Development of a clinical pathway for bariatric surgery as an integral part of a comprehensive treatment for adolescents with severe obesity in the Netherlands.

Introduction In the Netherlands, bariatric surgery in adolescents is currently only allowed in the context of scientific research. Besides this, there was no clinical pathway for bariatric surgery in adolescents. In this paper, the development of a comprehensive clinical pathway for bariatric surgery in adolescents with severe obesity in the is described. Methods The clinical pathway for bariatric surgery in adolescents consists of an eligibility assessment as well as comprehensive peri- and postoperative care. Regarding the eligibility assessment, the adolescents need to be identified by their attending pediatricians and afterwards be evaluated by specialized pediatric obesity units. If the provided treatment is considered to be insufficiently effective, the adolescent will anonymously be evaluated by a national board. This is an additional diligence procedure specifically established for bariatric surgery in adolescents. The national board consists of independent experts regarding adolescent bariatric surgery, and evaluates whether the adolescents meet the criteria defined by the national professional associations. The final step is an assessment by a multidisciplinary team for adolescent bariatric surgery. The various disciplines (pediatrician, bariatric surgeon, psychologist, dietician) evaluate whether an adolescent is eligible for bariatric surgery. In this decision-making process, it is crucial to assess whether the adolescent is expected to adhere to postoperative behavioral changes and follow-up. When an adolescent is deemed eligible for bariatric surgery, he or she will receive preoperative counselling by a bariatric surgeon to decide on the type of bariatric procedure (Roux-en-Y gastric bypass or sleeve gastrectomy). Postoperative care consists of intensive guidance by the multidisciplinary team for adolescent bariatric surgery. In this guidance, several regular appointments are included and additional care will be provided based on the needs of the adolescent and his or her family. Furthermore, the multidisciplinary lifestyle intervention, in which the adolescents participated before bariatric surgery, continues in coordination with the multidisciplinary team for adolescent bariatric surgery, and this ensures long-term counselling and follow-up. Conclusion The implementation of bariatric surgery as an integral part of a comprehensive treatment for adolescents with severe obesity requires the development of a clinical pathway with a variety of disciplines.

Testicular Vascularization after Pediatric Inguinal Hernia Repair: A Systematic Review and Meta-Analysis.

BACKGROUND: The effect of pediatric inguinal hernia repair (IHR) on testicular vascularization remains unclear. Manipulating the spermatic cord during surgery may reduce blood flow due to edema and vasoconstriction. This can lead to testicular atrophy. The study aims to review current knowledge of testicular vascular impairment following IHR in children. METHODS: A systematic literature search was conducted in PubMed/Medline, Embase, Cochrane Library, and Web of Science. Methodological quality was assessed using validated tools. Data were extracted, and a pooled data analysis was performed. RESULTS: Ten studies were included in the systematic review. Six of these studies were eligible for meta-analysis. This revealed a significant decrease in testicular vascularization during the short-term follow-up (1 day-1 week) after IHR using the open surgical approach. This decrease was not present after laparoscopic intervention. There was no more increased resistance in the vessels at long-term follow-up (1 month-6 months), suggesting that the impaired vascularity is only temporary. CONCLUSIONS: There seems to be a short-term transient vascular impairment of the testis after open IHR in children. This might be of clinical relevance to prefer the laparoscopic approach for IHR in children, even though the open approach is the gold standard, in contrast to adult IHR. The impact on testicular function and sperm quality later in life remains unclear. Comparative studies of both techniques are needed to determine if there is a significant difference in testicular vascularity. Long-term studies are necessary to assess the impact of transiently reduced vascularity on sperm quality and fertility later in life.

Antenatal Ureaplasma Infection Causes Colonic Mucus Barrier Defects: Implications for Intestinal Pathologies.

