Biomedical subjects

Chris J J Mulder

Publications and source records attributed to Chris J J Mulder.

15 recordsLinked to original sources

PubMed2004

The interferon gamma gene in celiac disease: augmented expression correlates with tissue damage but no evidence for genetic susceptibility.

Celiac disease (CD) is a complex genetic disorder characterized by gluten intolerance. The Th1 immune response, with a key position for interferon gamma (IFN-gamma), is an important determinant of intestinal remodeling in CD. We aimed at further ascertaining the role of IFN-gamma, either as a genetic factor in the etiology, or as a facilitator of disease initiation/progression. Duodenal biopsies were sampled across distinct histopathological stages of the disease, including refractory CD (RCD), and used to determine IFN-gamma gene (IFNG) expression by real-time RT-PCR. INFG expression correlated with the extent of tissue restructuring, reaching a 240-fold higher expression in total villous atrophy compared to healthy tissue. CD and RCD patients with similar lesions had comparable expression levels. Interestingly, patients in complete remission still had 7.6-fold residual over-expression. An INFG marker was tested in three cohorts of Dutch patients for both genetic linkage and association. Linkage analysis yielded no significant scores for IFNG or its flanking markers. In addition, IFNG allele frequencies were not differently distributed between cases and controls. Likewise, all alleles were randomly transmitted to affected children in parents-case trios. There is no evidence for IFNG as a predisposing gene in CD, despite its enhanced expression in patients in complete remission.

Adult↗

PubMed2004

CTLA4 +49 A/G and CT60 polymorphisms in Dutch coeliac disease patients.

Coeliac disease is an autoimmune disorder, characterised by villous atrophy of the small intestine, which results from a T-cell-mediated response to gluten-derived peptides. The cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is involved in the regulation of T-cell activation and the CTLA4 +49 A/G polymorphism in exon 1 has been implicated in several autoimmune disorders, including coeliac disease. However, this polymorphism was recently excluded as being the causal variant in Graves' disease, autoimmune hypothyroidism and type I diabetes mellitus. This causal variant was mapped to the 3' region of CTLA4, with the CT60 polymorphism showing the strongest association. The aim of this study was to determine the role of the CTLA4 gene in coeliac disease in the Dutch population. The +49 A/G and CT60 polymorphisms were genotyped in a case-control cohort of 215 patients and controls. The frequency of the +49 G-allele was increased in cases, although not significantly. However, the frequency of the CT60 G-allele was increased with borderline significance in coeliac disease patients (P = 0.048), although the genotype distributions did not show a significant difference between cases and controls. These results indicate the involvement of the CTLA4 gene in coeliac disease development. The haplotype carrying the CT60 G-allele was shown to be associated with lower mRNA levels of the soluble CTLA-4 isoform, providing a possible mechanism for the T-cell-mediated destruction of the small intestine.

Adult↗

PubMed2004

Microscopic colitis.

Microscopic colitis (MC) is viewed as an umbrella term applicable to both lymphocytic and collagenous colitis. The first case was published in 1976, a new entity with chronic watery diarrhea with lymphocytic colitis, with or without a subepithelial collagen deposition. Patients are usually middle-aged women, and the pathogenesis is unknown. The response to steroids and the female predominance underlines an autoimmune disease. Up to 40% NSAID's and Lanzoprazole-induced MC are well-known. Biopsies during sigmoidoscopy in unexplained diarrhea must be standard. Treatment is empirical. The most important step is to ban all NSAID's and other MC inducing agents. Immunosuppressive treatment must be considered. However the disease has a benign course and sometimes is selflimiting.

Colitis↗

PubMed2003

A major non-HLA locus in celiac disease maps to chromosome 19.

