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Biomedical subjects

Karel Geboes

Publications and source records attributed to Karel Geboes.

At least 37 records · Page 2Linked to original sources
PubMed2005

Liver receptor homolog 1 contributes to intestinal tumor formation through effects on cell cycle and inflammation.

Liver receptor homolog 1 (LRH-1) is an orphan nuclear receptor that synergizes with beta-catenin/T cell factor 4 signaling to stimulate intestinal crypt cell renewal. We evaluated here the impact of haploinsufficiency of LRH-1 on intestinal tumorigenesis by using two independent mouse models of human colon tumorigenesis. Haploinsufficiency of LRH-1 blunts intestinal tumorigenesis in the ApcMin/+ mice, a genetic model of intestinal cancer. Likewise, Lrh-1+/- mice are protected against the formation of aberrant crypt foci in the colon of mice exposed to the carcinogen azoxymethane. LRH-1 gene expression is reduced in tumors that express elevated levels of the proinflammatory cytokine TNF-alpha. Reciprocally, decreased LRH-1 expression in Lrh-1+/- mice attenuates TNF-alpha expression. Compared with normal human colon, expression and subcellular localization of LRH-1 is significantly altered in neoplastic colon. In combination, these data suggest a role of LRH-1 in the initiation of intestinal tumorigenesis both by affecting cell cycle control as well as through its impact on inflammatory pathways.

Animals↗
PubMed2005

Formation, distribution, and elimination of infliximab and anti-infliximab immune complexes in cynomolgus monkeys.

Infliximab (IFX) is a chimeric IgG1 monoclonal antibody specific for human tumor necrosis factor-alpha that is approved in the United States and Europe for the treatment of rheumatoid arthritis (RA) and Crohn's disease (CD). Approximately 10% of RA and CD patients receiving maintenance treatment with IFX will develop antibodies to IFX. The objective of this study was to develop a model to assess the in vivo formation, distribution, and elimination of immune complexes resulting from a low-level immune response in the presence of the excess concentration of a therapeutic antigen. In this model, cynomolgus monkeys were treated with a single intravenous injection of IFX, followed by injection of either radiolabeled, purified monkey anti-IFX IgG antibody (n = 3, test group) or radiolabeled monkey, nonimmune IgG (n = 3, control group). High-performance liquid chromatography analysis of collected sera revealed a rapid formation of immune complexes comprised of IFX and radiolabeled anti-IFX IgG antibody immune complexes. The terminal half-life of the anti-IFX IgG antibody immune complex was approximately 38 h compared with 86 h for the nonimmune antibody. However, the pharmacokinetic profile of IFX, although slightly lower in concentration over time for the test group, was not notably different relative to the control group. There were no macroscopic or microscopic histological findings in either treatment group. These data confirm that immune complexes between IFX and anti-IFX IgG antibodies can form in vivo and that these immune complexes are eliminated more rapidly than nonimmune antibodies in the presence of excess IFX.

Animals↗
PubMed2005

Pathology of early lower GI cancer.

Early colorectal cancer can be treated with curative resection if the depth of invasion is limited to the submucosa (pathologic T category pT1 in the TNM classification). Macroscopically early colorectal cancer and its precursor lesions present as elevated polyps or non-polypoid flat lesions. Microscopically, precursor lesions are characterized by intraepithelial neoplasia and present as classic adenomas or serrated adenomas. Precursor lesions may already contain foci of early colorectal cancer. Early colorectal cancer can be treated by endoscopic resection. Careful handling of the specimen is required in order to optimally identify the factors that may predict an adverse outcome. Whenever a favourable tumour grade is found, without vascular invasion and tumour budding, there seems to be a low risk for adverse outcome and laparotomy may thus be avoided.

Adenomatous Polyposis Coli↗
PubMed2005

Infliximab induces apoptosis of monocytes and T lymphocytes in a human-mouse chimeric model.

Tumor necrosis factor (TNF) antagonism with monoclonal antibodies is an effective therapy for severe Crohn's disease and rheumatoid arthritis. Recent studies have suggested that induction of apoptosis of inflammatory cells contributes to this therapeutic effect. We investigated whether infliximab (a mouse-human IgG1 chimeric anti-TNF monoclonal antibody) could induce apoptosis in vivo in human-mouse chimeras, created by reconstitution of severe combined immunodeficiency/beige mice with THP-1 (human monocytic cell line) or Jurkat cells (human T cell line). Infliximab treatment of chimeric mice depleted spleen and peritoneum from THP-1 cells and Jurkat cells and decreased production of the human cytokines IL-10 and IL-12 in vivo. Cell death was shown to occur already within 1 h of treatment. Infliximab effects were independent of FcgammaR binding or complement activation. Cell death resulted from apoptosis induction in a caspase-dependent pathway, as evidenced by the in vitro protective effect of the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyketone (Z-VAD-FMK). These data provide support for caspase-dependent apoptosis induction being the mechanism of action of infliximab in vivo.