Chorioamnionitis is a risk factor for necrotizing enterocolitis (NEC). Ureaplasma parvum (UP) is clinically the most isolated microorganism in chorioamnionitis, but its pathogenicity remains debated. Chorioamnionitis is associated with ileal barrier changes, but colonic barrier alterations, including those of the mucus barrier, remain under-investigated, despite their importance in NEC pathophysiology. Therefore, in this study, the hypothesis that antenatal UP exposure disturbs colonic mucus barrier integrity, thereby potentially contributing to NEC pathogenesis, was investigated. In an established ovine chorioamnionitis model, lambs were intra-amniotically exposed to UP or saline for 7 d from 122 to 129 d gestational age. Thereafter, colonic mucus layer thickness and functional integrity, underlying mechanisms, including endoplasmic reticulum (ER) stress and redox status, and cellular morphology by transmission electron microscopy were studied. The clinical significance of the experimental findings was verified by examining colon samples from NEC patients and controls. UP-exposed lambs have a thicker but dysfunctional colonic mucus layer in which bacteria-sized beads reach the intestinal epithelium, indicating undesired bacterial contact with the epithelium. This is paralleled by disturbed goblet cell MUC2 folding, pro-apoptotic ER stress and signs of mitochondrial dysfunction in the colonic epithelium. Importantly, the colonic epithelium from human NEC patients showed comparable mitochondrial aberrations, indicating that NEC-associated intestinal barrier injury already occurs during chorioamnionitis. This study underlines the pathogenic potential of UP during pregnancy; it demonstrates that antenatal UP infection leads to severe colonic mucus barrier deficits, providing a mechanistic link between antenatal infections and postnatal NEC development.

The Diagnostic Accuracy of Serum Alpha-Fetoprotein Levels in Follow-up for Recurrence of Sacrococcygeal Teratoma; a Nationwide Review of SCT Cases in the Netherlands.

BACKGROUND: Serum alpha-fetoprotein (AFP) is often used as tumour marker for recurrent sacrococcygeal teratoma (SCT). We aimed to assess the normal dynamics of serum AFP levels after initial resection and diagnostic accuracy of serum AFP levels the follow-up for recurrence in SCT. METHODS: This retrospective study included 57 patients treated for SCT in the six pediatric surgical centers in the Netherlands from 1980 to 2018. MAIN RESULTS: 57 patients were included in the study of whom 19 children developed 20 recurrences at a median of 14.0 months after initial resection. No significant difference was found in serum AFP level dynamics between the recurrence and non-recurrence group after initial resection (p = 0.950). Serum AFP levels did not significantly increase before recurrence (p = 0.106) compared to serum AFP levels of children without recurrence at the same time. However, serum AFP levels did significantly increase in malignant recurrences (n = 7) (p = 0.03) compared to patients without recurrence. A cut-off value of 55 µg/L was found to be predictive for recurrent SCT with an Area Under the Curve (AUC) of 0.636 with sensitivity of 50% and specificity of 100%. CONCLUSION: Dynamics of serum AFP levels are not different between patients with and without recurrence after initial resection of SCT. Serum AFP levels are not predictive for mature or immature recurrent SCT and normal AFP levels do not rule out recurrent SCT. However, serum AFP levels exceeding 55 µg/L can indicate recurrent SCT, especially malignant recurrences.

Robotic-Assisted Nissen Fundoplication in Pediatric Patients: A Matched Cohort Study.

BACKGROUND: Nissen Fundoplication (NF) is a frequently performed procedure in children. Robotic-assisted Nissen Fundoplication (RNF), with the utilization of the Senhance® Surgical System (SSS®) (Asensus Surgical® Inc., Durham, NC, USA) featuring 3 mm instruments, aims to improve precision and safety in pediatric surgery. This matched cohort study assesses the safety and feasibility of RNF in children using the SSS®, comparing it with Laparoscopic Nissen Fundoplication (LNF). METHODS AND RESULTS: Twenty children underwent RNF with the SSS® between 2020 to 2023 and were 1:1 matched with twenty LNF cases retrospectively selected from 2014 to 2023. Both groups were similar regarding male/female ratio, age, and weight. Two of the twenty RNF cases (10%) experienced intraoperative complications, whereas three in the LNF group of whom two required reinterventions. The observed percentage of postoperative complications was 5% in the RNF group compared to 15% in the LNF group (p = 0.625). The operative times in the RNF group significantly dropped towards the second study period (p = 0.024). CONCLUSIONS: Utilizing SSS® for NF procedures in children is safe and feasible. Observational results may tentatively suggest that growing experiences and continued development will lead to better outcomes based on more accurate and safe surgery for children.

