Markedly Elevated Procalcitonin in Food Protein Induced Enterocolitis Syndrome.

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated gastrointestinal food allergy. Some studies have reported that FPIES was associated with elevated C-reactive protein (CRP). However, the number of reports on the relationship between FPIES and procalcitonin (PCT) is limited. This case report highlights the fact that PCT levels can be markedly elevated in patients with acute FPIES. An 11-month-old girl previously diagnosed with FPIES underwent an oral food challenge test (OFC). Her serum PCT levels were measured after she developed severe symptoms including fever and shock following administration of 100mL of formula milk. The PCT levels were extremely elevated but improved without antibiotics the next day. The fact that serum PCT levels may be significantly elevated in FPIES means that differentiating severe FPIES from sepsis could be more challenging than was previously thought.

Evaluation of the Diagnostic Accuracy of Thymus and Activation-Regulated Chemokine to Discriminate Food Protein-Induced Enterocolitis Syndrome from Infectious Gastroenteritis.

BACKGROUND: Post-emetic elevation in thymus and activation-regulated chemokine (TARC) levels has been reported in patients with food protein-induced enterocolitis syndrome (FPIES); however, no studies have investigated differences in TARC levels between FPIES and other diseases. OBJECTIVES: We evaluated the clinical usefulness of TARC measurement in differentiating between FPIES and infectious gastroenteritis. METHODS: This study included 8 patients with solid-food FPIES (FPIES group; hen's egg [n = 6], rice [n = 1], and short-neck clam [n = 1]; a total of 11 episodes necessitating emergency department visit or positive result of oral food challenge test) and 17 patients with infectious gastroenteritis (control group), and all patients had no eczema. Post-emetic serum TARC levels and modified TARC levels (serum TARC value - normal mean for each age) were compared between the 2 groups. RESULTS: The median (range) ages for the FPIES and control groups were 0.7 (0.5-6.2) and 1.8 (0.1-4.4) years, respectively (p > 0.05). In the FPIES and control groups, median (range) TARC levels were 2,911 (1,062-7,816) and 600 (277-2,034) pg/mL, and median (range) modified TARC levels were 2,204 (355-7,109) and 129 (0-1,314), respectively. The TARC and modified TARC levels were significantly higher in the FPIES group than in the control group (p < 0.001 for both). CONCLUSION: In the absence of eczema, post-emetic serum TARC levels might be a potential diagnostic biomarker for distinguishing FPIES from infectious gastroenteritis.

Comparison of methemoglobin levels in food protein-induced enterocolitis syndrome and other gastrointestinal diseases in neonates

INTRODUCTION AND OBJECTIVES: Methemoglobinemia has been reported to be associated with severe food protein-induced enterocolitis syndrome (FPIES). However, no reports have evaluated methemoglobin (MHb) levels in FPIES without symptomatic methemoglobinemia or the usefulness of MHb measurement for the diagnostic prediction of FPIES. To evaluate the MHb levels of patients with neonatal-onset FPIES and determine whether MHb levels are higher in FPIES than in other gastrointestinal diseases. PATIENTS AND METHODS: Eleven neonates with severe acute FPIES (FPIES group) and 139 neonates with other gastrointestinal diseases (non-FPIES group) were included in this study. Patient characteristics, symptoms, and venous blood test values (MHb, pH, HCO3-, and C-reactive protein) were evaluated. RESULTS: The median age at onset was 16 days vs. 1 day; males comprised 64% vs. 46%, the median gestational age was 38 weeks vs. 38 weeks, the median birth weight was 2710g vs. 2880g, and the median hospitalization duration was 31 days vs. 6 days for the FPIES vs. non-FPIES groups, respectively. MHb (%) was higher in the FPIES group than in the non-FPIES group [median (range), 1.1 (0.6-10.9) and 0.6 (0.3-1.2), respectively, p < 0.001]. There were no differences in terms of pH, HCO3-, and C-reactive protein (p > 0.05). In the receiver operating characteristic analysis for FPIES diagnosis based on MHb (%), the area under the curve was 0.885, specificity was 97.1%, and sensitivity was 72.7% at a MHb cutoff of 1.0. CONCLUSION: High MHb levels may help diagnose severe acute FPIES in neonates, but careful evaluation is needed

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Experimental Evaluation of the Impact of Gadolinium Orthovanadate GdVO4:Eu3+ Nanoparticles on the Carrageenan-Induced Intestinal Inflammation.