BACKGROUND AND AIMS: The pathogenesis of celiac disease is still unknown despite its well-known association with human leukocyte antigen (HLA)-DQ2 and DQ8. It is clear that non-HLA genes contribute to celiac disease development as well, but none of the previous genome-wide screens in celiac disease have resulted in identification of these genes. METHODS: We, therefore, performed a 2-stage, genome-wide screen in 101 affected sibpairs from 82 Dutch families who met strict diagnostic criteria. The small intestinal biopsy samples, on which the original celiac disease diagnoses had been based, showed a Marsh III lesion in all patients on reevaluation by 1 pathologist. For association analysis of markers in regions linked to celiac disease, 216 independent MIII patients and 216 age- and sex-matched controls were available. RESULTS: As expected, highly significant linkage to the HLA-region was detected (multipoint maximum lod score [MMLS] = 8.14). More importantly, significant linkage was also present at 19p13.1 (MMLS = 4.31), with the peak at marker D19S899. Moreover, this marker was also significantly associated with celiac disease in the case-control study (corrected P = 0.016). Furthermore, we identified suggestive linkage to 6q21-22, which is approximately 70 cM downstream from the HLA region (MMLS = 3.10). CONCLUSIONS: Significant linkage of celiac disease to chromosome region 19p13.1 was detected in our genome-wide screen. These results were confirmed by the association of D19S899 to celiac disease in an independent case-control cohort. Furthermore, we identified a possible second celiac disease locus on chromosome region 6q21-22.

Adult↗

PubMed2003

6-Thioguanine seems promising in azathioprine- or 6-mercaptopurine-intolerant inflammatory bowel disease patients: a short-term safety assessment.

OBJECTIVE: 6-Mercaptopurine (6-MP) and azathioprine (AZA) have proven efficacy in the treatment of inflammatory bowel disease (IBD). However, adverse events leading to discontinuation may occur in 10-20% of patients. The efficacy of AZA and 6-MP is based on formation of their active metabolites, the 6-thioguaninenucleotides (6-TGNs). Therefore, 6-thioguanine (6-TG), an agent leading more directly to the formation of 6-TGNs and until recently used only in patients suffering from leukaemia, may be an alternative in AZA or 6-MP intolerance. The purpose of our study was to assess the short-term safety of 6-TG. METHODS: Thirty-two IBD patients with previously established AZA or 6-MP intolerance were treated with 6-TG in doses of 20 mg (n = 19) or 40 mg (n = 13) once daily. Safety parameters were obtained at 0, 1, 2, 4 and 8 weeks after start of medication. Primary outcome measures were the ability to tolerate 6-TG and the occurrence of adverse events. Secondary outcome definitions included laboratory parameters. RESULTS: Twenty-six (81%) patients were able to tolerate 6-TG during the first 8 weeks. In three of six patients, side effects leading to discontinuation were probably (n = 2) or obviously (n = 1) related to 6-TG. No clinically relevant haematological events or hepatotoxicity occurred in the observed period. Steady-state 6-TG levels were significantly higher with 40 mg once daily (1621 +/- 828 picomol/8 x 10(8) red blood cells (RBC)) than with 20 mg once daily (937 +/- 325 picomol/8 x 10(8) RBC; n = 0.001). CONCLUSIONS: 6-TG treatment seems promising in AZA- or 6-MP-intolerant IBD patients. However, long-term safety and efficacy have yet to be determined.

Adult↗

PubMed2003

Autoantibodies and histogenesis of celiac disease.

OBJECTIVE: Autoantibodies are used as markers for celiac disease (CD) identifying patients with mucosal lesions. The purpose of this study was to evaluate the sensitivity and role of the autoantibodies such as IgA antiendomysium (EMA), IgA antigliadin (AGA) and the IgA antitissue transglutaminase (tTGA) in histogenesis of celiac disease. METHODS: Seventy-nine cases including 30 untreated celiacs, 5 celiacs on gluten-free diet (GFD), 41 first degree relatives and 3 non-relatives suspected for CD were investigated. Three untreated celiacs with IgA deficiency were excluded from this study group. IgA antibodies to tTGA were determined by ELISA, as described before. Twelve of 41 relatives and 2 cases of non relatives suspected with positive serology underwent a small intestinal biopsy. Results were correlated with the degrees of abnormality of the intestinal mucosa in patients with CD. Intestinal biopsies obtained from study population were evaluated for histological quantification. RESULTS: Celiacs and suspected cases with positive EMA/AGA and or tTGA showed shorter villi (p < 0.007) and/or a higher number of intraepithelial lymphocytes (IEL) (p < 0.035). The sensitivity of serology (EMA, AGA, tTGA) in patients with Marsh IIIc was 100%. However, in patients with Marsh IIIa the sensitivity for EMA, AGA, and tTGA was 40%, 50% and 20% respectively. CONCLUSIONS: The appearance of antibodies is related to the degree of mucosal infiltration by IELs. Although tTGA, like EMA provide a highly sensitive parameter for the detection of celiacs with severe mucosal damage, it appears to be less sensitive (even less than AGA) in celiac patients with milder histopathological abnormalities. However, it should be recognized that the substantial part of the celiac population present with these milder forms of mucosal abnormalities. Using tTGA as a single test in screening may result in missing up to 60-70% of celiacs with mild mucosal abnormalities. Combination with other screening tests (at least with AGA) is essential and strongly recommended

Adolescent↗

PubMed2003

Intravenous midazolam sedation in pediatric diagnostic upper digestive endoscopy. A prospective study in a general hospital.