Protocol for the development of a core outcome set for the optimisation of treatment and follow-up of patients with an anorectal malformation (ARM): The ARM and OUtcome Review (ARMOUR)-project.

BACKGROUND: Primary treatment of an anorectal malformation (ARM) is surgical restoration of the anatomy. These children can experience many problems later in life; therefore, a long-term follow-up by an experienced team is needed. The aim of the ARM and OUtcome Review (ARMOUR-study) is to identify the lifetime outcomes that are important from a medical and patients' perspective and develop a core outcome set (COS) that can be implemented in a care pathway to support individual ARM management decisions. METHODS: First, a systematic review will identify clinical and patient-reported outcomes described in studies conducted in patients with an ARM. Second, qualitative interviews with patients of different age categories and their caregivers will be held to ensure that the COS will include outcomes that are relevant from the patient's perspective. Finally, the outcomes will be taken forward to a Delphi consensus exercise. Using multiple web-based Delphi rounds, key stakeholders (medical experts, clinical researchers and patients) will prioritise outcomes. During a face-to-face consensus meeting, the final COS will be determined. These outcomes can be evaluated in a life-long care pathway for patients with ARM. DISCUSSION: The development of a COS for ARMs aims to reduce heterogeneity in outcome reporting between (clinical) studies, enhancing the availability of comparable data, which will facilitate evidence-based patient care. Assessment of the outcomes in the COS during individual care pathways for ARM can support shared decisions regarding management. The ARMOUR-project has ethical approval and is registered with the Core Outcome Measures in Effectiveness Trials (COMET) initiative. LEVEL OF EVIDENCE: Treatment study level II.

Hypoxia-Driven Changes in a Human Intestinal Organoid Model and the Protective Effects of Hydrolyzed Whey.

Many whey proteins, peptides and protein-derived amino acids have been suggested to improve gut health through their anti-oxidant, anti-microbial, barrier-protective and immune-modulating effects. Interestingly, although the degree of hydrolysis influences peptide composition and, thereby, biological function, this important aspect is often overlooked. In the current study, we aimed to investigate the effects of whey protein fractions with different degrees of enzymatic hydrolysis on the intestinal epithelium in health and disease with a novel 2D human intestinal organoid (HIO) monolayer model. In addition, we aimed to assess the anti-microbial activity and immune effects of the whey protein fractions. Human intestinal organoids were cultured from adult small intestines, and a model enabling apical administration of nutritional components during hypoxia-induced intestinal inflammation and normoxia (control) in crypt-like and villus-like HIO was established. Subsequently, the potential beneficial effects of whey protein isolate (WPI) and two whey protein hydrolysates with a 27.7% degree of hydrolysis (DH28) and a 50.9% degree of hydrolysis (DH51) were assessed. In addition, possible immune modulatory effects on human peripheral immune cells and anti-microbial activity on four microbial strains of the whey protein fractions were investigated. Exposure to DH28 prevented paracellular barrier loss of crypt-like HIO following hypoxia-induced intestinal inflammation with a concomitant decrease in hypoxia inducible factor 1 alpha (HIF1α) mRNA expression. WPI increased Treg numbers and Treg expression of cluster of differentiation 25 (CD25) and CD69 and reduced CD4+ T cell proliferation, whereas no anti-microbial effects were observed. The observed biological effects were differentially mediated by diverse whey protein fractions, indicating that (degree of) hydrolysis influences their biological effects. Moreover, these new insights may provide opportunities to improve immune tolerance and promote intestinal health.

Antenatal Ureaplasma infection induces ovine small intestinal goblet cell defects: a strong link with NEC pathology.