AIM: To evaluate the effects of orally administered gadolinium orthovanadate GdVO4:Eu3+ nanoparticles (VNPs) on the course of chronic carrageenan-induced intestinal inflammation. METHODS: Samples of small intestinal tissue were collected from four groups of rats (intact, after administration of VNPs, with carrageenaninduced intestinal inflammation, with carrageenan-induced intestinal inflammation orally exposed to VNPs) to assess the intestinal morphology and HSP90α expression. Levels of seromucoid, C-reactive protein, TNF-α, IL-1ß and IL-10 were determined in blood serum. RESULTS: Oral exposure to VNPs was associated with neither elevation of inflammation markers in blood serum nor HSP90α overexpression in the small intestine, i.e. no toxic effects of VNPs were observed. Carrageenan-induced intestinal inflammation was accompanied by higher levels of TNF-α and IL-1ß, as well as HSP90α upregulation in the intestinal mucosa, compared with controls. Administration of VNPs to rats with enteritis did not lead to statistically significant changes in concentrations of circulating pro-inflammatory cytokines with the trend towards their increase. CONCLUSION: No adverse effects were observed in rats orally exposed to VNPs at a dose of 20 µg/kg during two weeks. Using the experimental model of carrageenan-induced enteritis, it was demonstrated that VNPs at the dose used in our study did not affect the course of intestinal inflammation.

Non-IgE-mediated food allergy during infancy.

PURPOSE OF REVIEW: Is to highlight the recent advances in the diagnosis and management of non-IgE-mediated food allergy which is a common consideration in primary care and in allergy and gastroenterology subspecialty practices evaluating infants. RECENT FINDINGS: The review focuses on food protein-induced enterocolitis syndrome (FPIES) and includes other non-IgE-mediated food allergy in nursing infants, food protein-induced allergic proctocolitis, and food protein-induced enteropathy. For FPIES, we review the 2017 International Consensus Guidelines that provided the first comprehensive framework for its diagnosis and management and that were supplemented by a 2019 position paper by the European Academy of Allergy and Clinical Immunology. We review recent reports that support FPIES as a diagnosis of primarily infants, highlight the problem of delayed diagnosis, reveal the need for improved biomarkers, emphasize new and common food protein triggers, and identify new approaches for evaluation of tolerance. SUMMARY: As formal diagnostic criteria for non-IgE-mediated food allergies are defined and prevalence data is increasingly reported, there will likely be improved recognition and evaluation of these conditions. Currently, large-scale prospective studies evaluating their incidence and prevalence, associated risk factors, and natural history are needed. Although avoidance of the suspected trigger food protein remains the cornerstone of management, additional studies of underlying pathophysiology and biomarkers of disease will likely reveal new avenues for therapeutics.

Inflammatory Bowel Disease Serological Immune Markers Anti-Saccharomyces cerevisiae Mannan Antibodies and Outer Membrane Porin C are Potential Biomarkers for Hirschsprung-associated Enterocolitis.

