Farnesoid X Receptor (FXR) Activation and FXR Genetic Variation in Inflammatory Bowel Disease

Contains fulltext : 96924.pdf (publisher's version ) (Open Access)BACKGROUND: We previously showed that activation of the bile salt nuclear receptor Farnesoid X Receptor (FXR) protects against intestinal inflammation in mice. Reciprocally, these inflammatory mediators may decrease FXR activation. We investigated whether FXR activation is repressed in the ileum and colon of inflammatory bowel disease (IBD) patients in remission. Additionally, we evaluated whether genetic variation in FXR is associated with IBD. METHODS: mRNA expression of FXR and FXR target gene SHP was determined in ileal and colonic biopsies of patients with Crohn's colitis (n = 15) and ulcerative colitis (UC; n = 12), all in clinical remission, and healthy controls (n = 17). Seven common tagging SNPs and two functional SNPs in FXR were genotyped in 2355 Dutch IBD patients (1162 Crohn's disease (CD) and 1193 UC) and in 853 healthy controls. RESULTS: mRNA expression of SHP in the ileum is reduced in patients with Crohn's colitis but not in patients with UC compared to controls. mRNA expression of villus marker Villin was correlated with FXR and SHP in healthy controls, a correlation that was weaker in UC patients and absent in CD patients. None of the SNPs was associated with IBD, UC or CD, nor with clinical subgroups of CD. CONCLUSIONS: FXR activation in the ileum is decreased in patients with Crohn's colitis. This may be secondary to altered enterohepatic circulation of bile salts or transrepression by inflammatory signals but does not seem to be caused by the studied SNPs in FXR. Increasing FXR activity by synthetic FXR agonists may have benefit in CD patients

MYO9B polymorphisms in multiple sclerosis

"Single-nucleotide polymorphisms (SNPs) in the 30 region of myosin IXB (MYO9B) gene have recently been reported to associate with different inflammatory or autoimmune diseases. We monitored for the association of MYO9B variants to multiple sclerosis (MS) in four Northern European populations. First, 18 SNPs including 6 SNPs with previous evidence for association to immune disorders, were tested in 730 Finnish MS families, but no linkage or family-based association was observed. To ensure the power to detect variants with a modest effect size, we further analyzed 10 variants in 899 Finnish cases and 1325 controls, and in a total of 1521 cases and 1476 controls from Denmark, Norway and Sweden, but found no association. Our results thereby do not support a major function of the tested MYO9B variants in MS. European Journal of Human Genetics (2009) 17, 840-843; doi: 10.1038/ejhg.2008.251; published online 14 January 2009""Single-nucleotide polymorphisms (SNPs) in the 30 region of myosin IXB (MYO9B) gene have recently been reported to associate with different inflammatory or autoimmune diseases. We monitored for the association of MYO9B variants to multiple sclerosis (MS) in four Northern European populations. First, 18 SNPs including 6 SNPs with previous evidence for association to immune disorders, were tested in 730 Finnish MS families, but no linkage or family-based association was observed. To ensure the power to detect variants with a modest effect size, we further analyzed 10 variants in 899 Finnish cases and 1325 controls, and in a total of 1521 cases and 1476 controls from Denmark, Norway and Sweden, but found no association. Our results thereby do not support a major function of the tested MYO9B variants in MS. European Journal of Human Genetics (2009) 17, 840-843; doi: 10.1038/ejhg.2008.251; published online 14 January 2009""Single-nucleotide polymorphisms (SNPs) in the 30 region of myosin IXB (MYO9B) gene have recently been reported to associate with different inflammatory or autoimmune diseases. We monitored for the association of MYO9B variants to multiple sclerosis (MS) in four Northern European populations. First, 18 SNPs including 6 SNPs with previous evidence for association to immune disorders, were tested in 730 Finnish MS families, but no linkage or family-based association was observed. To ensure the power to detect variants with a modest effect size, we further analyzed 10 variants in 899 Finnish cases and 1325 controls, and in a total of 1521 cases and 1476 controls from Denmark, Norway and Sweden, but found no association. Our results thereby do not support a major function of the tested MYO9B variants in MS. European Journal of Human Genetics (2009) 17, 840-843; doi: 10.1038/ejhg.2008.251; published online 14 January 2009"Peer reviewe

Long-term follow-up of two patients with metastatic neuroendocrine tumours treated with octreotide

Two patients are described with metastatic neuroendocrine tumours of the pancreas head and region of Vater. After surgery, administration of the long-acting somatostatin analogue octreotide was started. In the first patient we found an IgG-lambda paraproteinaemia and a parathyroid hormone-related protein (PTHrP) driven hypercalcaemia. By increasing the dose of octreotide the paraproteinaemia disappeared. In the second patient with a metastasized somatostatin producing neuroendocrine tumour, octreotide showed a long-term stabilizing effect on symptoms and progression of disease,The role of octreotide in the induction of changes in biological behaviour of malignant neuroendocrine cells is discussed. (C) 1998 Elsevier Science B.V. All rights reserved

