Pilot Study of Ondansetron in Improvement of Pediatric Colonoscopy Preparation Outcomes at an Urban Academic Center.

Objectives: To gather initial data on the effectiveness and tolerability of the addition of Ondansetron to bowel preparation regimens to justify a funded, larger, placebo-controlled study. Methods: Design, Setting, and Participants:: A total of 41 pediatric and young adult (age 2-22) patients participated in a single center, open label, parallel randomized trial, with simple randomization. All patients were recruited as outpatients, and all procedures occurred as outpatient procedures, with both recruitment and procedures occurring at a low-resource urban academic medical center in Brooklyn.Interventions and Outcome Measures:: The intervention studied was a single dose of oral-dissolving tablet Ondansetron provided before initiation of bowel preparation using a standardized prep of Polyethylene Glycol 3350 and Bisacodyl. There were 2 arms, a study arm using typical preparation (Polyethylene Glycol 3350 and Bisacodyl) and Ondansetron, and a control arm (Polyethylene Glycol 3350 and Bisacodyl). Patients received standard weight-based dosing. The primary outcome measure assessed was the Boston Bowel Preparation Scale (BBPS) to assess efficacy of preparation. Secondary objectives included evaluation of patient satisfaction via a survey answered by each patient. The questionnaire assessed the presence of the following symptoms during bowel prep: abdominal pain, nausea, bloating, vomiting, scale of ease/difficulty, and if the entire bowel prep was completed. Results: No benefit to BBPS from the addition of Ondansetron to bowel preparation was observed. Statistically significant improvement in reports of abdominal pain (35% decrease in Ondansetron arm) was noted with a P = 0.019. No statistically significant improvement was noted in other symptoms although all domains showed nonsignificant improvement in the Ondansetron arm. Conclusion: No benefit to efficacy of preparation as measured by the BBPS was observed. A single dose of Ondansetron before bowel preparation reduced reports of abdominal pain by 35%, with other symptomatic improvements suggesting possible improvements to be confirmed by a higher-powered study. Trial registration: NCT05439772.

Comparison of Risk and Severity of Helicobacter Pylori Infection in Non-Native Versus US Native Pediatric Patients.

Introduction: Helicobacter pylori (HP) infection is associated with gastritis, peptic ulcer disease (PUD) in the stomach and duodenum, and an increased risk of gastric cancer. The risk of infection, secondary symptoms, and negative outcomes is known to be increased in low- and middle-income countries and vastly less substantial in the United States and Europe. Current North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines recommend endoscopic diagnosis and susceptibility-guided therapy, which is not reflected by current adult guidelines for therapy. In this study, we complete a single-center retrospective review of HP risk by nativity status, as well as the results of the use of standard empiric therapy in HP and PUD patients. Methods: We retrospectively reviewed all endoscopies with patients aged 1-21 years with a known nativity status and identified all HP diagnoses. We also completed the classification of Kyoto scores and classified patients as gastritis versus PUD. Treatment records were obtained, as well as downstream documentation of the impact of empiric therapy. HP prevalence and severity were compared between non-native and native US populations. Results: In total 332 patients were identified, with 59 HP diagnoses. However, 64 patients were immigrants, and 268 were US natives. Totally 39.1% of all immigrant patients had an endoscopically identified HP infection, compared to only 12.7% of US native patients (P < 0.01, relative risk 3.07). HP severity was worse in immigrant patients (Kyoto score 1.5 versus 0.89; P = 0.008). Empiric high-dose amoxicillin triple therapy was equally effective in reducing symptoms in gastritis versus PUD patients. Conclusions: Immigrant patients have a substantially higher risk and severity of HP infection than US natives. Empiric therapy remains highly effective at relieving symptoms. These findings in aggregate suggest that North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines may not adequately serve non-native pediatric patients, with an additional prospective multicenter study needed to confirm. In addition, a prospective study of treatment based on stool antigen tests, as well as a larger prospective study of empiric therapy, may suggest alterations to our approach in line with recent changes to adult Gastroenterology practice.