OBJECTIVE: Hirschsprung-associated enterocolitis (HAEC) is the most frequent complication in Hirschsprung disease (HSCR) patients. Currently HAEC is diagnosed clinically, leaving uncertainty in the diagnosis thereby potentially leading to over- or undertreatment of patients. The aim of this study was to identify immune biomarkers to aid in the diagnosis of HAEC. METHODS: From 2012 to 2017, 43 children with HSCR enrolled in a multicenter study, underwent retrospective evaluation of their medical records, and questionnaire-directed parent interviews. HAEC status was determined using HAEC score with cutoff ≥4. Plasma was collected and analyzed by ELISA for the inflammatory bowel disease-associated antibodies: anti-Saccharomyces cerevisiae mannan antibodies (ASCA), outer membrane porin C (OmpC), CBir1, antineutrophil cytoplasmic antibodies. Data were analyzed using t test, univariate, multivariable, and binomial regression models. RESULTS: Eighteen patients had at least 1 episode of HAEC, 25 had no history of HAEC. The HAEC and NO HAEC groups had similar median ages (3 years) and family histories of HSCR. The HAEC group showed markedly elevated ASCA IgA and OmpC antibody levels compared with the NO HAEC group, whereas CBir1 and antineutrophil cytoplasmic antibodies were similar between the groups. Both univariate and multivariable analysis revealed higher OmpC antibody levels associated with HAEC (odds ratio 1.39, confidence interval 1-1.92, P = 0.048), whereas univariate analysis identified a trend toward elevated IgA and immunoglobulin G ASCA levels with HAEC. CONCLUSIONS: We identified elevated OmpC and ASCA serum antibody levels in HAEC patients, and that increased OmpC antibody levels correlated with HAEC occurrence, suggesting HAEC and Crohn disease share gut microbial-host immune responses. These antibodies may serve as potential biomarkers for HAEC, although prospective study with larger sample size is needed.

Differentiating Acute Food Protein-Induced Enterocolitis Syndrome From Its Mimics: A Comparison of Clinical Features and Routine Laboratory Biomarkers.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is frequently misdiagnosed and subject to diagnostic delay. Profuse vomiting, the cardinal feature of acute FPIES, may occur in more common pediatric disorders such as gastroenteritis and sepsis. OBJECTIVES: We sought to determine differentiating features at acute presentation between FPIES, gastroenteritis, and sepsis in young children presenting to an emergency department (ED) with profuse vomiting. METHODS: We conducted a retrospective case-control study of children aged 6 months to 4 years with a diagnosis of acute FPIES who had presented to ED and compared the clinical features, vital signs, and routine laboratory studies of this cohort to similarly aged children presenting to ED with vomiting diagnosed with bacterial/viral gastroenteritis or bacterial sepsis. RESULTS: A total of 181 acute FPIES ED presentations were compared with 55 gastroenteritis and 36 bacterial sepsis ED presentations. Children with FPIES were more likely to present with lethargy, floppiness, and pallor. Compared with children with FPIES, children with sepsis were likely to present with fever, tachycardia, tachypnea, and diarrhea, whereas those with gastroenteritis were likely to present with fever, diarrhea, and blood in stools. Normal C-reactive protein (CRP), leucocytosis, lymphocytosis, thrombocytosis, low MPV, and an elevated albumin/globulin ratio were more commonly seen in FPIES than in sepsis or gastroenteritis. No other clinical or laboratory markers examined reliably distinguished between the 3 disease groups. CONCLUSIONS: In the young vomiting child, lethargy, floppiness, pallor without fever, and normal CRP should alert clinicians to a possible diagnosis of FPIES. In contrast, a highly elevated CRP is not a feature of FPIES, and in such cases an alternative diagnosis must be considered.

Gfra1 Underexpression Causes Hirschsprung's Disease and Associated Enterocolitis in Mice.

