This investigation was conducted to establish whether guinea-pig trinitrobenzene sulfonic acid (TNBS)-colitis was associated with a change in the number of neurones of the myenteric plexus, and, if so, whether select subpopulations of neurones were affected. Total neurones were quantified with human (Hu) antiserum, and subpopulations were evaluated with antisera directed against choline acetyltransferase, nitric oxide synthase, calretinin, neuronal nuclear protein or vasoactive intestinal peptide (VIP). Colitis was associated with a loss of 20% of the myenteric neurones, most of which occurred during the first 12 h past-TNBS administration. During this period, myenteric ganglia were infiltrated with neutrophils while lymphocytes appeared at a later time-point. The neuronal loss persisted at a 56-day time-point, when inflammation had resolved. The decrease in myenteric neurones was not associated with a decrease in any given subpopulation of neurones, but the proportion of VIP-immunoreactive neurones increased 6 days following TNBS administration and returned to the control range at the 56 days. These findings indicate that there is an indiscriminant loss of myenteric neurones that occurs during the onset of TNBS-colitis, and the loss of neurones may be associated with the appearance of neutrophils in the region.
Foley KF, Pantano C, Ciolino A, Mawe GM. IFN-␥ and TNF-␣ decrease serotonin transporter function and expression in Caco2 cells. Am J Physiol Gastrointest Liver Physiol 292: G779 -G784, 2007. First published December 14, 2006; doi:10.1152/ajpgi.00470.2006.-Recent studies have shown that mucosal serotonin (5-HT) transporter (SERT) expression is decreased in animal models of colitis, as well as in the colonic mucosa of humans with ulcerative colitis and irritable bowel syndrome. Altered SERT function or expression may underlie the altered motility, secretion, and sensation seen in these inflammatory gut disorders. In an effort to elucidate possible mediators of SERT downregulation, we treated cultured colonic epithelial cells (Caco2) with conditioned medium from activated human lymphocytes. Application of the conditioned medium caused a decrease in fluoxetine-sensitive [3 H]5-HT uptake. Individual proinflammatory agents were then tested for their ability to affect uptake. Cells were treated for 48 or 72 h with PGE2 (10 M), IFN-␥ (500 ng/ml), TNF-␣ (50 ng/ml), IL-12 (50 ng/ml), or the nitric oxide-releasing agent S-nitrosoglutathione (GSNO; 100 M).[ 3 H]5-HT uptake was then measured. Neither PGE nor IL-12 had any effect on [ 3 H]5-HT uptake, and GSNO increased uptake. However, after 3-day incubation, both TNF-␣ and IFN-␥ elicited significant decreases in SERT function. Neither TNF-␣ nor IFN-␥ were cytotoxic when used for this period of time and at these concentrations. These two cytokines also induced decreases in SERT mRNA and protein levels. By altering SERT expression, TNF-␣ and IFN-␥ could contribute to the altered motility and expression seen in vivo in ulcerative colitis or irritable bowel syndrome.SERT; tumor necrosis factor; interferon; colitis; inflammatory bowel disease; inflammation SEROTONIN (5-hydroxytryptamine; 5-HT) is the main monoamine signaling molecule in the gut, where it acts as a paracrine neurotransmitter (9, 25). Specialized enteroendocrine cells, enterochromaffin cells, release 5-HT into the lamina propria of the intestines, where it activates receptors located on processes of intrinsic and extrinsic primary afferent neurons. This leads to activation of local motor and secretory reflexes and the transduction of sensory signals to the brain stem and spinal cord. A critical aspect of paracrine and neurotransmitter signaling is the termination of transmission by degradation or removal of the signaling molecule. In the case of 5-HT, this involves rapid clearance of 5-HT from the intercellular space by the 5-HT reuptake transporter (SERT), which is expressed by mucosal epithelial cells (7,21,36).SERT is a member of the highly conserved Na ϩ /Cl Ϫ -dependent transporter gene family containing 12 transmembrane domains (2). Transporters for 5-HT and other monoamines are of particular interest because they are sites of action for most clinically efficacious antidepressants, as well as for psychoactive drugs of abuse such as amphetamines, cocaine, and MDMA (ecstasy). Furthermore, abnormal expression o...
TEC has significant antitumor activity and is well tolerated in patients with progressive androgen-independent prostate cancer.
OBJECTIVES-Changes in mucosal serotonin (5-HT) signaling have been detected in a number of functional and inflammatory disorders of the gastrointestinal tract. This study was undertaken to determine whether chronic constipation (CC) is associated with disordered 5-HT signaling and to evaluate whether constipation caused by opiate use causes such changes.METHODS-Human rectal biopsy samples were obtained from healthy volunteers, individuals with idiopathic CC, and individuals taking opiate medication with or without constipation. EC cells were identified by 5-HT immunohistochemistry. 5-HT content and 5-HT release levels were determined Correspondence: Gary M. Mawe, Ph.D., D403A Given Building, Department of Anatomy and Neurobiology, University of Vermont, Burlington, VT, USA 05405, (802) 656-8257 (phone), (802) 656-8704 (fax), gary.mawe@uvm.edu. * MMC and MDC contributed equally to this work, with MMC concentrating primarily on the chronic constipation arm of the study and MDC working primarily on the opiate constipation experiments. Conflict of interest items 1. Guarantor of the manuscriptGary M. Mawe, PhD 2. Roles of each author Meagan M Costedio: patient screening, obtaining consent, tissue acquisition, tissue processing, data analysis, and manuscript preparation and editing Matthew D Coates: patient screening, obtaining consent, tissue acquisition, tissue processing, data analysis, and manuscript preparation and editing Elice M Brooks: tissue acquisition, data acquisition, and data analysis Lisa M Glass: data acquisition, and data analysis. Eric K Ganguly: aided in conception of the project, acquiring IRB approval, obtaining informed consent, and tissue acquisition. Hagen Blaszyk: evaluation of sections and blind scoring of inflammation levels in the chronic constipation component of the study Allison L. Ciolino: evaluation of sections and blind scoring of inflammation levels in the opiate constipation component of the study Michael J Wood: involved in obtaining informed consent, and tissue acquisition. Doris Strader: involved in obtaining informed consent, and tissue acquisition. Neil H Hyman: involved in study conceptualization, planning, and identifying potential candidates for the chronic constipation component of the study. Peter L Moses: involved in study conceptualization, planning, obtaining informed consent, and tissue acquisition, data analysis, and manuscript preparation and editing Gary M Mawe: involved in study conceptualization, planning, data analysis, and manuscript preparation and editing. All authors reviewed and approved the manuscript prior to submission. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript by enzyme immunoassay, and mRNA levels for the synthetic enzyme, tryptophan hydroxylase 1 (TpH1) and the serotonin transporter (SERT) were assessed by quantitative real-time RT-PCR.RESULTS-CC was associated with increases in TpH1 transcript, 5-HT content, and 5-HT release under basal and stimulated conditions, whereas EC cell numbers and SERT transcript leve...
Fluorescent in situ hybridization has become an essential tool for diagnosing and monitoring hematological disease. Testing for minimal residual disease requires precise and accurate normal cut-offs. There is no consensus in the field on the correct method of establishing a normal reference range. We discuss and compare several proposed statistical methods to calculate normal reference ranges, including Gaussian statistics, the beta inverse function, and a binomial treatment of the data. We demonstrate that a binomial treatment of the data is an accurate and simple method to calculate a normal reference range.
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