Pediatric Eosinophilic Esophagitis: Searching for Serologic Markers.

OBJECTIVE: Eosinophilic esophagitis (EoE) is a Th2 disease that presently is diagnosed and followed by clinical symptoms in the presence of endoscopic biopsies documenting elevated esophageal eosinophilia. To simplify clinical care, multiple studies have attempted to identify a disease specific serologic marker. None have been successful. The goal of this study was to employ custom designed Luminex multiplex bead assays to identify a reliable serologic marker for EoE. METHODS: Luminex assays were employed to measure serum levels of 11 analytes associated with EoE (IL-5, lL13, periostin, eotaxin-3, thymic stromal lymphopoietin, and immunoglobulins) in a cohort of pediatric patients consisting of active EoE (n=30), EoE in remission (n=13), and controls (n=34). RESULTS: No analyte was found to be elevated or depressed in active EoE compared to the other groups. Additionally, among the cohort with active EoE, none of the 11 analytes correlated with peak esophageal eosinophilia, endoscopic features of EoE quantitatively defined by an EoE validated endoscopic reference score (EREFS), or esophageal thickness as determined by endosonography. CONCLUSION: This is the largest prospective survey of heterogeneous markers studied in a consecutive cohort to determine whether they could diagnose or follow EoE. Although none were identified in this cohort, Luminex provides a rapid, economical tool to simultaneously screen multiple sera for proteins that are increased or decreased in disease states.

Histologically Remarkable Eosinophilic Esophagitis Responsive to Dupilumab in a Gastrostomy Tube-Dependent Pediatric Patient on Amino Acid Formula.

Eosinophilic esophagitis (EoE), an eosinophil predominant, TH2-mediated condition increasing in prevalence in pediatric and adult populations, is typically treated with dietary manipulations to avoid triggering antigens. However, identifying specific dietary causes remains a persistent challenge, and restrictive diets are burdensome. Total dietary modification using amino acid-based formula does not always produce symptomatic or histologic resolution, suggesting that exposure to ingested aeroallergens drives their disease. EoE patients demonstrate symptomatic exacerbation from July to September correlating with higher grass and ragweed pollen counts. We present a 7-year-old tracheostomy- and gastrostomy-dependent girl who was found on surveillance endoscopy to have profound eosinophilic infiltration throughout the esophagus with inflammatory changes including basal cell hyperplasia on histology. She responded partially to topical corticosteroid therapy with fluticasone and had complete resolution of esophageal eosinophilic infiltrate with subcutaneous dupilumab.

Persistent SARS-CoV-2 Nucleocapsid Protein Presence in the Intestinal Epithelium of a Pediatric Patient 3 Months After Acute Infection.

In addition to the severe impact of acute respiratory disease during the SARS-CoV-2 pandemic, the issue of "Long COVID" illness has impacted large numbers of patients following the initial infection. Wide ranges of Long Covid incidence have been reported, ranging from 30 to 87%. Long COVID has a variety of clinical manifestations, including gastrointestinal symptoms. Here, we report a case of persistent abdominal pain, 3 months following a SARS-CoV-2 diagnosis, associated with chronic colonic inflammation and the presence of mucosal SARS-CoV-2 virions.

Predicting pediatric esophageal wall thickness: An EUS study.