Animals↗
PubMed2005

Ornidazole for prophylaxis of postoperative Crohn's disease recurrence: a randomized, double-blind, placebo-controlled trial.

BACKGROUND & AIMS: Crohn's disease almost inevitably recurs after ileocolonic resection, and effective prophylactic therapy has not been identified. We investigated the efficacy and safety of ornidazole, a nitroimidazole antibiotic, for the prevention of clinical recurrence of Crohn's disease after curative ileocolonic resection in a placebo-controlled double-blind clinical trial. METHODS: Eighty patients were randomized to ornidazole 1 g/day or placebo started within 1 week of resection and continued for 1 year. The primary end point was the proportion of patients with clinical recurrence at 1 year. Secondary end points were endoscopic recurrence at 3 months and 12 months after resection. RESULTS: Two patients in the ornidazole group withdrew consent and were not dosed. Ornidazole significantly reduced the clinical recurrence rate at 1 year from 15 of 40 (37.5%) patients in the placebo group to 3 of 38 (7.9%) patients in the ornidazole group (Fisher exact test, 8.03; P = .0046; odds ratio, 0.14; 95% confidence interval, 0.037-0.546). Ornidazole reduced endoscopic recurrence at 12 months from 26 of 33 (79%) in the placebo group to 15 of 28 (53.6%) in the ornidazole group (chi2 , 4.37; P = .037; odds ratio, 0.31; 95% confidence interval, 0.10-0.94). Endoscopic recurrence at 3 and 12 months predicted clinical recurrence. Significantly more patients in the ornidazole group dropped out from the study because of side effects (P = .041). CONCLUSIONS: Ornidazole 1 g/day is effective for the prevention of recurrence of Crohn's disease after ileocolonic resection.

Adult↗
PubMed2005

Cytochrome P450 3A4 and P-glycoprotein activity and assimilation of tacrolimus in transplant patients with persistent diarrhea.

Renal transplant recipients suffering from persistent diarrhea have been repeatedly reported to have increased tacrolimus (Tac) trough levels. This study aimed to explore this phenomenon in detail in 15 renal transplant recipients with diarrhea, whose immunosuppression consisted of corticosteroids, mofetil mycophenolate and Tac. Both hepatic and intestinal CYP3A4 and PGP activity, important determinants of Tac bioavailability, were assessed, together with global CYP activity and investigations for gastrointestinal infection, function and morphology. Global CYP, CYP3A4, PGP and trough/dose levels of Tac were compared with diarrhea-free controls. In addition, a pharmacokinetic study of Tac was performed in 11 patients affected by diarrhea versus 9 controls. As expected, diarrhea was associated with increased Tac trough levels. An even stronger, significant increase of dose-normalized Tac levels was observed between 90 and 360 min after Tac intake. Time to peak concentration and drug half-life, however, were not altered. In addition, a concomitant decrease (+/-50%) of intestinal PGP activity was noticed in patients with diarrhea. For global CYP, CYP3A4 and hepatic PGP activity no such differences were noted. This pattern was not influenced by the specific cause of diarrhea. These data strongly suggest that persistent diarrhea is associated with an increased oral bioavailability of Tac.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology.

The discovery of a series of genetic and serological markers associated with disease susceptibility and phenotype in inflammatory bowel disease has led to the prospect of an integrated classification system involving clinical, serological and genetic parameters. The Working Party has reviewed current clinical classification systems in Crohn's disease, ulcerative colitis and indeterminate colitis, and provided recommendations for clinical classification in practice. Progress with respect to integrating serological and genetic markers has been examined in detail, and the implications are discussed. While an integrated system is not proposed for clinical use at present, the introduction of a widely acceptable clinical subclassification is strongly advocated, which would allow detailed correlations among serotype, genotype and clinical phenotype to be examined and confirmed in independent cohorts of patients and, thereby, provide a vital foundation for future work.

Biomarkers↗
PubMed2005

Endoscopic and histologic evidence of persistent mucosal healing and correlation with clinical improvement following sustained infliximab treatment for Crohn's disease.