Disruption of the intestinal mucus barrier and intestinal epithelial endoplasmic reticulum (ER) stress contribute to necrotizing enterocolitis (NEC). Previously, we observed intestinal goblet cell loss and increased intestinal epithelial ER stress following chorioamnionitis. Here, we investigated how chorioamnionitis affects goblet cells by assessing their cellular characteristics. Importantly, goblet cell features are compared with those in clinical NEC biopsies. Mucus thickness was assessed as read-out of goblet cell function. Fetal lambs were intra-amniotically (IA) infected for 7d at 122 gestational age with Ureaplasma parvum serovar-3, the main microorganism clinically associated with chorioamnionitis. After preterm delivery, mucus thickness, goblet cell numbers, gut inflammation, epithelial proliferation and apoptosis and intestinal epithelial ER stress were investigated in the terminal ileum. Next, goblet cell morphological alterations (TEM) were studied and compared to human NEC samples. Ileal mucus thickness and goblet cell numbers were elevated following IA UP exposure. Increased pro-apoptotic ER stress, detected by elevated CHOP-positive cell counts and disrupted organelle morphology of secretory cells in the intestinal epithelium, was observed in IA UP exposed animals. Importantly, comparable cellular morphological alterations were observed in the ileum from NEC patients. In conclusion, UP-driven chorioamnionitis leads to a thickened ileal mucus layer and mucus hypersecretion from goblet cells. Since this was associated with pro-apoptotic ER stress and organelle disruption, mucus barrier alterations seem to occur at the expense of goblet cell resilience and may therefore predispose to detrimental intestinal outcomes. The remarkable overlap of these in utero findings with observations in NEC patients underscores their clinical relevance.

Did Age at Surgery Influence Outcome in Patients With Hirschsprung Disease? A Nationwide Cohort Study in the Netherlands.

OBJECTIVES: Hirschsprung disease (HD) requires surgical resection of affected bowel, but the current evidence is inconclusive regarding the optimal age for resection. The aim of this study was to assess whether age at resection of the aganglionic segment is a determinant for surgical outcomes. METHODS: A cross-sectional cohort study was done including all consecutive patients with HD between 1957 and 2015, aged 8 years or older (n = 830), who were treated in 1 of the 6 pediatric surgical centers in the Netherlands. Outcome measures were mortality, postoperative complications, stoma rate and redo surgery rate, retrieved from the medical records. Additionally, constipation and fecal incontinence rate in long term were assessed with the Defecation and Continence Questionnaire (DeFeC and P-DeFeC). RESULTS: The medical records of 830 patients were reviewed, and 346 of the 619 eligible patients responded to the follow-up questionnaires (56%). There was a small increase in the risk of a permanent stoma [odds ratio (OR) 1.01 (95% confidence interval {CI}: 1.00-1.02); P = 0.019] and a temporary stoma [OR 1.01 (95% CI: 1.00-1.01); P = 0.022] with increasing age at surgery, regardless of the length of the aganglionic segment and operation technique. Both adjusted and unadjusted for operation technique, length of disease, and temporary stoma, age at surgery was not associated with the probability and the severity of constipation and fecal incontinence in long term. CONCLUSIONS: In this study, we found no evidence that the age at surgery influences surgical outcomes, thus no optimal timing for surgery for HD could be determined.

Familial Experience With Hirschsprung's Disease Improves the Patient's Ability to Cope.

Introduction: Familial occurrence of Hirschsprung's disease may have a positive effect on patients' ability to cope with the disease. The aim was to compare long-term bowel function and generic quality of life between patients with familial and non-familial Hirschsprung's disease. Methods: This was a nationwide, cross-sectional study in which we included all 830 Hirschsprung patients of 8 years and older who had undergone surgery between 1957 and 2015. We excluded patients with a permanent stoma, intellectual disability, or an unknown or foreign address. We requested patients to complete the validated pediatric or adult Defecation and Fecal Continence questionnaire and the Child Health Questionnaire Child Form-87, or the World Health Organization Quality of Life-100 Assessment Instrument. Results: We analyzed 336 Hirschsprung patients, 15.8% of whom were familial cases and 84.2% were non-familial cases. After adjusting for aganglionic length, sex, and age, patients with familial Hirschsprung's disease were twice more likely to suffer from constipation (OR = 2.47, 95% CI, 1.21-5.05, p = 0.013). The quality of life of the pediatric patients was comparable, but in adult patients the energy/fatigue, thinking/learning/concentration, and work capacity facets showed better scores in the familial patients with Hirschsprung's disease of the rectosigmoid (p = 0.029, p = 0.024, p = 0.036, respectively). Conclusions: Different facets of generic quality of life are better in adult patients with familial Hirschsprung's disease of the rectosigmoid. It seems that familial experience with the disease influences patients' coping abilities positively.