BACKGROUND & AIMS: RET, the receptor for the glial cell line-derived neurotrophic factor (GDNF) family ligands, is the most frequently mutated gene in congenital aganglionic megacolon or Hirschsprung's disease (HSCR). The leading cause of mortality in HSCR is HSCR-associated enterocolitis (HAEC), which is characterized by altered mucin composition, mucin retention, bacterial adhesion to enterocytes, and epithelial damage, although the order of these events is obscure. In mice, loss of GDNF signaling leads to a severely underdeveloped enteric nervous system and neonatally fatal kidney agenesis, thereby precluding the use of these mice for modeling postnatal HSCR and HAEC. Our aim was to generate a postnatally viable mouse model for HSCR/HAEC and analyze HAEC etiology. METHODS: GDNF family receptor alpha-1 (GFRa1) hypomorphic mice were generated by placing a selectable marker gene in the sixth intron of the Gfra1 locus using gene targeting in mouse embryonic stem cells. RESULTS: We report that 70%-80% reduction in GDNF co-receptor GFRa1 expression levels in mice results in HSCR and HAEC, leading to death within the first 25 postnatal days. These mice mirror the disease progression and histopathologic findings in children with untreated HSCR/HAEC. CONCLUSIONS: In GFRa1 hypomorphic mice, HAEC proceeds from goblet cell dysplasia, with abnormal mucin production and retention, to epithelial damage. Microbial enterocyte adherence and tissue invasion are late events and therefore unlikely to be the primary cause of HAEC. These results suggest that goblet cells may be a potential target for preventative treatment and that reduced expression of GFRa1 may contribute to HSCR susceptibility.

The effect of flavonoid quercetine on the indices of nitric oxide system in rats with chronic enterocolitis combined with streptozotocin-induced diabetes.

OBJECTIVE: Introduction: Chronic hyperglycemia is accompanied by significant physiological, biochemical, and histological changes, e.g. development of oxidative and nitrosative stress that affects the motor activity of the intestine. The aim: The present study was designed to evaluate the indices of nitric oxide (NO) system in blood serum and a colon tissue supernatant of rats with chronic enterocolitis combined with streptozotocin-induced diabetes. PATIENTS AND METHODS: Materials and methods: The total NOS activity was performed by monitoring the rate of conversion of L-arginine into citrulline. The total contents of NO metabolites was assessed by evaluation of their amount, which included nitrite ions that were previously presented in the sample (NO2-) and also nitrate ions reducted to nitrites (NO3-). RESULTS: Results and conclusions: Thus, in rats with modeled chronic enterocolitis activation of nitroxydergic process in blood serum and colon tissue has been established. Herewith more pronounced intensification of nitroxydergic processes was observed in rats with chronic enterocolitis combined with streptozotocin-induced diabetes. The liposomal form of quercetin - Lipoflavon significantly reduces nitrosative stress in rats with chronic enterocolitis combined with streptozotocin-induced diabetes.

Increased serum cortisol on oral food challenge in infants with food protein-induced enterocolitis syndrome.

BACKGROUND: An increase in absolute neutrophil count (ANC) is seen after oral food challenge test (OFC) in patients with food protein-induced enterocolitis syndrome (FPIES). Although it has been suggested that interleukin (IL)-8 is involved in this phenomenon, a possible role for cortisol has not yet been studied. METHODS: Six positive OFC in five patients with FPIES due to cows' milk (CM) proteins, and two negative OFC in two patients with suspected FPIES were analyzed. Absolute neutrophil count, serum IL-8, and serum cortisol were measured before OFC, 6 and 24 h after the ingestion of CM formula. RESULTS: For the positive OFC, ANC measured 6 h after the ingestion of CM formula was significantly higher than that measured before the OFC (median, 8,761 versus 2,297/µL; P < 0.05). Significant increases in serum cortisol and IL-8 were observed 6 h after OFC (cortisol, median 1,119 pg/mL before versus 2,141 pg/mL after, P < 0.05; IL-8, median 15.5 pg/mL before versus 165.3 pg/mL after, P < 0.05). The change ratio (i.e. ratio of that after OFC to that before OFC) of ANC was significantly correlated not only with that of serum IL-8 (r = 0.90, P < 0.01) but also with that of serum cortisol (r = 0.76, P < 0.05). Moreover, the serum cortisol change ratio was significantly higher in subjects with vomiting than in those without (median, 2.5 versus 1.0, P < 0.05). CONCLUSIONS: Serum cortisol, in combination with IL-8, affects the increase in ANC after OFC.

