Simultaneous Colonic Pressure Waves in Children and Young Adults with Gastrointestinal Motility Disorders: Artefact or Colonic Physiology?

BACKGROUND: Simultaneous pressure waves (SPW) spanning all recording sites in colonic manometry studies have been described as a potential biomarker of normal gas transit and extrinsic neural reflexes. In pediatric studies utilizing combined antroduodenal and colonic manometry, it was noted that most colonic SPWs appeared to also span all sensors in the gastric and small bowel regions. This suggests that a proportion of colonic SPWs may represent an artefact caused by forces extrinsic to the colon. Our aim was to characterize colonic SPWs and determine how many of these spanned most of the digestive tract. METHODS: In 39 combined high-resolution antroduodenal and colonic manometry traces from 27 pediatric patients, we used our purpose-built software to identify all SPWs that spanned either (i) all recording sites in the digestive tract or (ii) those restricted to the colon. RESULTS: A total of 14,565 SPWs were identified (364 ± 316 SPWs/study), with 14,550 (99.9%) spanning the entire antroduodenal and colonic recording sites. Only 15 SPWs (0.1% of the total) were restricted to the colon (all in one recording). CONCLUSIONS: Based on these findings, we suggest that, in pediatric studies, SPWs should not form part of any diagnostic criteria, as these events appear to be an artefact caused by factors outside the colon (abdominal strain, body motion)

Unexpected role of ceruloplasmin in intestinal iron absorption

SummaryFerroxidases are essential for normal iron homeostasis in most organisms. The paralogous vertebrate ferroxidases ceruloplasmin (Cp) and hephaestin (Heph) are considered to have nonidentical functions in iron transport: plasma Cp drives iron transport from tissue stores while intestinal Heph facilitates iron absorption from the intestinal lumen. To clarify the function of Cp, we acutely bled Cp−/− mice to stress iron homeostasis pathways. Red cell hemoglobin recovery was defective in stressed Cp−/− mice, consistent with low iron availability. Contrary to expectations, iron was freely released from spleen and liver stores in Cp−/− mice, but intestinal iron absorption was markedly impaired. Phlebotomy of wild-type mice caused a striking shift of Cp from the duodenal epithelium to the underlying lamina propria, suggesting a critical function of Cp in basolateral iron transport. Regulated relocalization of intestinal Cp may represent a fail-safe mechanism in which Cp shares with Heph responsibility for iron absorption under stress

Fc-Epsilon-RI, the High Affinity IgE-Receptor, Is Robustly Expressed in the Upper Gastrointestinal Tract and Modulated by Mucosal Inflammation

Background: The role of the high affinity IgE receptor, FcεRI, in IgE-mediated immune responses of the gastrointestinal (GI) mucosa is poorly understood. Currently, a detailed characterization of FcεRI expression throughout the human gut is lacking. The aim of this study was to define the expression pattern of FcεRI in the GI tract. Methods/Principal Findings: We compared FcεRI expression in children with gastritis/esophagitis (n = 10), celiac disease (n = 10), inflammatory bowel disease (IBD) (n = 9), and normal mucosa (n = 5). The α–subunit of FcεRI (FcεRIα), detected by immunohistochemistry, was found on cells infiltrating the mucosa of the esophagus, the stomach, and the duodenum, but was rarely detected in more distal sections of the GI tract. Accordingly, quantitative RT-PCR analysis on esophagus, stomach, duodenum, colon, and rectum biopsies revealed that FcεRIα and -β expression levels decreased towards the distal intestine. mRNA transcripts of the common Fc-receptor-γ chain were present in the entire GI mucosa. Double-immunofluorescence staining of esophageal specimens confirmed that FcεRIα was expressed on intraepithelial mast cells and Langerhans cells. The mRNA expression levels of the α, β, and γ subunits of FcεRI did not correlate with total serum IgE but were associated with mucosal inflammation. Conclusion/Significance: Our data define the upper GI tract as the main site for IgE-mediated immune activation via FcεRI. Tissue mRNA levels of FcεRIα are regulated by inflammatory conditions rather than serum IgE, indicating that FcεRI might also play a role in pathologies other than allergy

A Distinct Esophageal mRNA Pattern Identifies Eosinophilic Esophagitis Patients With Food Impactions