Functional Outcomes After Surgery for Total Colonic, Long-Segment, Versus Rectosigmoid Segment Hirschsprung Disease.

OBJECTIVES: Knowledge on long-term outcomes in patients with Hirschsprung disease is progressing. Nevertheless, differences in outcomes according to aganglionic lengths are unclear. We compared long-term bowel function and generic quality of life in Hirschsprung patients with total colonic or long-segment versus rectosigmoid aganglionosis. METHODS: In this nationwide, cross-sectional study participants with proven Hirschsprung disease received the Defecation and Fecal Continence questionnaire, and the Child Health Questionnaire Child Form-87, or the WHO Quality of Life-100. We excluded deceased patients, patients who were younger than 8 years, lived abroad, had a permanent enterostomy, or were intellectually impaired. RESULTS: The study population (n = 334) was operated for rectosigmoid (83.9%), long-segment (8.7%), or total colonic aganglionosis (7.5%). Fecal incontinence in general was not significantly different between the three groups, but liquid fecal incontinence was significantly associated with total colonic aganglionosis (odds ratio [OR] = 6.00, 95% confidence interval [CI] 2.07-17.38, P = 0.001). Regarding constipation, patients with total colonic or long-segment aganglionosis were less likely to suffer from constipation than the rectosigmoid group (OR = 0.21, 95% CI, 0.05-0.91, P = 0.038 and OR = 0.11, 95% CI, 0.01-0.83, P = 0.032). Quality of life was comparable between the three groups, except for a lower physical score in children with total colonic aganglionosis (P = 0.016). CONCLUSIONS: Over time Hirschsprung patients with total colonic or long-segment aganglionosis do not suffer from worse fecal incontinence in general. A difference in stool consistency may underlie the association between liquid fecal incontinence and total colonic aganglionosis and constipation in patients with rectosigmoid aganglionosis. Despite these differences, generic quality of life is comparable on reaching adulthood.

Enteral Feeding Interventions in the Prevention of Necrotizing Enterocolitis: A Systematic Review of Experimental and Clinical Studies.

Necrotizing enterocolitis (NEC), which is characterized by severe intestinal inflammation and in advanced stages necrosis, is a gastrointestinal emergency in the neonate with high mortality and morbidity. Despite advancing medical care, effective prevention strategies remain sparse. Factors contributing to the complex pathogenesis of NEC include immaturity of the intestinal immune defense, barrier function, motility and local circulatory regulation and abnormal microbial colonization. Interestingly, enteral feeding is regarded as an important modifiable factor influencing NEC pathogenesis. Moreover, breast milk, which forms the currently most effective prevention strategy, contains many bioactive components that are known to support neonatal immune development and promote healthy gut colonization. This systematic review describes the effect of different enteral feeding interventions on the prevention of NEC incidence and severity and the effect on pathophysiological mechanisms of NEC, in both experimental NEC models and clinical NEC. Besides, pathophysiological mechanisms involved in human NEC development are briefly described to give context for the findings of altered pathophysiological mechanisms of NEC by enteral feeding interventions.

Chorioamnionitis induces hepatic inflammation and time-dependent changes of the enterohepatic circulation in the ovine fetus.

Chorioamnionitis, inflammation of fetal membranes, is an important cause of preterm birth and a risk factor for the development of adverse neonatal outcomes including sepsis and intestinal pathologies. Intestinal bile acids (BAs) accumulation and hepatic cytokine production are involved in adverse intestinal outcomes. These findings triggered us to study the liver and enterohepatic circulation (EHC) following intra-amniotic (IA) lipopolysaccharide (LPS) exposure. An ovine chorioamnionitis model was used in which circulatory cytokines and outcomes of the liver and EHC of preterm lambs were longitudinally assessed following IA administration of 10 mg LPS at 5, 12 or 24h or 2, 4, 8 or 15d before preterm birth. Hepatic inflammation was observed, characterized by increased hepatic cytokine mRNA levels (5h - 2d post IA LPS exposure) and increased erythropoietic clusters (at 8 and 15 days post IA LPS exposure). Besides, 12h after IA LPS exposure, plasma BA levels were increased, whereas gene expression levels of several hepatic BA transporters were decreased. Initial EHC alterations normalized over time. Concluding, IA LPS exposure induces significant time-dependent changes in the fetal liver and EHC. These chorioamnionitis induced changes have potential postnatal consequences and the duration of IA LPS exposure might be essential herein.