BACKGROUND AND OBJECTIVE: EUS has been shown in two small series to be capable of documenting increases in the total esophageal wall thickness (TWT) in children and adults with eosinophilic esophagitis (EoE). To apply EUS-derived TWT in clinical situations or in scientific investigations in pediatric EoE, measurements of esophageal TWT in children of differing ages and heights are required. MATERIALS AND METHODS: Thirty patients (18M: 12F, 7 months to 20 years and 10 months) with a history of esophageal symptoms, but no endoscopic or histologic criteria of EoE were studied using a through the scope 20 MHZ Olympus Ultrasound miniprobe UM-3R (Olympus America, Center Valley Pa 18034) through a GIF Q180 or 160 (Olympus) standard pediatric upper endoscope. The mucosa, the mucosa plus submucosa, and the TWT were measured in the mid- and distal esophagus immediately before taking diagnostic biopsies. RESULTS: Measurements from both sites showed a statistically significant increase in TWT as a function of age (P < 0.001) and height (P < 0.001), as did the individual layers. The width of the mucosa and the submucosa were equivalent and together, they contributed more than half of the entire TWT. There were no significant differences between the means of the mid- and distal esophageal measurements. A multiple regression equation that can predict TWT based on age, with 95% confidence limits, is presented. CONCLUSIONS: EUS has demonstrated that esophageal TWT in a cohort of control children correlates with height and with age and has provided insights into the organization of the esophageal wall. Esophageal TWT values obtained by EUS can now be interpreted to recognize esophageal wall thickening throughout childhood.

Applying the Eosinophilic Esophagitis Endoscopic Reference Scores (EREFS) to Different Aged Children.

OBJECTIVES: The eosinophilic esophagitis (EoE) endoscopic reference score (EREFS) was developed to analyze adults with EoE and has been successfully applied to a pediatric cohort. The present study compares EREFS in younger and older children with EoE. METHODS: The 99 patients were divided among 3 cohorts: 44 active EoE (EoE-A); 16 EoE remission (EoE-R); and 39 controls (esophageal dysfunction but <15 eos/hpf). The cohorts were then subdivided into 2 groups: younger (≤10 years) and older (>10 years) that were compared based on the composite and the individual components of their EREFS. RESULTS: EREFS identified EoE-A in all children with an area under the receiving operating characteristics curve (AUC) of 0.85, in older children with an AUC of 0.90 and in younger children with an AUC of 0.77. Mean EREFS for ≤10 years was 1.26 ±â€Š1.19 and 2.71 ±â€Š1.33 for >10 years (P < 0.01). The 3 most common findings in our entire EoE-A cohort and in both ages were furrows, edema, and exudates. EREFS in patients with EoE-A had similar specificities (0.88 vs 0.89) and positive predictive values (0.89 vs 0.91) in both ages. CONCLUSIONS: The present investigation confirms the utilization of EREFS in Pediatric EoE. Furthermore, EREFS can detect EoE and document response to treatment in both younger and older children. EREFS, however, predicted EoE in the older children with a higher sensitivity (0.89 vs 0.63) and a higher negative predictive value (0.87 vs 0.59) than was seen in the younger cohort.

Treatment of Pyoderma Gangrenosum in Pediatric Inflammatory Bowel Disease.

Pyoderma gangrenosum (PG) is a rare, necrotizing dermatologic condition associated with neoplastic and immune dysregulatory states, including adult and pediatric inflammatory bowel disease (IBD). Over the last decade, the elucidation of inflammatory mediators in PG has led to a plethora of localized and systemic corticosteroid sparing therapies including antibiotics, antiinflammatory, and immunomodulatory agents. Herein, we describe the case of a 17-year-old female with ulcerative colitis in clinical remission, who presented with a long-standing, large, deep, and painful lower extremity PG lesion. Following failed attempts both at local and at systemic therapies, her PG was successfully treated with the tumor necrosis factor-alpha (TNF-α) monoclonal antibody adalimumab, and the lesion remains in remission after four years of subcutaneous anti-TNF therapy. This case serves as the basis for our presenting a review of the pathogenesis, diagnostic criteria, differential diagnosis, therapies and treatment outcomes for pediatric IBD-associated PG. Our experience adds to earlier reports suggesting anti-TNF-α biologic therapy is most likely to achieve long-term resolution of IBD-associated PG in children and adolescents with severe lesions or who failed other treatments.

