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    Gut 11/2013;
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    ABSTRACT: The use of patient reported outcome measures to support routine inflammatory bowel disease (IBD) care is not widespread and suggests that existing questionnaires lack relevance to day-to-day decisions or are too cumbersome to administer. We developed a simple, generic tool for capturing disease control from the patient's perspective to address these barriers. Development based on literature review, patient focus groups/interviews and a steering group, defining a limited set of generic questions. The 'IBD-Control' questionnaire comprises 13 items plus a visual analogue scale (VAS) (0-100). Prospective validation involved baseline completion of IBD-Control, quality of life (QoL) questionnaire (UK-IBD-Q), EuroQol (EQ-5D), Hospital Anxiety and Depression Score; and clinician assessment (blinded to questionnaire; recording Harvey-Bradshaw Index or Simple Clinical Colitis Activity Index; Global Clinician Rating; treatment outcome). 299 patients returned baseline surveys (Crohn's disease, n=160; ulcerative colitis, n=139) and 138 attended for repeat visits. Completion time (mean; SD): 1 min 15 s; 25 s; Internal consistency: Cronbach's α for all 13 items (0.85); for subgroup of eight questions ('IBD-Control-8'; 0.86). Strong correlation between IBD-Control-8 and IBD-Control-VAS (r=0.81). Test-retest reliability (2 week repeat): intra-class correlation=0.97 for IBD-Control-8 and 0.96 for IBD-Control-VAS. Construct validity: Moderate-to-strong correlations between IBD-Control-8 and IBD-Control-VAS versus activity indices, UK-IBD-Q and EQ-5D (utility) with r values 0.52-0.86. Discriminant validity (mean instrument scores for remission, mild, moderate or severe): p<0.001 (analysis of variance (ANOVA)). Sensitivity to change: Effect sizes: 0.76-1.44. The IBD-Control is a rapid, reliable, valid and sensitive instrument for measuring overall disease control from the patient's perspective. Unlike existing patient reported outcome measures, its simplicity, ease-of-use and generic applicability make it a candidate for supporting routine care.
    Gut 10/2013;
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    ABSTRACT: Nutrient delivery to the gut activates neuroendocrine mechanisms that control digestion and energy intake and utilisation. These include the release from enteroendocrine cells of mediators including 5HT, CCK, GLP-1, PYY and ghrelin that act on vagal afferent neurons regulating food intake and autonomic reflexes controlling motility, secretion, inflammatory responses and mucosal defence. The mediators may act locally on vagal afferent fibres running close to their cell of origin, or distally after delivery in the circulation. Recent work indicates that the signalling mechanisms are strongly influenced by nutrient status. Thus, both food withdrawal and diet-induced obesity alter the sensitivity of vagal afferent neurons to stimulation as well as their patterns of expression of receptors and neuropeptide transmitters. Normally, leptin potentiates vagal afferent stimulation by CCK but this is lost in obesity. Recent studies suggest changes in the gut microbiota in obesity lead to increased LPS which suppresses leptin effects on vagal afferent neurons. There are obvious limitations to direct studies of vagal afferent signalling in man but recent work indicates fMRI brain imaging of CNS responses to CCK and ghrelin is feasible, informative and provides opportunities for future progress in human studies of gut-brain signalling.
    Current Opinion in Pharmacology 09/2013;
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    ABSTRACT: Colorectal cancer (CRC) is the fourth most common cause of cancer-related death worldwide. Accurate non-invasive screening for CRC would greatly enhance a population's health. Adenomatous polyposis coli (Apc) gene mutations commonly occur in human colorectal adenomas and carcinomas, leading to Wnt signalling pathway activation. Acute conditional transgenic deletion of Apc in murine intestinal epithelium (AhCre(+)Apc(fl/fl)) causes phenotypic changes similar to those found during colorectal tumourigenesis. This study comprised a proteomic analysis of murine small intestinal epithelial cells following acute Apc deletion to identify proteins that show altered expression during human colorectal carcinogenesis, thus identifying proteins that may prove clinically useful as blood/serum biomarkers of colorectal neoplasia. Eighty-one proteins showed significantly increased expression following iTRAQ analysis, and validation of nine of these by Ingenuity Pathaway Analysis showed they could be detected in blood or serum. Expression was assessed in AhCre(+)Apc(fl/fl) small intestinal epithelium by immunohistochemistry, western blot and quantitative real-time PCR; increased nucelolin concentrations were also detected in the serum of AhCre(+)Apc(fl/fl) and Apc(Min/+) mice by ELISA. Six proteins;heat shock 60kDa protein 1, Nucleolin, Prohibitin, Cytokeratin 18, Ribosomal protein L6 and DEAD (Asp-Glu-Ala-Asp) box polypeptide 5,were selected for further investigation. Increasedexpression of 4 of thesewas confirmed in human CRC by qPCR. In conclusion, several novel candidate biomarkers have been identified from analysis of transgenic mice in which the Apc gene was deleted in the intestinal epithelium that also showed increased expression in human CRC. Some of these warrant further investigation as potential serum-based biomarkers of human CRC.