Corrigendum: Chronic Intra-Uterine Ureaplasma parvum Infection Induces Injury of the Enteric Nervous System in Ovine Fetuses.

[This corrects the article DOI: 10.3389/fimmu.2020.00189.].

Prophylactic Intra-Uterine ß-Cyclodextrin Administration during Intra-Uterine Ureaplasma parvum Infection Partly Prevents Liver Inflammation without Interfering with the Enterohepatic Circulation of the Fetal Sheep.

Chorioamnionitis can lead to inflammation and injury of the liver and gut, thereby predisposing patients to adverse outcomes such as necrotizing enterocolitis (NEC). In addition, intestinal bile acids (BAs) accumulation is causally linked to NEC development. Plant sterols are a promising intervention to prevent NEC development, considering their anti-inflammatory properties in the liver. Therefore, we investigated whether an intra-amniotic (IA) Ureaplasma parvum (UP) infection affected the liver and enterohepatic circulation (EHC) and evaluated whether an IA administered plant sterol mixture dissolved in ß-cyclodextrin exerted prophylactic effects. An ovine chorioamnionitis model was used in which liver inflammation and the EHC were assessed following IA UP exposure in the presence or absence of IA prophylactic plant sterols (a mixture of ß-sitosterol and campesterol dissolved in ß-cyclodextrin (carrier)) or carrier alone. IA UP exposure caused an inflammatory reaction in the liver, histologically seen as clustered and conflated hepatic erythropoiesis in the parenchyma, which was partially prevented by IA administration of sterol + ß-cyclodextrin, or ß-cyclodextrin alone. In addition, IA administration of ß-cyclodextrin prior to UP caused changes in the expression of several hepatic BAs transporters, without causing alterations in other aspects of the EHC. Thereby, the addition of plant sterols to the carrier ß-cyclodextrin did not have additional effects.

Chronic Intra-Uterine Ureaplasma parvum Infection Induces Injury of the Enteric Nervous System in Ovine Fetuses.

Background: Chorioamnionitis, inflammation of the fetal membranes during pregnancy, is often caused by intra-amniotic (IA) infection with single or multiple microbes. Chorioamnionitis can be either acute or chronic and is associated with adverse postnatal outcomes of the intestine, including necrotizing enterocolitis (NEC). Neonates with NEC have structural and functional damage to the intestinal mucosa and the enteric nervous system (ENS), with loss of enteric neurons and glial cells. Yet, the impact of acute, chronic, or repetitive antenatal inflammatory stimuli on the development of the intestinal mucosa and ENS has not been studied. The aim of this study was therefore to investigate the effect of acute, chronic, and repetitive microbial exposure on the intestinal mucosa, submucosa and ENS in premature lambs. Materials and Methods: A sheep model of pregnancy was used in which the ileal mucosa, submucosa, and ENS were assessed following IA exposure to lipopolysaccharide (LPS) for 2 or 7 days (acute), Ureaplasma parvum (UP) for 42 days (chronic), or repetitive microbial exposure (42 days UP with 2 or 7 days LPS). Results: IA LPS exposure for 7 days or IA UP exposure for 42 days caused intestinal injury and inflammation in the mucosal and submucosal layers of the gut. Repetitive microbial exposure did not further aggravate injury of the terminal ileum. Chronic IA UP exposure caused significant structural ENS alterations characterized by loss of PGP9.5 and S100ß immunoreactivity, whereas these changes were not found after re-exposure of chronic UP-exposed fetuses to LPS for 2 or 7 days. Conclusion: The in utero loss of PGP9.5 and S100ß immunoreactivity following chronic UP exposure corresponds with intestinal changes in neonates with NEC and may therefore form a novel mechanistic explanation for the association of chorioamnionitis and NEC.