Measurement of Microvascular Function in Pediatric Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Altered vascular flow is known to both play a role in the pathogenesis and influence the severity of inflammatory bowel disease (IBD). This phenomenon has been described in other systemic conditions and contributes to disease progression by facilitating inflammation and thrombosis. Microvascular dysfunction may represent an early sign of generalized vascular disease (VD). It manifests by failure to achieve a normal response of vasodilation and increased blood flow following a period of vaso-occlusion. Although thromboembolic complications are well described in IBD, their pathogenesis is not fully understood. This study sought to assess microvascular responsiveness in pediatric subjects with IBD, by recording postocclusion peripheral arterial pulsatile volume changes. PATIENTS AND METHODS: A total of 32 pediatric subjects were studied, including 16 with IBD and 16 age-matched controls. All patients with IBD were in clinical remission, and none had known VD. Vascular reactivity was evaluated using the Itamar Medical EndoPAT2000, a noninvasive device utilizing plethysmography to measure microvascular flow. Results were reported as the reactive hyperemia index (RHI), indicating post- to preocclusion pulsatile volume changes. RESULTS: Baseline characteristics, including body mass index, plasma lipid levels, hemoglobin, and serum albumin, were similar in both study groups. All patients with IBD were in clinical remission, assessed by standard disease activity scoring methods. Measurements of microvascular function indicated patients with IBD exhibited a mean RHI both within the range associated with VD risk in adults (≤1.67) and significantly lower than that in controls (IBD vs control = 1.66 vs 2.02, P = 0.036). CONCLUSIONS: Microvascular plethysmography is a safe and noninvasive method for assessing microvascular function in children with IBD. Patients with IBD in clinical remission demonstrate an attenuated, postocclusion microvascular hyperemic response, compared with the normal response in controls. These findings suggest pediatric IBD subjects with a mean RHI within the VD "at risk" range should be monitored for thromboembolic phenomena. Further studies in a larger patient population and over longer periods should be conducted to validate our findings and to determine the importance of these measurements in guiding IBD management.

Pediatric Helicobacter pylori gastropathy demonstrates a unique pattern of gastric foveolar hyperplasia.

OBJECTIVES: Helicobacter pylori (Hp) are the most common agents causing gastric mucosal injury worldwide. Foveolar hyperplasia is a key component of the stomach's reaction to injury. This study examines histopathologic characteristics associated with Helicobacter pylori and with non- Helicobacter pylori-associated gastropathy in children and adolescents, and compares the prevalence of foveolar hyperplasia among these disease subgroups and normal control subjects. METHODS: Eighty-one gastric antral and corpus biopsies from subjects 2-19 years of age were studied. Twenty-two subjects with Helicobacter pylori gastritis were compared to 23 with non-Helicobacter pylori gastropathy and to 36 controls (normal biopsies). Foveolar length, full mucosal thickness, and the foveolar length: full mucosal thickness ratio were derived by a morphometric technique previously developed to analyze adult gastric tissue. RESULTS: Compared to controls, Helicobacter pylori gastritis demonstrated significant increases in antral foveolar length (P < .0001), full mucosal thickness (P < .0001), as well as corpus foveolar length (P < .05) and corpus full mucosal thickness (P < .05). Non-Helicobacter pylori-associated gastropathy also was characterized by increased antral foveolar length (P < .0001) and full mucosal thickness (P < .001) but corresponding corpus measurements did not differ from controls. Antral foveolar length in non-Helicobacter pylori gastropathy was increased, when compared to Helicobacter pylori gastritis (P < .05), while corpus values were not. The non-Helicobacter pylori gastropathy group demonstrated increased antral foveolar length: full mucosal thickness ratios, compared with Helicobacter pylori gastritis (P < .001) and with normal controls (P < .0001). DISCUSSION: An objective, quantitative approach to measuring foveolar hyperplasia in adults was successfully applied to pediatric biopsies and yielded a richer characterization of gastric pathology in children. Foveolar hyperplasia appears to be a generalized phenomenon in the presence of pediatric Helicobacter pylori gastritis but is limited to the antrum in non-Helicobacter pylori gastropathy.