Inflammatory events during food protein-induced enterocolitis syndrome reactions.

BACKGROUND: An increasing number of infants are diagnosed with food protein-induced enterocolitis syndrome (FPIES), a non-IgE-mediated food allergy. Until now, T-cell, food-specific mechanisms have been hypothesized. METHODS: Sixteen children (11M, 5F), affected by FPIES from cow's milk, wheat, fruit, rice, and others, experienced 25 acute episodes managed at our emergency department (ED) and eight FPIES reactions during oral food challenges (OFC). We compared the laboratory data in resting conditions, in the absence of infectious diseases, with data collected during the 25 acute ED episodes (blood samples drawn at 2-12 hours) and the eight positive OFCs (three samples at 2, 6, and 12 hours). The onset of symptoms was used as a reference time point. RESULTS: In basal conditions, total IgE, WBC, neutrophil and eosinophil count, CRP, and SGPT were found normal. LDH and SGOT values were high (627.81±97.88 and 45.75±10.26 UI/L, respectively). During ED reactions, LDH and SGOT increased to 794.21±247.28 (P=.028) and 51.08±16.99 UI/L (P=.14) and neutrophils count and CRP to 8.44±3.82×103 /µL (P=.0009) and 3.27±5.73 mg/dL (P=.0014), respectively. During positive OFC, LDH and SGOT did not vary significantly; CRP increased from 0.14±0.18 to 2.49±3.65 mg/dL (P=.00189) and neutrophil count from 2.79±1.42 to 7.10±3.98×103 /µL (P=.00096). CONCLUSIONS: FPIES reactions are characterized by neutrophilia and by a time-dependent, significant increase in CRP, indicating that inflammatory mechanisms are in place. This suggests new directions for research on FPIES pathogenesis.

Prognosis of infantile food protein-induced enterocolitis syndrome in Japan.

BACKGROUND: Although serum C-reactive protein (CRP) and the percentage of eosinophils in peripheral blood (Eo) are increased at onset in infants with food protein-induced enterocolitis syndrome (FPIES), the relationship of these laboratory findings to prognosis is presently unknown. METHODS: Correlation of serum CRP and Eo at onset with prognosis was analyzed in 32 patients with FPIES caused by cow's milk (CM). RESULTS: The rate of tolerance acquisition was 18.8%, 56.3%, 87.5%, and 96.9% at the ages of 6, 12, 24, and 36 months, respectively. Serum CRP increased in 50% of subjects at onset (median, 0.21 mg/dL; range, <0.20-18.2 mg/dL) and Eo was elevated in 71.9% of subjects at onset (median, 7.1%; range, 1.0-50.5%). Age at tolerance acquisition was significantly positively correlated with serum CRP at onset (r = 0.45, P < 0.01), and significantly negatively correlated with Eo at onset (r = -0.36, P < 0.05). Although CM-specific immunoglobulin E antibody (sIgE) was positive in nine of 32 FPIES patients at onset (median, 0.93; range, 0.38-18.9 kU/L), it decreased thereafter. CM-sIgE at onset did not correlate significantly with prognosis (r = 0.22, P > 0.05). CONCLUSIONS: Serum CRP is not only an indicator of the activity of intestinal inflammation, it is also a useful parameter of poor prognosis in FPIES. In contrast, eosinophilia at onset could be used as a marker of good prognosis, suggesting that it has some beneficial effects in the pathophysiology of FPIES.

Cytokine profile after oral food challenge in infants with food protein-induced enterocolitis syndrome.