The positive role of benzodiazepines (Midazolam) in conscious sedation in pediatric patients is widely known. However, problems concerning the role of sedation in diagnostic upper endoscopy are a matter for debate as little is known about dosage and timing. We prospectively evaluated the efficacy, safety and optimal intravenous sedation dosage of midazolam in 257 consecutive patients, aged 2 months to 18 years old, who underwent upper endoscopy of the gastrointestinal tract. The initial midazolam dosage was 0.2 mg/kg Bw (Body weight) i.v. for 1 minute and, if necessary, another 0.1 mg/kg Bw was administered 5 minutes later. If sedation was sufficient, the procedure would be started 4-5 minutes later; if not, another 0.1 - 0.2 mg/kg Bw would be administered. All procedures were performed by a pediatrician together with a gastroenterologist. No serious complications occurred in any of the procedures. Oxygen saturation (OS) was maintained at over 90%, if necessary with blowby oxygen. Flumazenil was administered to 7 children (OS < 90%). Endoscopy could not be completed in 1 child. All endoscopies were completed within 10 minutes. No unexpected hospital admissions were necessary. The mean midazolam dosage was 0.4 mg/kg Bw in patients up to 6 years, for the over 6 years-olds the mean dosage was decreased to 0,2 mg/kg Bw. Particular attention was paid to the importance of informing patients before the procedure. Endoscopic diagnostic procedures can be performed safely and effectively in children with intravenous sedation in a well equipped pediatric endoscopy unit.

Adolescent↗

PubMed2002

Small intestinal biopsies in celiac disease: duodenal or jejunal?

BACKGROUND: For diagnosis and follow-up of celiac disease, pediatric societies advise that intestinal mucosal specimens should be obtained using suction capsule from the jejunum. This procedure is strenuous for patients, time-consuming, expensive and requires radiographic guidance. Mucosal biopsies from the distal duodenum can be obtained more easily under endoscopic vision using forceps. The aim of the present study was to compare biopsies taken from the duodenal mucosa by forceps and from the jejunal mucosa using suction capsule with respect to histological outcome. METHODS: For this study, 171 paired biopsies were taken from 109 patients (1-75 years) from the distal duodenal mucosa using jumbo forceps and from the jejunal mucosa using Crosby suction capsule. Histological interpretation was performed according to a modified Marsh classification, including partial-, subtotal and total villous atrophy as Marsh IIIA, B, and C. RESULTS: Fourteen suction capsule biopsies were of insufficient quality to be interpreted (8%). All duodenal forceps biopsies produced adequate material for histological scoring. No differences in histological scoring were seen in 145 of 157 compared biopsies (92%). Of 12 biopsies in which a discrepancy was present, 4 showed more severe lesions in the duodenum and 8 more severe lesions in the jejunum. The differences were of clinical significance, i.e., including the presence and absence of villous atrophy in 9 of 157 paired biopsies (6%). CONCLUSION: In the present study, we demonstrated that mucosal specimens taken from the distal duodenal and jejunal mucosa are strongly correlated. Clinically significant discrepancies were present in only 6% of paired biopsies. Therefore we suggest that, in diagnosis and follow-up of celiac disease, mucosal specimens may be taken from the duodenum using forceps to obtain adequate material for histological interpretation.

Adolescent↗

PubMed2002

Celiac sprue.

Explore the source record for details and available documents.

Aged↗

PubMed2002

Octreotide in patients with active ulcerative colitis treated with high dose corticosteroids (OPUS 1).