OBJECTIVES: The long-term effect of infliximab on endoscopic and histologic disease activity and expression of inflammatory markers was assessed in Crohn's disease patients who received infliximab as episodic or scheduled maintenance therapy therapy over 54 weeks (ACCENT 1). METHODS: All patients received Infliximab 5 mg/kg at week 0 and at week 2 were then randomized as responders or nonresponders to placebo or infliximab (5 or 10mg/kg). Patients received placebo or infliximab 5 mg/kg at weeks 2 and 6 followed by placebo or infliximab (5 or 10mg/kg) every 8 weeks or episodically on loss of response. Crohn's Disease Activity Index (CDAI), Crohn's Disease Endoscopic Index of Severity (CDEIS), Inflammatory Bowel Disease Questionnaire (IBDQ), and colonic and ileal Global Histologic Disease Activity (CGHAS and IGHAS) scores were determined at weeks 0, 10, and 54. Tumor necrosis factor-alpha (TNF-alpha), gelatinase B, Infliximab, tenascin, clusters of differentiation marker 68 (CD68), and intercellular adhesion molecule-1 (ICAM-1) were detected in mucosal biopsies by immunohistochemistry. RESULTS: At baseline, CDEIS significantly correlated with CGHAS only. Further at baseline, both CDEIS and the worst CGHAS or IGHAS, were significantly correlated with CD68, ICAM-1, and gelatinase B expression. At week 10, improvement in CGHAS only, correlated significantly with better CDAI, CDEIS, and IBDQ scores. Improvements in CDEIS and GHAS at week 10 correlated with reductions in gelatinase B and CD68, whereas only GHAS improvement correlated with decreased TNF-alpha expression. At week 54, decreased gelatinase B expression continued to correlate with improved CDEIS and GHAS while decreased CD68 and TNF-alpha expression correlated with GHAS and CDEIS improvement, respectively. CONCLUSIONS: Endoscopic and histologic evidence of mucosal healing was associated with a sustained reduction in the expression of inflammatory markers. Infliximab-induced improvement in the clinical signs and symptoms of Crohn's disease was associated with endoscopic and histologic evidence of sustained mucosal healing.

Adult↗
PubMed2005

Is adenocarcinoma of the esophagogastric junction or cardia different from Barrett adenocarcinoma?

Over time the relative distribution of cancers of the proximal digestive tract has changed. Squamous cell carcinomas of the esophagus have become less common, while numbers of adenocarcinomas have greatly increased. This shift most likely reflects an increase in the incidence of gastroesophageal reflux. Moreover, there is a decline in the incidence of distal gastric cancer, which in turn may be related to Heliobacter pylori eradication. Simultaneously, there is a time trend toward a more proximal localization of gastric cancer. If the above-mentioned etiopathologic links are correct, this could indicate that the so-called cardia adenocarcinomas are not related to H pylori infection and that they may instead be related to gastroesophageal reflux and eventually may not be considered to be "gastric" cancers. The rapidly growing quantity of literature on this subject is, however, confounding. A major source of discordance would seem to be a Babylonian confusion of tongues concerning the terms cardia and cardiac carcinomas. Unfortunately, this confusion is also apparent in the classification systems available for staging of cancer, thus closing the "vicious" circle.

Adenocarcinoma↗
PubMed2004

Diagnostic accuracy of ten second-generation (human) tissue transglutaminase antibody assays in celiac disease.

BACKGROUND: Anti-tissue transglutaminase (tTG) assays that use human tTG as antigen have recently become available. We evaluated commercially available assays with human tTG antigen to estimate their diagnostic accuracies and to determine whether they agree sufficiently to be used interchangeably. METHODS: Ten commercially available second-generation anti-tTG assays were evaluated. The following populations were studied: celiac disease (CD) patients at the time of diagnosis without (n = 70) or with (n = 5) IgA deficiency; diseased controls (n = 70); and CD patients without (n = 28) or with (n = 2) IgA deficiency during follow-up. All individuals included in the study underwent intestinal biopsy. Technical performance (linearity, interference, precision, correlation, and agreement) and diagnostic accuracy (sensitivity and specificity) were compared. Anti-gliadin and anti-endomysium antibodies were also measured. RESULTS: IgA anti-tTG results correlated well overall, but numerical values differed. Diagnostic sensitivity ranged between 91% and 97% and specificity between 96% and 100%. These were higher than the sensitivity and specificity of the IgA endomysium assay and the IgA gliadin assay. Generally, IgG anti-tTG was less sensitive but more specific than IgG anti-gliadin for the diagnosis of CD in the small group of IgA-deficient patients. CONCLUSIONS: Overall diagnostic performance of IgA tTG assays is acceptable and comparable among the different assays, but numerical values differ. Standardization is needed.