    Biochemical and Biophysical Research Communications 08/2013;
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    ABSTRACT: The classical nuclear factor-kappaB (NF-κB) signaling pathway has been shown to be important in a number of models of inflammation-associated cancer. In a mouse model of Helicobacter-induced gastric cancer, impairment of classical NF-κB signaling in the gastric epithelium led to the development of increased preneoplastic pathology, however the role of specific NF-κB proteins in Helicobacter-associated gastric cancer development remains poorly understood. To investigate this C57BL/6, Nfkb1(-/-), Nfkb2(-/-) and c-Rel(-/-) mice were infected with Helicobacter felis for 6 weeks or 12 months. Bacterial colonization, gastric atrophy and preneoplastic changes were assessed histologically and cytokine expression was assessed by qPCR. Nfkb1(-/-) mice developed spontaneous gastric atrophy when maintained for 12 months in conventional animal house conditions. They also developed more pronounced gastric atrophy after short-term H. felis colonization with a similar extent of preneoplasia to wild-type (WT) mice after 12 months. c-Rel(-/-) mice developed a similar degree of gastric atrophy to WT mice; 3 of 6 of these animals also developed lymphoproliferative lesions after 12 months of infection. Nfkb2(-/-) mice developed minimal gastric epithelial pathology even 12 months after H. felis infection. These findings demonstrate that NF-κB1- and NF-κB2-mediated signaling pathways differentially regulate the epithelial consequences of H. felis infection in the stomach, while c-Rel-mediated signaling also appears to modulate the risk of lymphomagenesis in gastric mucosa-associated lymphoid tissue.Oncogene advance online publication, 26 August 2013; doi:10.1038/onc.2013.334.
    Oncogene 08/2013;
  • Gut 08/2013;
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    ABSTRACT: BACKGROUND & AIMS:: Many colon cancers produce the hormone progastrin, which signals via autocrine and paracrine pathways to promote tumor growth. Transgenic mice that produce high circulating levels of progastrin (hGAS) have increased proliferation of colonic epithelial cells and are more susceptible to colon carcinogenesis than control mice. We investigated whether progastrin affects signaling between colonic epithelial and myofibroblast compartments to regulate tissue homeostasis and cancer susceptibility. METHODS:: Colonic myofibroblast numbers were assessed in hGAS and C57BL/6 mice by immunohistochemistry. Human CCD18Co myofibroblasts were incubated with recombinant human progastrin (rhPG)(1-80) for 18 hours and proliferation was assessed in the presence of pharmacologic inhibitors. The proliferation of human HT29 colonic epithelial cells was assessed following addition of conditioned media from CCD18Co cells incubated with progastrin. The effects of the insulin-like growth factor (IGF)1 receptor antagonist AG1024 were investigated in cultured HT29 cells and on the colonic epithelium of hGAS mice, compared with mice that did not express transgenic progastrin (controls). RESULTS:: The colonic mucosa of hGAS mice contained greater numbers of myofibroblasts that expressed α-smooth muscle actin and vimentin than controls. Incubation of CCD18Co myofibroblasts with 0.1 nM rhPG(1-80) increased their proliferation, which required activation of protein kinase C and phosphatidylinositol-3 kinase. CCD18Co cells secreted IGF2 in response to rhPG(1-80), and conditioned media from CCD18Co cells that had been incubated with rhPG(1-80) increased the proliferation of HT29 cells. The colonic epithelial phenotype of hGAS mice (crypt hyperplasia, increased proliferation, and altered proportions of goblet and enteroendocrine cells) was inhibited by AG1024. CONCLUSIONS:: Progastrin stimulates colonic myofibroblasts to release IGF2, which increases proliferation of colonic epithelial cells. Progastrin might therefore alter colonic epithelial cells via indirect mechanisms to promote neoplasia.
