used CYP2C19 inducers and inhibitors on the drug's pharmacokinetics. METHODS A total of 156 pantoprazole concentration measurements from 20 patients (10 days to 16.4 years of age) at risk for or with upper gastrointestinal bleeding, who received pantoprazole doses ranging from 19.9 to 140.6 mg/1.73 m2/day, were analysed using a population pharmacokinetic approach (nonmem program). RESULTS The best structural model for pantoprazole was a two-compartment model with zero order infusion and first-order elimination. Body weight, SIRS, age, hepatic dysfunction and presence of CYP2C19 inhibitors were significant covariates affecting clearance (CL), accounting for 75% of interindividual variability. Only body weight significantly influenced central volume of distribution ( Vc). In the final population model, the estimated CL and Vc were 5.28 l h−1 and 2.22 l, respectively, for a typical 5-year-old child weighing 20 kg. Pantoprazole CL increased with weight and age, whereas the presence of SIRS, CYP2C19 inhibitors and hepatic dysfunction, when present separately, significantly decreased pantoprazole CL by 62.3, 65.8 and 50.5%, respectively. For patients aged between 6 months and 5 years without SIRS, CYP2C19 inhibitor or hepatic dysfunction, the predicted pantoprazole CL is faster than that reported in adults. CONCLUSION These results provide important information for physicians regarding selection of a starting dose and dosing regimens of pantoprazole for paediatric intensive care patients based on factors frequently encountered in this population. [ABSTRACT FROM AUTHOR]

The use of proton pump inhibitors (PPIs) has become widespread in children and infants for the management of paediatric acid-related disease. Pharmacokinetic profiles of only omeprazole and lansoprazole have been well characterised in children over 2 years of age with acid-related diseases. Few data have been recently published regarding the pharmacokinetics of pantoprazole in children, and none are available for rabeprazole or esomeprazole. The metabolism of PPI enantiomers has never been studied in the paediatric population. A one-compartment model best describes the pharmacokinetic behaviour of omeprazole, lansoprazole and pantoprazole in children, with important interindividual variability for each pharmacokinetic parameter. Like adults, PPIs are rapidly absorbed in children following oral administration; the mean time to reach maximum plasma concentration varies from 1 to 3 hours. Since these agents are acid labile, their oral formulations consist of capsules containing enteric-coated granules. No liquid formulation is available for any of the PPIs. Thus, for those patients unable to swallow capsules, extemporaneous liquid preparations for omeprazole and lansoprazole have been reported; however, neither the absolute nor the relative bioavailabilities of these oral formulations have been studied in children. Intravenous formulations are available for omeprazole (in Europe), lansoprazole and pantoprazole. PPIs are rapidly metabolised in children, with short elimination half-lives of around 1 hour, similar to that reported for adults. All PPIs are extensively metabolised by the liver, primarily by cytochrome P450 (CYP) isoforms CYP2C19 and CYP3A4, to inactive metabolites, with little unchanged drug excreted in the urine. Similar to that seen in adults, the absolute bioavailability of omeprazole increases with repeated dosing in children; this phenomenon is thought to be due to a combination of decreased first-pass elimination and reduced systemic clearance. The apparent clearance (CL/F) of omeprazole, lansoprazole and pantoprazole appears to be faster for children than for adults. A higher metabolic capacity in children as well as differences in the extent of PPI bioavailability are most likely responsible for this finding. This may partly account for the need in children for variable and sometimes considerably greater doses of PPIs, on a per kilogram basis, than for adults to achieve similar plasma concentrations. Furthermore, no studies have been able to demonstrate a statistically significant correlation between age and pharmacokinetic parameters among children. Despite the small number of very young infants studied, there is some evidence for reduced PPI metabolism in newborns. The limited paediatric data regarding the impact of CYP2C19 genetic polymorphism on PPI metabolism are similar to those reported for adults, with poor metabolisers having 6- to 10-fold higher area under the concentration-time curve values compared with extensive metabolisers. Finally, because a pharmacokinetic/pharmacodynamic relationship exists for PPIs, the significant interindividual variability in their disposition may partly explain the wide range of therapeutic doses used in children. Further studies are needed to better define the pharmacokinetics of PPIs in children <2 years of age. [ABSTRACT FROM AUTHOR]

The hypothesis that BMPs (bone morphogenetic proteins), which act early in gut morphogenesis, also regulate specification and differentiation in the developing enteric nervous system (ENS) was tested. Expression of BMP-2 and BMP-4, BMPR-IA (BMP receptor subunit), BMPR-IB, and BMPR-II, and the BMP antagonists, noggin, gremlin, chordin, and follistatin was found when neurons first appear in the primordial bowel at embryonic day 12 (E12). Agonists, receptors, and antagonists were detected in separated populations of neural crest- and noncrest-derived cells. When applied to immunopurified E12 ENS precursors, BMP-2 and BMP-4 induced nuclear translocation of phosphorylated Smad-1 (Sma and Mad-related protein). The number of neurons developing from these cells was increased by low concentrations and decreased by high concentrations of BMP-2 or BMP-4. BMPs induced the precocious appearance of TrkC-expressing neurons and their dependence on neurotrophin-3 for survival. BMP-4 interacted with glial cell line-derived neurotrophic factor (GDNF) to enhance neuronal development but limited GDNF-driven expansion of the precursor pool. BMPs also promoted development of smooth muscle from mesenchymal ceils immunopurified at E12. To determine the physiological significance of these observations, the BMP antagonist noggin was overexpressed in the developing ENS of transgenic mice under the control of the neuron-specific enolase promoter. Neuronal numbers in both enteric plexuses and smooth muscle were increased throughout the postnatal small intestine. These increases were already apparent by E18. In contrast, TrkC-expressing neurons decreased in both plexuses of postnatal noggin-overexpressing animals, again an effect detectable at E18. BMP-2 and/or BMP-4 thus limit the size of the ENS but promote the development of specific subsets of enteric neurons, including those that express TrkC. [ABSTRACT FROM AUTHOR]