Packed red blood cell transfusions as a risk factor for parenteral nutrition associated liver disease in premature infants.

AIM: To determine if packed red blood cell transfusions contribute to the development of parenteral nutrition associated liver disease. METHODS: A retrospective chart review of 49 premature infants on parenteral nutrition for > 30 d who received packed red blood cell (PRBC) transfusions was performed. Parenteral nutrition associated liver disease was primarily defined by direct bilirubin (db) > 2.0 mg/dL. A high transfusion cohort was defined as receiving > 75 mL packed red blood cells (the median value). Kaplan-Meier plots estimated the median volume of packed red blood cells received in order to develop parenteral nutrition associated liver disease. RESULTS: Parenteral nutritional associated liver disease (PNALD) was noted in 21 (43%) infants based on db. Among the 27 high transfusion infants, PNALD was present in 17 (64%) based on elevated direct bilirubin which was significantly greater than the low transfusion recipients. About 50% of the infants, who were transfused 101-125 mL packed red blood cells, developed PNALD based on elevation of direct bilirubin. All infants who were transfused more than 200 mL of packed red blood cells developed PNALD. Similar results were seen when using elevation of aspartate transaminase or alanine transaminase to define PNALD. CONCLUSION: In this retrospective, pilot study there was a statistically significant correlation between the volume of PRBC transfusions received by premature infants and the development of PNALD.

Lipogenesis in Huh7 cells is promoted by increasing the fructose: Glucose molar ratio.

AIM: To determine whether hepatocyte lipogenesis, in an in vitro cell culture model, is modulated by adjusting culture media monosaccharide content and concentration. METHODS: Hepatocytes (Huh7), demonstrating glucose and fructose uptake and lipid biosynthesis, were incubated in culture media containing either glucose alone (0.65-0.72 mmol/L) or isosmolar monosaccharide (0.72 mmol/L) comprising fructose:glucose (F:G) molar ratios ranging from 0.58-0.67. Following a 24-h incubation, cells were harvested and analyzed for total protein, triglyceride (TG) and cholesterol (C) content. Significant differences (P < 0.05) among groups were determined using analysis of variance followed by Dunnett's test for multiple comparisons. RESULTS: After a 24 h incubation period, Huh7 cell mass and viability among all experimental groups were not different. Hepatocytes cultured with increasing concentrations of glucose alone did not demonstrate a significant change either in C or in TG content. However, when the culture media contained increasing F:G molar ratios, at a constant total monosaccharide concentration, synthesis both of C and of TG increased significantly [F:G ratio = 0.58, C/protein (µg/µg) = 0.13; F:G = 0.67, C/protein = 0.18, P < 0.01; F:G ratio = 0.58, TG/protein (µg/µg) = 0.06; F:G ratio = 0.67, TG/protein = 0.11, P < 0.01]. CONCLUSION: In an in vitro hepatocyte model, glucose or fructose plus glucose support total cell mass and lipogenic activity. Increasing the fructose:glucose molar ratio (but not glucose alone) enhances triglyceride and cholesterol synthesis. These investigations demonstrate fructose promotes hepatocellular lipogenesis, and they provide evidence supporting future, in vivo studies of fructose's role in the development of hepatic steatosis and non-alcoholic fatty liver disease.

The role of folate receptor autoantibodies in preterm birth.