    Gastroenterology 03/2013;
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    ABSTRACT: The levels of compounds in exhaled mouth air do not necessarily reflect levels in the systemic circulation as bacteria can bio-transform substrates to produce compounds within the mouth. This should be of concern to researchers measuring breath volatiles with the aim of diagnosing systemic or metabolic conditions as very little is known about the origin of many compounds detected on the breath. This pilot study investigated the production of volatile compounds by bacterial communities present within the mouth. Solid-phase micro-extraction was used to extract volatiles from the headspace gas of two Gram-positive and two Gram-negative bacterial cultures known to be present within the mouth and from tongue biofilm microflora. Analyses were undertaken using gas chromatography mass spectrometry. Between 64 and 82 volatile compounds were detected from sampling the headspace gas above each of the cultures. Gram-negative anaerobes were found to produce more volatile sulfur compounds (VSCs) and amines. Solobacterium moorei, a Gram-positive species was however found to produce higher levels of acids, hydrocarbons, alcohols and aldehydes than the other species studied. Tongue-scrape biofilm systems at lower pH gave more hydrocarbons, ketones and fatty acids whilst at higher pH more alcohols, aldehydes, VSCs and amines were detected in the headspace. The results show that a number of compounds detected in mouth breath are produced by anaerobic bacteria in tongue biofilms. Thus, the contribution of volatiles from oral anaerobes cannot be ignored and more research is required to identify the major source of breath compounds as this will help determine their clinical significance as indicators of systemic disease or metabolic disorders in the body.
    Journal of Breath Research 03/2013; 7(1):017114.
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    ABSTRACT: PURPOSE: Cytokines such as IL-6 and G-CSF are important metastasis promoters. This study has investigated the functional significance of the increased circulation of galectin-3, a common feature in cancer patients and in particular those with metastasis, on cytokine secretion from the blood vascular endothelium in cancer. EXPERIMENTAL DESIGN: The effects of galectin-3 on secretion of cytokines from human microvascular lung endothelial cells were assessed in vitro by cytokine array and in vivo in mice. The consequences of galectin-3-induced cytokine secretion on endothelial cell behaviours were determined and the relationship between the levels of circulating galectin-3 and cytokines in colorectal cancer patients with and without metastasis was investigated. RESULTS: Galectin-3 at pathological concentrations found in cancer patients induces secretion of IL-6, G-CSF, sICAM-1 and GM-CSF from blood vascular endothelial cells in vitro and in mice. These cytokines autocrinely/paracrinely interact with the vascular endothelium to increase the expressions of endothelial cell surface adhesion molecules integrinαvβ1, E-selectin, ICAM-1 and VCAM-1, resulting in increased cancer cell-endothelial adhesion and increased endothelial cell migration and tubule formation. In patients with metastatic colon cancer, higher serum galectin-3 levels correlated significantly with increased serum G-CSF, IL-6 and sICAM1 concentrations. CONCLUSIONS: The increased circulation of galectin-3 in cancer patients induces secretion of several metastasis-promoting cytokines from the blood vascular endothelium that enhances endothelial cell activities in metastasis. Targeting the actions of circulating galectin-3 in cancer patients therefore represents a promising therapeutic strategy to reduce metastasis and improve survival.
    Clinical Cancer Research 02/2013;
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    ABSTRACT: Crohn's disease (CD) incidence has increased over the past fifty years but the explanation is unclear. CD can be brought into remission by liquid enteral feeding, but the mechanism for this response is unknown. We suggest that consumption of emulsifiers in processed foods may promote CD by increasing bacterial translocation. This is supported by evidence that (i) geographical variation in CD correlates with emulsifier consumption as does the increasing incidence of CD in Japan; (ii) although CD incidence also correlates with fat consumption, the response to enteral feeding is not affected by the fat content of the feed and (iii) very small concentrations of the emulsifier polysorbate 80 enhance bacterial translocation across intestinal epithelia. Undigested emulsifiers may increase bacterial translocation, particularly in the small intestine where the mucus layer is discontinuous. The hypothesis should be testable by trials of enteral feeding with/without emulsifiers.
    Journal of Crohn s and Colitis 01/2013;
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