BACKGROUND: In ulcerative colitis the intestinal somatostatin content is reduced. Somatostatin has several immune-inhibitory effects. In vitro it diminishes activity of intestinal lymphocytes and peripheral blood monocytes. Its long-acting analogue octreotide has beneficial effects on mucosal damage in acute experimental acetic acid colitis in rats. AIMS: To determine the potential benefits of octreotide as a treatment for patients with severe ulcerative colitis treated with high dose corticosteroids. PATIENTS: Forty-two patients with severe ulcerative colitis (more than 10 points on the Powell-Tuck scoring system and mucosal disease Heatly grade III or IV). METHODS: In a multi-centre, double blind, placebo-controlled trial all patients were treated with oral 5-ASA (1.6-2.4 g daily) and high dose corticosteroids (tapering off from 60 to 80 mg daily). They were randomly assigned to receive subcutaneous placebo (n = 22) or octreotide 500 microg (n = 20) thrice daily during 21 days. Clinical and endoscopic disease activity, histology and laboratory parameters were obtained during the study period. RESULTS: Clinical disease activity for both octreotide and placebo were not significantly different at baseline and after 21 days of treatment. Endoscopic disease activities (mean +/- SD) changed from 12.5 +/- 4.7 to 7.2 +/- 5.3 for octreotide, and from 11.5 +/- 5.0 to 5.0 +/- 3.4 for placebo (NS). Seven patients from both groups received additional treatment (colectomy (n = 6), cyclosporin (n = 1)). Adverse events occurred equally in both groups. CONCLUSIONS: Subcutaneous administration of octreotide 500 microg thrice daily is not of additional benefit as adjuvant therapy to high dose corticosteroids in severe ulcerative colitis.

Adult↗

PubMed2002

Histologic follow-up of people with celiac disease on a gluten-free diet: slow and incomplete recovery.

To assess histologic recovery in response to gluten withdrawal in celiac disease, 158 patients seen in our hospital during a 15-year period underwent follow-up small intestine biopsies (SIBs) within 2 years after starting a gluten-free diet; further SIBs were done if villous atrophy was present. A modified Marsh classification was used (IIIA, partial villous atrophy; IIIB, subtotal villous atrophy; IIIC, total villous atrophy). Of patients with Marsh IIIA, IIIB, or IIIC lesions, histologic remission was seen in 65.0% within 2 years, 85.3% within 5 years, and 89.9% in long-term follow-up. Eleven patients (7.0%) with persisting (partial) villous atrophy had symptoms and signs of malabsorption and were considered to have refractory celiac disease; 5 of them developed an enteropathy-associated T-cell lymphoma. Children recovered up to 95% within 2 years and 100% in the long-term. Histologic recovery in celiac disease after starting a gluten-free diet takes time and is incomplete or absent in a substantial subgroup of patients (10.1% villous atrophy after 5 years). Systematic follow-up of patients with celiac disease and the malabsorption syndrome and secondary complications is needed.

Adolescent↗

PubMed2002

Coeliac disease: more than villous atrophy.

A continuing flow of new scientific developments concerning coeliac disease in the last decade asks for the formulation of a new concept of pathophysiology and clinical approach of the coeliac condition. Immunogenetic studies have shown a correlation of the disease to the HLA region on the short arm of chromosome 6. Immunological research has led to the concept of a T-cell driven immunologic response of the small intestine, with the identification of highly sensitive and specific antibodies, and in addition the understanding of the histopathology of coeliac disease has changed dramatically, initiated by the proposition of a spectrum of gluten sensitive enteropathy by Marsh in 1992. Clinical studies report a significant change in patient characteristics and epidemiology. The incidence of the disease has shifted to a majority of adult coeliacs and the disease may present with less severe symptoms of malabsorption while screening studies suggest an overall prevalence of up to 1 in 200-300. In the present paper (an update on histopathology) we specifically describe the work of our group in Arnhem, concerning the identification and validation of the spectrum of intestinal histopathology in gluten sensitive enteropathy, i.e. lymphocytic enteritis (Marsh I lesion), lymphocytic enteritis with crypthyperplasia (Marsh II lesion), and villous atrophy, subdivided in partial villous atrophy (Marsh IIIA), subtotal villous atrophy (Marsh IIIB) and total villous atrophy (Marsh IIIC). Special attention is given to a subgroup of "refractory coeliacs", including the identification of (pre-) malignant aberrant T-cells in the intestinal mucosa of these patients. The new data on immunogenetics, epidemiology, histo-pathology and patient characteristics point to a significant change of views on coeliac disease.

Adult↗

PubMed2002

Coeliac disease--has the time come for routine mass screening? In 2002--2010--2020?