Eosinophilic esophagitis (EoE), a Th2-type allergic immune disorder characterized by an eosinophil-rich esophageal immune infiltrate, is often associated with food impaction (FI) in pediatric patients but the molecular mechanisms underlying the development of this complication are not well understood. We aim to identify molecular pathways involved in the development of FI. Due to large variations in disease presentation, our analysis was further geared to find markers capable of distinguishing EoE patients that are prone to develop food impactions and thus expand an established medical algorithm for EoE by developing a secondary analysis that allows for the identification of patients with food impactions as a distinct patient population. To this end, mRNA patterns from esophageal biopsies of pediatric EoE patients presenting with and without food impactions were compared and machine learning techniques were employed to establish a diagnostic probability score to identify patients with food impactions (EoE+FI). Our analysis showed that EoE patients with food impaction were indistinguishable from other EoE patients based on their tissue eosinophil count, serum IgE levels, or the mRNA transcriptome-based p(EoE). Irrespectively, an additional analysis loop of the medical algorithm was able to separate EoE+FI patients and a composite FI-score was established that identified such patients with a sensitivity of 93% and a specificity of 100%. The esophageal mRNA pattern of EoE+FI patients was typified by lower expression levels of mast cell markers and Th2 associated transcripts, such as FCERIB, CPA3, CCL2, IL4, and IL5. Furthermore, lower expression levels of regulators of esophageal motility (NOS2 and HIF1A) were detected in EoE+FI. The EoE+FI -specific mRNA pattern indicates that impaired motility may be one underlying factor for the development of food impactions in pediatric patients. The availability of improved diagnostic tools such as a medical algorithm for EoE subpopulations will have a direct impact on clinical practice because such strategies can identify molecular inflammatory characteristics of individual EoE patients, which, in turn, will facilitate the development of individualized therapeutic approaches that target the relevant pathways affected in each patient

Characterization of the colonic response to bisacodyl in children with treatment-refractory constipation

Background: Colonic manometry with intraluminal bisacodyl infusion can be used to assess colonic neuromuscular function in children with treatment‐refractory constipation. If bisacodyl does not induce high‐amplitude propagating contractions (HAPCs), this can be an indication for surgical intervention. A detailed characterization of the colonic response to intraluminal bisacodyl in children with constipation may help to inform clinical interpretation of colonic manometry studies. / Methods: Studies were performed in five pediatric hospitals. Analysis included identification of HAPCs, reporting HAPCs characteristics, and an area under the curve (AUC) analysis. Comparisons were performed between hospitals, catheter type, placement techniques, and site of bisacodyl infusion. / Results: One hundred and sixty‐five children were included (median age 10, range 1‐17 years; n = 96 girls). One thousand eight hundred and ninety‐three HAPCs were identified in 154 children (12.3 ± 8.8 HAPCs per child, 0.32 ± 0.21 HAPCs per min; amplitude 113.6 ± 31.5 mm Hg; velocity 8.6 ± 3.8 mm/s, propagation length 368 ± 175 mm). The mean time to first HAPC following bisacodyl was 553 ± 669 s. Prior to the first HAPC, there was no change in AUC when comparing pre‐ vs post‐bisacodyl (Z = −0.53, P = .60). The majority of HAPCs terminated in a synchronous pressurization in the rectosigmoid. Defecation was associated with HAPCs (χ 2(1)=7.04, P < .01). Site of bisacodyl administration, catheter type, and hospital location did not alter the response. / Conclusions and Inferences: Intraluminal bisacodyl induced HAPCs in 93% of children with treatment‐refractory constipation. The bisacodyl response is characterized by ≥1 HAPC within 12 minutes of infusion. The majority of HAPCs terminate in a synchronous pressurization in the rectosigmoid. Optimal clinical management based upon colonic manometry findings is yet to be determined

Inter- and intra-rater reliability of the Chicago Classification in pe-diatric high-resolution esophageal manometry recordings