Protection of the Ovine Fetal Gut against Ureaplasma-Induced Chorioamnionitis: A Potential Role for Plant Sterols.

Chorioamnionitis, clinically most frequently associated with Ureaplasma, is linked to intestinal inflammation and subsequent gut injury. No treatment is available to prevent chorioamnionitis-driven adverse intestinal outcomes. Evidence is increasing that plant sterols possess immune-modulatory properties. Therefore, we investigated the potential therapeutic effects of plant sterols in lambs intra-amniotically (IA) exposed to Ureaplasma. Fetal lambs were IA exposed to Ureaplasma parvum (U. parvum, UP) for six days from 127 d-133 d of gestational age (GA). The plant sterols ß-sitosterol and campesterol, dissolved with ß-cyclodextrin (carrier), were given IA every two days from 122 d-131 d GA. Fetal circulatory cytokine levels, gut inflammation, intestinal injury, enterocyte maturation, and mucosal phospholipid and bile acid profiles were measured at 133 d GA (term 150 d). IA plant sterol administration blocked a fetal inflammatory response syndrome. Plant sterols reduced intestinal accumulation of proinflammatory phospholipids and tended to prevent mucosal myeloperoxidase-positive (MPO) cell influx, indicating an inhibition of gut inflammation. IA administration of plant sterols and carrier diminished intestinal mucosal damage, stimulated maturation of the immature epithelium, and partially prevented U. parvum-driven reduction of mucosal bile acids. In conclusion, we show that ß-sitosterol and campesterol administration protected the fetus against adverse gut outcomes following UP-driven chorioamnionitis by preventing intestinal and systemic inflammation.

FXR agonism protects against liver injury in a rat model of intestinal failure-associated liver disease.

BACKGROUND: Intestinal failure-associated liver disease (IFALD) is a clinical challenge. The pathophysiol-ogy is multifactorial and remains poorly understood. Disturbed recirculation of bile salts, e.g. due to loss of bile via an enterocutaneous fistula, is considered a major contributing factor. We hypothesize that impaired signaling via the bile salt receptor FXR underlies the development of IFALD. The aim of this study was to investigate whether activation of FXR improves liver homeostasis during chronic loss of bile in rats. METHODS: To study consequences of chronic loss of bile, rats underwent external biliary drainage (EBD) or sham surgery for seven days, and the prophylactic potential of the FXR agonist INT-747 was assessed. RESULTS: EBD for 7 days resulted in liver test abnormalities and histological liver damage. Expression of the intestinal FXR target gene Fgf15 was undetectable after EBD, and this was accompanied by an anticipated increase in hepatic Cyp7a1 expression, indicating increased bile salt synthesis. Treatment with INT-747 improved serum biochemistry, reduced loss of bile fluid in drained rats and prevented development of drainage-associated histological liver injury. CONCLUSIONS: EBD results in extensive hepatobiliary injury and cholestasis. These data suggest that FXR activation might be a novel therapy in preventing liver dysfunction in patients with intestinal failure. RELEVANCE FOR PATIENTS: This study demonstrates that chronic loss of bile causes liver injury in rats. Abro-gated recycling of bile salts impairing of enterohepatic bile salt/FXR signaling underlies these pathological changes, as administration of FXR agonist INT747 prevents biliary drainage-induced liver damage. Phar-macological activation of FXR might be a therapeutic strategy to treat disorders accompanied by a per-turbed enterohepatic circulation such as intestinal failure-associated liver disease.

The timing of surgery of antenatally diagnosed choledochal malformations: A descriptive analysis of a 26-year nationwide cohort.