BACKGROUND: Although food protein-induced enterocolitis syndrome (FPIES) is supposed to be caused by inflammation, the role of cytokines has not yet been clarified. METHODS: To elucidate the role of cytokines in the development of symptoms and abnormal laboratory findings at an oral food challenge (OFC), changes in serum cytokine levels were analyzed for 6 OFCs in 4 patients with FPIES. The result of OFC was judged positive if any gastrointestinal (GI) symptoms (vomiting, diarrhea, or bloody stool) were induced. RESULTS: Among 11 cytokines profiled, serum levels of interleukin (IL)-2, IL-5, and IL-8 were clearly increased in all 4 positive OFCs in which elevations of the serum level of C-reactive protein (CRP) and peripheral blood neutrophilia were also seen. The level of serum IL-10 also rose in 2 positive OFCs. Remarkable increases in the serum level of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), IL-6, and IL-12 were observed in a positive OFC where the serum level of CRP rose markedly (6.75 mg/dL). The serum levels of IL-5 were also elevated in 2 negative OFCs. No apparent specific correlations were found between cytokines and GI symptoms. CONCLUSIONS: These results suggest that IL-2 and IL-8 are involved in the antigen-specific immune responses in most patients with FPIES. Further studies are needed to elucidate the significance of these cytokine in the pathogenesis of FPIES.

[THE STATUS OF VITAMIN В UNDER DISEASES OF SMALL INTESTINE IN CHILDREN IN THE ZONE OF INCREASED SUN INSOLATION].

The study was carried out to trace clinical laboratory parallels between levels of vitamin D under diseases of small intestine in children. The examined sampling included 160 children aged from 6 months to 18 years with diseases of small intestine. The patients were separated to three groups: 60 children with celiac disease aged from 3-16 years; 60 children with chronic post-infectious enterocolitis aged from 2 to 12 years; 40 children with allergic enterocolitis aged from 6 months to 4 years. The control group consisted of 31 children, including 15 children aged from 6 months to 4 years and 16 children aged from 5 to 18 years. The standard clinical, para-clinical and instrumental techniques of investigation were applied to every nosology. To analyze status of vitamin В the levels of calcidiol and parathormone were determined. In the process of tracing clinical laboratory parallels between levels of vitamin D under diseases of small intestine in children high percentage of decreasing of vitamin D (96.9%) was detected, and at that in 100% under celiac disease and chronic post-infectious enterocolitis. The feedback was established between levels of vitamin D and levels of calcidiol and parathormone and also activity of alkaline phosphatase in all groups of patients though more evident in patients with celiac disease and chronic post-infectious enterocolitis. The low values of level of vitamin D were detected in all children with celiac disease and chronic post-infectious enterocolitis whereas only in 87% under allergic enterocolitis. The decreasing of level of vitamin D was accompanied by increasing of content of calcidiol and parathormone and activity of alkaline phosphatase at that the most high numbers are observed in patients with celiac disease and then chronic post-infectious enterocolitis and allergic enterocolitis.

Serum C-reactive protein in food protein-induced enterocolitis syndrome versus food protein-induced proctocolitis in Japan.

BACKGROUND: Some infants with food protein-induced enterocolitis syndrome (FPIES) have increased serum C-reactive protein (CRP) and fever in Japan. The aim of this study was therefore to clarify and compare the incidence of this in patients with FPIES versus patients with food protein-induced proctocolitis (FPIP). METHODS: One hundred and sixteen infants with non-IgE-mediated gastrointestinal food allergies were enrolled in this study and classified into three phenotypes: FPIES presenting with vomiting and/or diarrhea (n = 47); FPIP with bloody stool alone (n =19); and the mixed phenotype (MP), bloody stool with vomiting and/or diarrhea (n = 50). RESULTS: Serum CRP was increased in 55.3% of the FPIES group, similar to that in the MP group (54.0%), and significantly higher than in the FPIP group (15.8%; P < 0.01). Fever was observed in 29.8% of the FPIES group, significantly higher than in the MP group (8.0%; P < 0.01) and in the FPIP group (0%; P < 0.05). Patients with fever had significantly higher serum CRP than patients without fever (median, 12.8 vs <0.2 mg/dL, P < 0.00001). CONCLUSIONS: Serum CRP was significantly higher in the FPIES group than in the FPIP group. This suggests that serum CRP is a useful marker for differentiating the pathogenesis of FPIES from FPIP. From the perspective of serum CRP, the pathology of the intestinal inflammation in MP subjects is suggested to be similar to that of FPIES.