OBJECTIVE: Cellular uptake of folate is mediated by folate receptor (FR)α. Prior studies indicate that a FRα autoantibody (FRAb) is implicated in poor pregnancy outcomes. The aims of this study were to determine the prevalence of FRAbs in women with preterm and term pregnancies, and to investigate the role of maternal FRAbs in preterm birth. METHODS: This prospective observational study included 23 mothers and 25 preterm infants (two twin births) born at gestational age (GA) ≤32 wk and/or birth weight ≤1500 g (group 1) and 25 mother-term infant pairs (infants born at GA ≥37 wk, group 2). Blocking and binding FRAbs in maternal and in cord blood were determined. The association between maternal FRAbs and pregnancy outcome was measured using multiple logistic regression, adjusted for maternal age and previous preterm birth. RESULTS: The prevalence of FRAbs was 65.2% in women with preterm birth, which was twofold higher than in those with term pregnancy (28%; relative risk [RR], 2.3; 95% confidence interval [CI], 1.2-4.7). The prevalence of FRAbs in preterm infants (64%) was significantly higher than in term infants (24%; RR, 2.7; 95% CI, 1.3-5.7). Pregnant women with positive FRAbs had 4.9 times higher odds of having preterm birth (odds ratio, 4.9; 95% CI, 1.4-17.7), adjusted for maternal age and previous preterm birth. CONCLUSIONS: These findings suggest that the presence of FRAbs might be a contributing factor to preterm birth, which could be prevented with appropriate testing and therapeutic interventions. Further studies are warranted to investigate the possible mechanisms of fetal sensitization resulting in FRAb production in utero and its possible clinical correlates.

Inverse correlation between Helicobacter pylori colonization and obesity in a cohort of inner city children.

BACKGROUND: Recently, publications in adults and children have documented a potential role of Helicobacter pylori (H. pylori) in decreasing the likelihood of obesity. The present study compares the prevalence of H. pylori colonization between obese (body mass index [BMI] ≥ 95th percentile) and healthy weight (BMI ≥ 5th to <85th percentiles) children seen at an inner city medical center in the United States. METHODS: This retrospective study reviewed clinical features, BMI, and gastric histology of consecutive children aged 1-18 years undergoing an esophagogastroduodenoscopy. BMI percentile was calculated for age and gender. Helicobacter pylori colonization was determined by histopathologic identification of the organism. Multiple logistic regression was employed to measure the association between BMI and H. pylori colonization, controlling for baseline age, gender, and presenting symptoms. RESULTS: Among 340 patients (51.5% female, mean age of 10.5 ± 4.7 years), 98 (29%) were obese and 173 (51%) were healthy weight. The H. pylori colonization rate of the entire cohort was 18.5% (95% CI = 14.7-23.0%). Among obese children, 10% had H. pylori colonization compared to 21% of the healthy weight children (RR = 2.1, 95% CI = 1.1-4.0). Conversely, 39% of noncolonized children, but only 21% of the infected children, were obese (RR = 1.8, 95% CI = 1.1-3.3). Multivariate analysis revealed that being colonized with H. pylori is associated with a 50% reduction in the odds of being obese (adjusted OR = 0.5, 95% CI = 0.2-1.0). CONCLUSIONS: Our findings in a North American cohort are in agreement with studies from Asia and Europe suggesting that H. pylori infection decreases the prevalence of obesity in children. Further work to characterize the extent and nature of this relationship is warranted.

The liver in pediatric gastrointestinal disease.

Hepatic involvement is often encountered in gastrointestinal (GI) diseases, in part because of the close anatomic and physiologic relations between the liver and GI tract. Drainage of the mesenteric blood supply to the portal vein permits absorbed and/or translocated nutrients, toxins, bacterial elements, cytokines, and immunocytes to gain hepatic access. Liver problems in digestive disorders may range from nonspecific hepatocellular enzyme elevations to significant pathologic processes that may progress to end-stage liver disease. Hepatobiliary manifestations of primary GI diseases in childhood and adolescence are not uncommon and include several well-described associations, such as sclerosing cholangitis with inflammatory bowel disease. Liver damage may also result from the effects of drugs used to treat GI diseases, for example, the hepatotoxicity of immunomodulatory therapies. This review highlights the important features of the hepatic and biliary abnormalities associated with 3 common pediatric GI conditions: inflammatory bowel disease, celiac disease, and cystic fibrosis.