INTRODUCTION: Choledochal malformations (CMs) are increasingly diagnosed antenatally. There is a dilemma between early surgery to prevent CM-related symptoms and postponing surgery to reduce complications. We aimed to identify the optimal timing of surgery in asymptomatic neonates with antenatally diagnosed CM and to identify predictors for development of symptoms. METHODS: Using the Netherlands Study group on CHoledochal Cyst/malformation (NeSCHoc) we retrospectively collected demographic, biochemical and surgical data from all Dutch patients with an antenatally detected CM. RESULTS: Between 1989 and 2014, antenatally suspected CM was confirmed in 17 patients at a median age of 10days (1day-2months). Four patients developed symptoms directly after birth (24%). Thirteen patients (76%) remained asymptomatic. Two of these progressed to symptoms before surgical intervention at 0.7 and 2.1months resp. Postoperatively, four patients developed short-term complications and three developed long-term complications. Patients <5.6kg (the series median) showed more short-term complications (66%) when compared to patients >5.6kg (0%, p=0.02). CONCLUSION: When not symptomatic within the first days of life, the majority of children with antenatally detected CM remains asymptomatic. Surgery might safely be delayed to the age of 6months or a weight of 6kg. Postponing surgery in the clinically and biochemical asymptomatic patient might decrease the complication rate. LEVELS OF EVIDENCE: Level III.

Intestinal lengthening and reversed segment in a piglet short bowel syndrome model.

BACKGROUND: Treatment of short bowel syndrome (SBS) remains difficult, entailing severe morbidity and mortality. Accepted surgical treatment modalities for SBS are the Bianchi intestinal lengthening procedure and reversed-segment procedure. We seek to investigate the short-term effects regarding growth, nutrition, and microscopic and functional adaptation after the intestinal lengthening and RS procedures in a piglet SBS-model. MATERIAL AND METHODS: Twenty-four piglets (Sus scrofa, ±30 kg) were divided into four groups (n = 6 each) as follows: sham, SBS, Bianchi lengthening procedure (BIA), and reversed-segment (RS). At day one either sham laparotomy (sham) or 75% small bowel resection (SBS, BIA, and RS) was performed. After 2 wk sham laparotomy (sham and SBS), BIA, or RS procedure was performed. After 8 wk all animals were terminated. During the experimental time course, the following parameters were assessed: body weight, intestinal length, diameter, and weight, fat absorption, and biochemical parameters from serum and urine. Citrulline was used as a marker of absorptive enteral mass to demonstrate massive functional bowel loss. Intestinal biopsies were obtained for histologic analysis and electrophysiological measurements to analyze glucose absorptive capacity. RESULTS: Eight weeks after bowel resection, piglet growth was reduced in SBS, BIA, and RS piglets as demonstrated by reduced weight (51 ± 4 kg, 47 ± 2 kg, and 53 ± 1 kg, respectively) compared with sham (69 ± 3 kg; P < 0.01), with no demonstrable difference between SBS and treatment groups. Malabsorption and malnutrition occurred in SBS, BIA, and RS piglets reflected by increased fecal fat loss per 24 h (35 ± 4%, 30 ± 2%, and 32 ± 4%, respectively versus 18 ± 1% in sham; P < 0.01) and reduced serum albumin levels (24 ± 1 g/L, 22 ± 1 g/L, and 24 ± 1 g/L, respectively versus sham 33 ± 1 g/L; P < 0.01), but there was no significant difference between SBS and treatment groups. Serum citrulline levels reflected massive functional bowel loss (SBS 36 ± 7 µmol/L, BIA 23 ± 1 µmol/L, and RS 24 ± 2 µmol/L) compared with sham (64 ± 5 µmol/L; P < 0.01). Electrophysiological measurements demonstrated reduced glucose absorption after intestinal resection, which did not return to base levels within the experimental time course. However, the intestine of BIA and RS piglets adapted more profoundly than SBS piglets, as reflected by a greater crypt depth (490 ± 25 µm and 492 ± 21 µm versus 388 ± 20 µm; P < 0.01); and BIA piglets showed greater villus length (884 ± 58 µm) than RS or SBS piglets (715 ± 30 µm and 737 ± 64 µm, respectively; P < 0.01) after 8 wk. CONCLUSIONS: Despite increased histologic intestinal adaptation, neither intestinal lengthening nor RS procedure demonstrated significantly improved absorption, nutrition, or weight gain for the treatment of SBS during the study period. Reduced glucose uptake on electrophysiology measurements and persistent low levels of citrulline may indicate reduced small bowel enterocyte functioning during the initial phase of intestinal adaptation.