Increased C-reactive protein and fever in Japanese infants with food protein-induced enterocolitis syndrome.

BACKGROUND: Increased C-reactive protein (CRP) and fever are observed in some infants with food protein-induced enterocolitis syndrome (FPIES) in Japan, but the reproducibility of these findings has not yet been confirmed on oral food challenge (OFC). METHODS: Fourteen infants with FPIES induced by cow's milk (CM) formula were enrolled. OFC using CM formula was performed on each infant once or repeatedly (total 18 tests), with a stepwise incremental protocol in an infection-controlled setting. CRP was measured 24 h after the last ingestion of the CM formula. RESULTS: Increased CRP was observed in 11 of the 18 OFC conducted (median, 2.60 mg/dL; range, 0.22-4.84 mg/dL). Fever was induced in six occasions during OFC. Serum CRP in the patients with fever increased to median 3.76 mg/dL (range, <0.7-4.84 mg/dL), which was significantly higher than that of the patients without fever (median <0.1 mg/dL; range, <0.1-2.6 mg/dL; P < 0.001). CRP during OFC significantly correlated with that at disease onset (rs = 0.62, P < 0.02). Three of the four patients with fever at disease onset also had fever during OFC. CONCLUSIONS: Increased CRP and fever are reproducible during OFC in some infants with FPIES, suggesting that these are not accidental phenomena, but instead are associated with FPIES itself in Japanese patients.

Mucosal healing effect of nilotinib in indomethacin-induced enterocolitis: A rat model.

AIM: To investigate the effects of nilotinib in a rat model of indomethacin-induced enterocolitis. METHODS: Twenty-one Wistar albino female rats obtained from Dokuz Eylul University Department of Laboratory Animal Science were divided into the following three groups: control (n = 7), indomethacin (n = 7) and nilotinib (n = 7). A volume of 0.25 mL of physiological serum placebo was administered to the control and indomethacin groups through an orogastric tube for 13 d. To induce enterocolitis, the indomethacin and nilotinib groups received 7.5 mL/kg indomethacin dissolved in 5% sodium bicarbonate and administered subcutaneously in a volume of 0.5 mL twice daily for three days. Nilotinib was administered 20 mg/kg/d in two divided doses to the nilotinib group of rats for 13 d through an orogastric tube, beginning on the same day as indomethacin administration. For 13 d, the rats were fed a standard diet, and their weights were monitored daily. After the rats were sacrificed, the intestinal and colonic tissue samples were examined. The macroscopic and microscopic pathology scores were evaluated. The pathologist stained all tissue samples using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling method. Mucosal crypts and apoptotic cells were quantified. The platelet-derived growth factor receptor (PDGFR) α and ß scores assessed by immunohistochemical staining method and tissue and serum tumor necrosis factor (TNF) α levels were determined by enzyme-linked immunosorbent assay. RESULTS: Between days 1 and 13, the rats in the nilotinib and indomethacin groups lost significantly more weight than the controls (-11 g vs +14.14 g, P = 0.013; -30 g vs +14.14 g, P = 0.003). In the small intestinal and colonic tissues, the macroscopic scores were significantly lower in the nilotinib group than in the indomethacin group (1.14 ± 0.38 and 7.29 ± 2.98, P = 0.005; 1.14 ± 0.38 and 7.43 ± 2.64, P = 0.001, respectively), but the values of the nilotinib and indomethacin groups were similar to the control group. In the small intestinal and colonic tissues, the microscopic scores were significantly lower in the nilotinib group than in the indomethacin group (3.43 ± 2.99 and 7.67 ± 3.67, P = 0.043; 2.29 ± 0.76 and 8.80 ± 2.68, P = 0.003, respectively), but the values were similar to the control group. The PDGFR ß scores in the small intestine and colon were significantly lower in the nilotinib group than in the indomethacin group (1.43 ± 0.79 and 2.43 ± 0.54, P = 0.021; 1.57 ± 0.54 and 3 ± 0, P =0.001), and the values were similar to controls. The colonic PDGFR α scores were significantly lower in the nilotinib group than in the indomethacin group (1.71 ± 0.49 and 3 ± 0, P = 0.001). The colonic apoptosis scores were significantly lower in the controls than in the nilotinib group (1.57 ± 1.13 and 4 ± 1.29, P = 0.007). Furthermore, the serum and tissue TNF-α levels were similar between the nilotinib and indomethacin groups. CONCLUSION: In the indomethacin-induced enterocolitis rat model, nilotinib has a positive effect on the macroscopic and microscopic pathologic scores, ensuring considerable mucosal healing. Nilotinib decreases PDGFR α and ß levels and increases the colonic apoptotic scores, but it has no significant effects on weight loss and the TNF-α levels.

