A immunohistologic pilot study was completed which assessed interleukin-6 (IL-6), mast cell infiltrates, and serotonin (5-HT) levels on gastrointestinal tissue biopsies, with degrees of perceived abdominal pain in two groups, inflammatory and non-inflammatory pediatric gastrointestinal (GI) disorders. In comparison to the inflammatory group, the non-inflammatory group was significantly less likely (p=.018) to respond to standard of care treatment as evidenced by higher pain reports. Mast cell number and 5-HT immunoreactivity correlate in GI biopsies from pediatric patients perceived abdominal pain intensity which may contribute to perceived abdominal pain by interacting with neuronal afferents in the gastrointestinal tract. Another pilot study tested the role of substance P and mast cells as immunohistologic biomarkers for chronic abdominal pain in children. Substance P increases colonic propulsive movement and stimulates smooth muscles. Therefore, substance P and mast cells may be involved with the stimulation of the enteric nervous system thereby yielding pain. Mast cells have been recently implicated as potential mediators of interest in both inflammatory and non-inflammatory abdominal pain syndromes. This study compared the expression of the neuropeptide substance P and mast cell numbers in gastrointestinal mucosa in children with chronic abdominal pain with and without evidence of inflammatory gastrointestinal disease. Formalin-fixed paraffin-embedded gastrointestinal biopsy blocks from pain positive patients with pathology confirmed inflammatory bowel disease or recurrent abdominal pain/irritable bowel syndrome, (upper GI =15, lower GI =33) were cut in to 7m sections. Mouse monoclonal antibody SP-DE4-21 (Abcam # ab14184), specific to detect human substance P was utilized. Mast cells were stained via toluidine blue staining and counted as numbers of cells per 40x high powered field for 10 fields then averaged. The sample (n=48) mean age 11.92.9 years, 54.2% were females, 90% Caucasian, comprised of a non-inflammatory (n=26) and inflammatory (n=22) phenotypes. Substance P positive staining was found in 28 patients, expression was found to be increased and multifocal within the gastrointestinal mucosa in patients with chronic abdominal pain with a trend toward increased expression in non-inflammatory female patient biopsies. Identification of biomarkers to help differentiate phenotypes of chronic abdominal pain is needed to improve assessment and develop novel treatments. The aforementioned pilot studies informed and provided justification for a prospective clinical natural history protocol. This Brain-Gut Natural History protocol (approved in January 2009) has to date enrolled 86 participants of which 79 have completed the protocol. There are three measures of intestinal inflammation;fecal calprotectin, intestinal permeability, and serum cytokine IL-6 levels. Intestinal permeability will be measured with the administration of a sugar based test solution which will be given orally to participants after an overnight fast. Excreted urine sugar ratios, expressed per m2 of body surface area, will measure gastrointestinal permeability. Serum IL-6 cytokine levels will be measured via ELISA. Body mass and body fat analysis (plethysmography), intra-abdominal and liver ultrasound, and Fibroscan measures will also be collected. The intestinal permeability test solution was developed and tested and has been administered to 55 participants. The plan for the next fiscal year is to continue to enroll participants during the two year recruitment phase. Additional pilot testing and validation of the biomarkers will be undertaken. The Gastrointestinal Pain Pointer (GIPP) is a technology that has been developed and beta tested, and validated. The GIPP electronically gathers data on participants subjective location, type, and intensity of GI symptoms along with real-time synchronized objective measures of heart rate and blood pressure. The patient uses a graphical interface to choose their gender and body type, record the location and intensity of the GI distress, and selects descriptive words for the GI discomfort. Abdominal pain was assessed in 40 patients using the short-form McGill Pain Questionnaire and the GIPP. Patients were given an intestinal permeability test solution to induce GI discomfort and were monitored for 5 hours following the ingestion of the solution. The sample was 57.5% female;age range 14-45 yrs, (mean = 27.4 7.3). The GIPP discriminated between those persons with and without abdominal pain. Time points were significantly correlated (p<.007) between the McGill and the GIPP;within-sample correlation was .8391 and between-sample correlation was .9739. This study found the GIPP to be a valid and reliable instrument thereby allowing clinicians to have a more integrated resource for pain assessment that includes location, intensity, and quality along with physiologic parameters. Recent findings include genetic expression of inflammatory biomarkers in irritable bowel syndrome (IBS) patients with a history of chronic abdominal pain. IBS patients (n=12) and age-matched healthy controls (n=12) were included. The expression of 96 genes of interest in inflammatory response was then analyzed using a custom quantitative real-time PCR array. CCL-16 gene expression was upregulated by more than 7-fold in IBS when compared to controls. CCL-16 was overexpressed by over 130-fold in IBS-constipation patients compared to both controls and IBS-diarrhea patients. These results further suggest a subclinical inflammatory component underlying IBS. To better understand the phenotypic differences in IBS it is important to broaden the study of these inflammatory and other biomarkers. Additional findings were published regarding symptom distress in other comorbid digestive diseases. The psychometric properties of a patient questionnaire for patients with liver disease co-morbidities was tested, validated, and published.

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