Validation of Risk Factors for Fecal Incontinence in Patients With Crohn's Disease

Background: Fecal incontinence has a great impact on daily life, and many patients are reluctant to report it. Objective: The purpose of this study was to estimate the prevalence of fecal incontinence in patients with Crohn's disease, validate risk factors, and relate outcome with quality of life. Design: The design was cross-sectional. Settings: The study was conducted at an academic tertiary center. Patients: Consecutive patients with Crohn's disease treated between 2003 and 2013 were included in this study. Main Outcome Measures: A questionnaire was sent out in October 2013 to evaluate perianal disease, current symptoms of fecal incontinence, and its impact on quality of life (Fecal Incontinence Quality of Life questionnaire). Risk factors were validated with univariate and multivariate analyses. RESULTS: The questionnaire was responded by 325 (62%) of 528 patients. Median age was 42 years (range, 18-91 y), 215 (66%) were women, and a diagnosis of Crohn's disease was established for a median period of 12 years (interquartile range, 6-21 y). Fecal incontinence was reported by 65 patients (20%). Fecal incontinence was associated with liquid stools (p = 0.0001), previous IBD-related bowel resections (p = 0.001), stricturing behavior of disease (p = 0.02), and perianal disease (p = 0.03). Quality of life (lifestyle, coping, depression, and embarrassment) was poor in patients with fecal incontinence, particularly in patients with more frequent episodes of incontinence. Limitations: There was no correction for disease activity in the multivariate regression analysis. Conclusions: The prevalence of fecal incontinence in a tertiary population with Crohn's disease is substantially higher than in the community-dwelling population. Considering the reduced quality of life in incontinent patients, active questioning to identify fecal incontinence is recommended in those with liquid stools, perianal disease, or previous (intestinal or perianal) surgery

Intravenous citrulline generation test to assess intestinal function in intensive care unit patients

Job HC Peters,1 Nicolette J Wierdsma,2,3 Albertus Beishuizen,4,5 Tom Teerlink,6 Ad A van Bodegraven,3,7 1Department of Gastroenterology and Hepatology, Red Cross Hospital, Beverwijk, 2Department of Nutrition and Dietetics, VU University Medical Center, Amsterdam, 3Department of Gastroenterology, Small Bowel Disease Unit, VU University Medical Center, Amsterdam, 4Department of Intensive Care, VU University Medical Center, Amsterdam, 5Department of Intensive Care, Intensive Care Center, Medisch Spectrum Twente, Enschede, 6Department of Clinical Chemistry, Metabolic Laboratory, VU University Medical Center, Amsterdam, 7Department of Gastroenterology, Geriatrics, Intensive Care and Internal Medicin (Co-MIK), Zuyderland MC, Heerlen-Sittard-Geleen, the Netherlands Background: Assessment of a quantifiable small intestinal function test is cumbersome. Fasting citrulline concentrations have been proposed as a measure of enterocyte function and elaborated into a citrulline generation test (CGT), which is applicable only when glutamine is administered orally. CGT is an oral test, limiting its use, for example, in critically ill patients.Objective: Assessment of normative values and feasibility of an intravenously performed CGT in intensive care unit (ICU) patients with presumed gastrointestinal motility disturbances, especially when performed intravenously.Design: CGT reference values were determined in 16 stable ICU patients using two different CGT methods, namely following either enteral or intravenous glutamine administration and both with simultaneous arterial and venous plasma citrulline sampling at six time-points. Plasma amino acid analysis was performed using reverse-phase high-performance liquid chromatography.Results: The median total generation of citrulline in 90 min (CGT iAUCT90) was markedly higher with arterial citrulline sampling compared with venous citrulline sampling, being 724±585 and 556±418 µmol/L/min for enteral glutamine, respectively (p=0.02) and 977±283 and 769±231 µmol/L/min for intravenous glutamine, respectively (p=0.0004). The median slope (time-dependent increase) for plasma arterial and venous citrulline during the CGT was 0.20±0.16 and 0.18±0.12 µmol/L/min for enteral glutamine, respectively (p=0.004) and 0.22±0.16 and 0.19±0.05 µmol/L/min for intravenous glutamine, respectively (p=0.02). Conclusion: Intravenous glutamine administration combined with arterial plasma citrulline sampling yielded the least variation in CGT characteristics in stable ICU patients. A 2-point measurement test had comparable test characteristics as a 6-point measurement CGT and seems promising. Keywords: citrulline, citrulline generation test, critical illness, enterocyte, intestinal function, intensive care, ICU, glutamine, HPL