Adolescent↗
PubMed2004

CXCR1-binding chemokines in inflammatory bowel diseases: down-regulated IL-8/CXCL8 production by leukocytes in Crohn's disease and selective GCP-2/CXCL6 expression in inflamed intestinal tissue.

Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) that are characterized by chronic intestinal inflammation and a constant influx of leukocytes mediated by pro-inflammatory cytokines and chemokines. The intestinal expression of the CXCR1-binding chemokines IL-8/CXCL8 and GCP-2/CXCL6 and the participation of immunocompetent cells in IBD were evaluated. IL-8 production by peripheral blood mononuclear cells (PBMC) from IBD patients, stimulated with endotoxin, plant lectin or double-stranded RNA, was significantly lowered in patients with CD, but not in UC patients or healthy subjects. The reduced chemokine production by PBMC from IBD patients was both IL-8 and CD specific, but not inducer dependent. In serum, most chemokines remained undetectable, while the levels of those that were measurable remained unaltered in IBD patients. GCP-2, but not ENA-78/CXCL5, nor IL-8, were highly expressed by endothelial cells in inflamed intestinal tissue of IBD patients. In contrast, stimulated endothelial cell cultures produced more IL-8 than GCP-2. The selective GCP-2 staining of endothelial cells at sites of ulcerations suggests that GCP-2, despite its low production capacity in vitro, plays a role in IBD that is different from that of structurally (ENA-78) and functionally (IL-8) related ELR(+) CXC chemokines. Thus, the chemokine network shows complementarity rather than redundancy.

Chemokine CXCL6↗
PubMed2004

In vivo activation of gelatinase B/MMP-9 by trypsin in acute pancreatitis is a permissive factor in streptozotocin-induced diabetes.

Matrix metalloproteinases, in particular gelatinase B/MMP-9, are key mediators in autoimmune diseases like multiple sclerosis and rheumatoid arthritis, but their pathogenic roles in diabetes are not well established. Gelatinase B has previously been shown to be upregulated in pancreas tissue from patients with acute and chronic pancreatitis and was suggested to exacerbate diabetes by cleaving insulin. In this study, the role of gelatinase B in diabetes was investigated using two streptozotocin-induced animal models of type I diabetes. In both a hyperacute and a subacute model, gelatinase B upregulation was found to be associated with disease activity. However, gelatinase B deficiency did not significantly protect against diabetes development, and wild-type and gelatinase B-deficient animals behaved similarly in terms of beta-cell apoptosis or necrosis. The fact that gelatinase B was found almost exclusively as the inactive pro-enzyme in most of the streptozotocin-induced diabetic animals may explain the lack of a gelatinase B effect. On the contrary, gelatinase B was completely activated in a minority (15%) of wild-type animals. This coincided with exocrine pancreatic inflammation, as revealed by the presence of active trypsin. The discovery of in vivo activation of progelatinase B by trypsin in acute pancreatitis is extended in a model of caerulein-induced pancreatitis. In the latter model, trypsinogen activation is systematically achieved and gelatinase B is found in its active form. In conclusion, gelatinase B itself is not a causative factor but, when activated by endogenous trypsin, is a permissive factor for insulin degradation and diabetes.

Acute Disease↗
PubMed2004

Chemokines and gelatinases in the aqueous humor of patients with active uveitis.

PURPOSE: To investigate the involvement of the chemokines CXCL10/IP-10, CXCL11/I-TAC, CXCL8/1L-8, CXCL6/GCP-2, CCL3/MIP-1alpha, and CCL18/PARC, and gelatinases A and B in uveitis. DESIGN: Prospective, experimental, case-control study. METHODS: Aqueous humor samples from 30 patients with active uveitis, and 14 control patients and paired serum samples were assayed for chemokines with specific enzyme-linked immunosorbent assays (ELISAs) and for gelatinase levels by quantitative zymography. RESULTS: In control AH, none of the chemokines was detected. Gelatinase A was detected in all samples, and gelatinase B was detected in only one sample. In patients with uveitis, IP-10 was detected in all AH samples, whereas I-TAC, IL-8, GCP-2, MIP-1alpha, and PARC were detected in three, 16, six, two, and 12 samples, respectively. IP-10 levels were significantly higher in AH samples than those of serum (P =.006). Gelatinase A was detected in 29 AH samples and gelatinase B was detected in 26 samples. Gelatinase A levels were significantly higher in AH samples from patients than those of controls (P <.0001). In 11 AH samples, gelatinase B was detected in complex with lipocalin (NGAL). Disease activity correlated significantly with the levels of IP-10 (r =.627; P <.0001), gelatinase A (r =.508; P =.002), gelatinase B (r =.685; P <.0001), and NGAL-gelatinase B complex (r =.595; P <.0001). CONCLUSIONS: These data suggest a pathogenic role of the T lymphocyte chemoattractant IP-10 and gelatinases in the recruitment and activity of T cells into the eye in patients with uveitis and in the pathogenesis of uveitis.