This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving'.Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.Background The Chicago Classification (CC) facilitates interpretation of high-resolution manometry (HRM) recordings. Application of this adult based algorithm to the pediatric population is unknown. We therefore assessed intra and interrater reliability of software-based CC diagnosis in a pediatric cohort. Methods Thirty pediatric solid state HRM recordings (13M; mean age 12.1 ± 5.1 years) assessing 10 liquid swallows per patient were analyzed twice by 11 raters (six experts, five non-experts). Software-placed anatomical landmarks required manual adjustment or removal. Integrated relaxation pressure (IRP4s), distal contractile integral (DCI), contractile front velocity (CFV), distal latency (DL) and break size (BS), and an overall CC diagnosis were software-generated. In addition, raters provided their subjective CC diagnosis. Reliability was calculated with Cohen's and Fleiss’ kappa (κ) and intraclass correlation coefficient (ICC). Key Results Intra- and interrater reliability of software-generated CC diagnosis after manual adjustment of landmarks was substantial (mean κ = 0.69 and 0.77 respectively) and moderate-substantial for subjective CC diagnosis (mean κ = 0.70 and 0.58 respectively). Reliability of both software-generated and subjective diagnosis of normal motility was high (κ = 0.81 and κ = 0.79). Intra- and interrater reliability were excellent for IRP4s, DCI, and BS. Experts had higher interrater reliability than non-experts for DL (ICC = 0.65 vs ICC = 0.36 respectively) and the software-generated diagnosis diffuse esophageal spasm (DES, κ = 0.64 vs κ = 0.30). Among experts, the reliability for the subjective diagnosis of achalasia and esophageal gastric junction outflow obstruction was moderate-substantial (κ = 0.45–0.82). Conclusions & Inferences Inter- and intrarater reliability of software-based CC diagnosis of pediatric HRM recordings was high overall. However, experience was a factor influencing the diagnosis of some motility disorders, particularly DES and achalasia

Demographic and clinical characteristics associated with glomerular filtration rates in living kidney donors

Due to the shortage of organs, living donor acceptance criteria are becoming less stringent. An accurate determination of the glomerular filtration rate (GFR) is critical in the evaluation of living kidney donors and a value exceeding 80 ml/min per 1.73 m2 is usually considered suitable. To improve strategies for kidney donor screening, an understanding of factors that affect GFR is needed. Here we studied the relationships between donor GFR measured by 125I-iothalamate clearances (mGFR) and age, gender, race, and decade of care in living kidney donors evaluated at the Cleveland Clinic from 1972 to 2005. We report the normal reference ranges for 1057 prospective donors (56% female, 11% African American). Females had slightly higher mGFR than males after adjustment for body surface area, but there were no differences due to race. The lower limit of normal for donors (5th percentile) was less than 80 ml/min per 1.73 m2 for females over age 45 and for males over age 40. We found a significant doubling in the rate of GFR decline in donors over age 45 as compared to younger donors. The age of the donors and body mass index increased over time, but their mGFR, adjusted for body surface area, significantly declined by 1.49±0.61 ml/min per 1.73 m2 per decade of testing. Our study shows that age and gender are important factors determining normal GFR in living kidney donors

Novel pressure-impedance parameters for evaluating esophageal function in pediatric achalasia

Objective: In achalasia, absent peristalsis and reduced esophagogastric junction (EGJ) relaxation and compliance underlie dysphagia symptoms. Novel high-resolution impedance manometry variables, that is, bolus presence time (BPT) and trans-EGJ-bolus flow time (BFT) have been developed to estimate the duration of EGJ opening and trans-EGJ bolus flow. The aim of this study was to evaluate esophageal motor function and bolus flow in children diagnosed with achalasia using these variables. Methods: High-resolution impedance manometry recordings from 20 children who fulfilled the Chicago Classification (V3) criteria for achalasia were compared with recordings of 15 children with normal esophageal high-resolution manometry findings and no other evidence suggestive of achalasia. Matlab-based analysis software was used to calculate BPT and BFT. Results: Both BPT and BFT were significantly reduced in achalasia patients compared with children with normal esophageal motility (BPT 3.3 s vs 5.1 s P < 0.01; BFT 1.4 s vs 4.3 s P < 0.001). BFT was significantly lower than BPT (achalasia difference 1.9 s ± 1.3 s, P = 0.001 and normal difference 0.9 ± 0.3 s, P = 0.001). Overall, there was a significant correlation between BPT and BFT (r = 0.825, P < 0.001). We observed a 2-way differentiation of achalasia patients; those in whom the BPT and BFT were proportional, but significantly lower than in patients with normal peristalsis, and those in whom BFT was disproportionately lower than BPT. Conclusions: Calculation of BPT and BFT may help determine whether esophageal bolus transport to the EGJ and/or esophageal emptying through the EGJ are aberrant. For achalasia, this may detect flow resistance at the EGJ, potentially improving both diagnosis and objective assessment of therapeutic effects