Ω-3 fatty acids prevent hepatic steatosis, independent of PPAR-α activity, in a murine model of parenteral nutrition-associated liver disease.

OBJECTIVES: ω-3 Fatty acids (FAs), natural ligands for the peroxisome proliferator-activated receptor-α (PPAR-α), attenuate parenteral nutrition-associated liver disease (PNALD). However, the mechanisms underlying the protective role of ω-3 FAs are still unknown. The aim of this study was to determine the effects of ω-3 FAs on hepatic triglyceride (TG) accumulation in a murine model of PNALD and to investigate the role of PPAR-α and microsomal triglyceride transfer protein (MTP) in this experimental setting. METHODS: 129S1/SvImJ wild-type or 129S4/SvJaePparatm/Gonz/J PPAR-α knockout mice were fed chow and water (controls); oral, fat-free PN solution only (PN-O); PN-O plus intraperitoneal (IP) ω-6 FA-predominant supplements (PN-ω-6); or PN-O plus IP ω-3 FA (PN-ω-3). Control and PN-O groups received sham IP injections of 0.9% NaCl. Hepatic histology, TG and cholesterol, MTP activity, and PPAR-α messenger RNA were assessed after 19 days. RESULTS: In all experimental groups, PN feeding increased hepatic TG and MTP activity compared with controls. Both PN-O and PN-ω-6 groups accumulated significantly greater amounts of TG when compared with PN-ω-3 mice. Studies in PPAR-α null animals showed that PN feeding increases hepatic TG as in wild-type mice. PPAR-α null mice in the PN-O and PN-ω-6 groups demonstrated variable degrees of hepatic steatosis, whereas no evidence of hepatic fat accumulation was found after 19 days of oral PN plus IP ω-3 FAs. CONCLUSIONS: PN induces TG accumulation (steatosis) in wild-type and PPAR-α null mice. In PN-fed wild-type and PPAR-α null mice given IP ω-3 FAs, reduced hepatic TG accumulation and absent steatosis are found. Prevention of steatosis by ω-3 FAs results from PPAR-α-independent pathways.

Dietary GD3 ganglioside reduces the incidence and severity of necrotizing enterocolitis by sustaining regulatory immune responses.

OBJECTIVES: Gangliosides are glycosphingolipids, rich in colostrum and in membrane microdomains, which promote enterocyte growth and differentiation, and modulate TH1/TH2 responses. In an in vitro intestinal explant model of necrotizing enterocolitis (NEC), gangliosides have been shown to ameliorate intestinal injury; however, possible immunomodulatory mechanisms associated with this observation, as well as potential in vivo protective effects of gangliosides, remain unknown. The present study evaluates the effects of dietary GD3, the predominant ganglioside in neonatal rat intestine, both on the clinicopathologic expression of disease and on ileal Foxp3+ T regulatory cell immune responses in an experimental NEC model. METHODS: Newborn rat pups were fed gavage formula (NEC) or formula supplemented with 15 µg/mL GD3 (GD3-NEC). Dam-fed (DF) littermates served as controls. NEC was induced by asphyxia and cold stress. At 96 hours, ileal gross and histologic changes were evaluated, and ileal cytokine profiles, Foxp3 expression, and Foxp3+ cell numbers were determined. RESULTS: GD3 decreased the incidence and gross and histopathologic severity of NEC. Ileal Foxp3 expression and Foxp3+ cell numbers were significantly decreased in the NEC group compared with DF. GD3 increased ileal Foxp3 expression and Foxp3+ cell numbers, in association with upregulation of anti-inflammatory cytokine interleukin (IL)-10 and chemokines, tissue inhibitor of metalloproteinases 1, IL-1 receptor antagonist (IL-1ra), and suppressed proinflammatory mediators. CONCLUSIONS: These data suggest that dietary GD3 protects newborn rats from NEC, in part, by augmenting mucosal Foxp3+ T regulatory immune responses.