Adolescent↗
PubMed2004

Functional expression of 4-1BB (CD137) in the inflammatory tissue in Crohn's disease.

4-1BB ligand (L) expressed on antigen presenting cells (APC) interacts with 4-1BB, expressed on activated T cells and this interaction costimulates T cells to secrete cytokines and to proliferate. We investigated whether 4-1BB/4-1BBL interactions might be involved in the pathogenesis of Crohn's disease (CD). In immunohistochemistry, we found 4-1BB expression on lamina propria (LP) cells in inflamed and to a lesser extend in non-inflamed gut tissue from CD patients. mRNA levels for 4-1BB were also elevated in intestinal CD tissue. In contrast, only few 4-1BB-expressing cells were found in inflamed tissue from ulcerative colitis (UC) patients and almost no positive cells were found in control intestinal tissue. 4-1BB expression was better sustained on in vitro activated lamina propria T cells from CD patients compared to controls. Finally, agonistic anti-4-1BB antibody enhanced interferon-gamma (IFN-gamma) production and proliferation of lamina propria T cells from CD patients. Taken together, our data suggest that 4-1BB/4-1BBL interactions contribute to the persistence of gut inflammation in CD.

4-1BB Ligand↗
PubMed2004

Overexpression of indoleamine 2,3-dioxygenase in human inflammatory bowel disease.

T-cells are causally involved in the pathogenesis of inflammatory bowel disease (IBD). The tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase (IDO) regulates T-cell proliferation and survival. We show in this report that IDO mRNA is markedly induced in lesional colonic biopsies of IBD patients. IDO is primarily expressed in CD123(+) mononuclear cells infiltrating the submucosal areas of the inflamed lesions. In Crohn's disease (CD), IDO is also strongly expressed in perifollicular regions of lymphoid follicles. Upregulation of IDO is of functional significance, as we detected an increase of kynurenine and of the kynurenine/tryptophan ratio in supernatants from colonic explant cultures (CECs) of CD patients. Immunohistochemistry of colonic biopsies taken from CD patients prior and after treatment with the TNF-blocking antibody Infliximab revealed reduced IDO expression in patients with good clinical response to Infliximab. In summary, high local expression of IDO may represent an anti-inflammatory mechanism tempting to counterbalance the tissue-damaging effects of activated T-cells infiltrating the colonic mucosa in IBD.

Adult↗
PubMed2004

Inhibition of glycolipid biosynthesis by N-(5-adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin protects against the inflammatory response in hapten-induced colitis.

Since glycolipid biosynthesis is potentially involved in immunological and inflammatory responses, we tested the effect of a novel inhibitor of intracellular glycolipid biosynthesis N-(5-adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin (AMP-DNM) in two hapten-induced colitis models: trinitrobenzene sulphonic acid (TNBS)- and oxazolone (4-ethoxymethylene-2phenyl-2oxazoline-5-one; Oxa)-induced colitis. AMP-DNM was given either by intraperitoneal injection or orally via the diet. Mice treated with AMP-DNM had less severe colitis and a more rapid weight recovery, less edema and less wall thickness. Cellular infiltration, goblet cell loss and myeloperoxidase (MPO) activity were reduced in colons of AMP-DNM-treated animals. Intralesional IFN-gamma and IL-18 production were lower in mice of the AMP-DNM-treated groups. Furthermore, AMP-DNM treatment reduced the serum anti-TNBS and anti-Oxa antibody levels. Our findings show that the glycolipid biosynthesis inhibitor AMP-DNM has a strong anti-inflammatory and immune suppressive activity on both TNBS- and Oxa-induced colitis. The data also provide evidence that glycolipid biosynthesis is involved in the inflammatory cascade in these inflammatory bowel disease (IBD) models.

1-Deoxynojirimycin↗