Probiotics prevent Hirschsprung's disease-associated enterocolitis: a prospective multicenter randomized controlled trial.

BACKGROUND: Enterocolitis (EC) is the most common and serious postoperative complication of Hirschsprung's disease (HD). Probiotics potentially play a protective role in maintaining intestinal mucosal integrity. Based on the beneficial effects of probiotics, we hypothesized that oral probiotics could decrease the incidence and severity of Hirschsprung's disease-associated enterocolitis (HAEC). METHODS: We conducted a prospective, multicenter, randomized, and controlled trial to assess whether oral probiotics could decrease the incidence and severity of HAEC. HD patients were randomly assigned into the control group and probiotic-treated group. All children in probiotic-treated group were fed with probiotics per day for 4 weeks. In next 3 months, the incidence and severity of HAEC were analyzed. The peripheral blood T lymphocyte subsets and cytokines, including TNF-α, IFN-γ, IL-6, and IL-10, were analyzed by flow cytometry and enzyme immunoassay (EIA). RESULTS: Compared with the control group, the incidence of HAEC in the probiotic-treated group was significantly diminished. The severity of EC was also remarkably decreased. Furthermore, probiotics balanced T lymphocyte subsets. Moreover, pro-inflammatory cytokines TNF-α, IFN-γ, and IL-6 were significantly decreased and anti-inflammatory cytokine IL-10 was notably increased in probiotic-treated group. CONCLUSIONS: Probiotics not only significantly diminished the incidence but also decreased the severity of HAEC. Moreover, our study revealed that probiotics decreased pro-inflammatory cytokine and increased anti-inflammatory cytokine and furthermore balanced T lymphocytes (registered with ClinicalTrials.gov, NCT number: NCT01934959).

Clinical manifestations of food protein-induced enterocolitis syndrome.

PURPOSE OF REVIEW: To raise awareness among healthcare providers about the clinical and laboratory findings in acute and chronic food protein-induced enterocolitis syndrome (FPIES). RECENT FINDINGS: FPIES can be caused by trivial exposure or rare foods. SUMMARY: FPIES is a non-IgE-mediated reaction that usually presents with acute severe repetitive vomiting and diarrhea associated with lethargy, pallor, dehydration, and even hypovolemic shock. Manifestations resolve usually within 24-48 h of elimination of the causative food. In chronic cases, symptoms may include persistent diarrhea, poor weight gain, failure to thrive, and improvement may take several days after the food elimination. In the acute cases, laboratory evaluation may reveal thrombocytosis and neutrophilia, peaking about 6 h postingestion. Depending on the severity, metabolic acidosis and methemoglobinemia may occur. In chronic cases, anemia, hypoalbuminemia and eosinophilia may be seen. Radiologic evaluation or other procedures, such as endoscopy and gastric juice analysis may show nonspecific abnormal findings. The diagnosis is based on clinical manifestations. Further studies looking at the phenotypes of FPIES are needed to identify clinical subtypes, and to understand the predisposing factors for developing FPIES compared with immediate-type, IgE-mediated gastroenteropathies.