Cardiac arrest upon induction of anesthesia in children with cardiomyopathy: an analysis of incidence and risk factors.

INTRODUCTION: It is thought that patients with cardiomyopathy have an increased risk of cardiac arrest on induction of anesthesia, but there is little available data. The purpose of this study was to identify the incidence and potential risk factors for cardiac arrest upon induction of anesthesia in children with cardiomyopathy in our institution. METHODS: A retrospective chart review was performed. Eligible patients included patients admitted between 1998 and 2008 with the International Statistical Classification of Disease code for cardiomyopathy (ICD-9 code 425) who underwent airway intervention for sedation or general anesthesia in the operating room, cardiac diagnostic and interventional unit (CDIU) or intensive care unit. Patients undergoing emergency airway intervention following cardiovascular collapse were excluded. For each patient, we recorded patient demographics, disease severity, anesthesia location, and anesthetic technique. RESULTS: One hundred and twenty-nine patients with cardiomyopathy underwent a total of 236 anesthetic events, and four cardiac arrests were identified. One was related to bradycardia (HR<60), two were attributed to bradycardia in association with severe hypotension (systolic blood pressure<45), and the fourth arrest was related to isolated severe hypotension. Two occurred in the operating suite and two in the CDIU. There was no resulting mortality. One patient progressed to heart transplantation. Multiple combinations of anesthetic drugs were used for induction of anesthesia. CONCLUSION: We performed a review of the last 10 years of anesthesia events in children with cardiomyopathy. We report four cardiac arrests in two patients and 236 anesthetic events (1.7%). To the best of our knowledge, this is the largest review of these patients to date but is limited by its retrospective nature. The low cardiac arrest incidence prevents the identification of risk factors and the development of a cardiac arrest risk predictive clinical tool.

Ileal immune dysregulation in necrotizing enterocolitis: role of CD40/CD40L in the pathogenesis of disease.

OBJECTIVES: CD40, a co-stimulatory molecule, plays a critical role in coordinating enteric inflammatory immune responses. In necrotizing enterocolitis (NEC), upregulation of IL-10, a CD40-modulated cytokine, has been described, but the role of the IL-10 receptor (IL-10Rß), CD40, and its ligand CD40L in disease pathogenesis is unknown. The study herein investigates ileal expression of CD40, CD40L, and IL-10R in a rat model of NEC. SUBJECTS AND METHODS: NEC was induced in newborn rats using established methods of formula feeding, asphyxia, and cold stress. Expression of CD40, CD40L, IL-10Rß, and other proinflammatory molecules, including Toll-like receptor-4 (TLR-4) and IL-18, was assessed by immunoblotting. Tissue infiltration by macrophages, monocytes, and T cells was examined by confocal immunohistochemistry. RESULTS: Ileum from rat pups with NEC showed increased expression of TLR-4, IL-18, and IL-10Rß. Sections from both NEC and control pups demonstrated preservation of ileal cells expressing CD40/CD40L. The distal ileum of controls expressed both CD40 and CD40L; conversely, neither molecule was detected in ileal tissue from NEC pups. Additional studies showed that treatment with epidermal growth factor (EGF), previously shown to ameliorate the severity of NEC in an animal model, did not restore CD40 expression. CONCLUSIONS: Ileal cytokine dysregulation, manifested by decreased CD40/CD40L and increased IL-10Rß expression, may be involved in the pathogenesis of NEC. Dampened CD40 signaling may be related to enhanced IL-10 expression and a suppressed T-cell response to injury. We speculate that augmenting CD40-CD40L interactions may achieve a protective effect in this NEC model.