It might be clinically relevant to have a very low threshold when screening for coeliac disease. The question is how low? In countries familiar with coeliac disease, the classic pattern of severe malabsorption and cachexia, as described in textbooks, has become rare. Coeliac disease is not born in the minds of doctors diagnosing dyspepsia and/or irritable bowel syndrome, or associated auto-immune diseases, such as thyroid, diabetes mellitus type I, Sjögren's disease etc. The consequence is a delay in diagnosis, with secondary problems as long term autoimmune stimulation, osteoporosis and secondary malignancies. Enteropathy associated T-cell lymphomas are well known, but considering coeliac disease in T-cell lymphomas outside the gastrointestinal tract is not yet common sense. Large-scale screening studies on coeliac disease have been published and suggest a prevalence of coeliac disease in USA, Europe, Middle-East and Australia of about 1:200. Coeliac disease can be classified due to all these studies as an important health problem. However nation-wide screening programmes have not started yet, which are common for phenylketonuria and other metabolic defects. Probably they will be initiated as pilot-studies in national programmes within 10 years at the age of 2, and due to the bimodal distribution in CD with a later peak in the fourth decade, at 40 years. Additional data about cohorts of certain age groups are mandatory (f.i. 40 and/or 60 years), while initial discussions begin with national health authorities.

Celiac Disease↗

PubMedDate not supplied

Single-dose brachytherapy versus metal stent placement for the palliation of dysphagia from oesophageal cancer: multicentre randomised trial.

BACKGROUND: Both single-dose brachytherapy and self-expanding metal stent placement are commonly used for palliation of oesophageal obstruction due to inoperable cancer, but their relative merits are unknown. We undertook a randomised trial to compare the outcomes of brachytherapy and stent placement in patients with oesophageal cancer. METHODS: Nine hospitals in the Netherlands participated in our study. Between December, 1999, and June, 2002, 209 patients with dysphagia from inoperable carcinoma of the oesophagus or oesophagogastric junction were randomly assigned to stent placement (n=108) or single-dose (12 Gy) brachytherapy (n=101), and were followed up after treatment. Primary outcome was relief of dysphagia during follow-up, and secondary outcomes were complications, treatment for persistent or recurrent dysphagia, health-related quality of life, and costs. Analysis was by intention to treat. FINDINGS: Nine patients (six [brachytherapy] vs three [stent placement]) did not receive their allocated treatments. None was lost to follow-up. Dysphagia improved more rapidly after stent placement than after brachytherapy, but long-term relief of dysphagia was better after brachytherapy. Stent placement had more complications than brachytherapy (36 [33%] of 108 vs 21 [21%] of 101; p=0.02), which was mainly due to an increased incidence of late haemorrhage (14 [13%] of 108 vs five [5%] of 101; p=0.05). Groups did not differ for persistent or recurrent dysphagia (p=0.81), or for median survival (p=0.23). Quality-of-life scores were in favour of brachytherapy compared with stent placement. Total medical costs were also much the same for stent placement (8215) and brachytherapy (8135). INTERPRETATION: Despite slow improvement, single-dose brachytherapy gave better long-term relief of dysphagia than metal stent placement. Since brachytherapy was also associated with fewer complications than stent placement, we recommend it as the primary treatment for palliation of dysphagia from oesophageal cancer.

Aged↗

PubMedDate not supplied

Plugged-percutaneous liver biopsy in patients with impaired coagulation and ascites.

In liver cirrhosis coagulation is impaired due to decreased synthesis of vitamin K-dependent and vitamin K-independent coagulation factors. In such patients routine liver biopsy is contraindicated due to the increased risk of bleeding. Treatment with recombinant factor VIIa or fresh frozen plasma reduces the complication rate of liver biopsy, but both have disadvantages. In this observational study, we evaluated the safety and efficacy of plugged-percutaneous liver biopsy in 36 patients with ascites (n = 9), impaired coagulation (n = 22), or both (n = 5) due to severe chronic liver disease. Among patients with clotting disorders, mean prothrombin time was 16.3 s (range 11.4-20.3) and the mean platelet count was 53 x 10(9)/l (range 19-153). Plugged-percutaneous liver biopsy was in none of the cases associated with bleeding complications (95% confidence interval 0-0.097). All biopsies were adequate for histological interpretation and therefore diagnostically successful. In our experience, plugged-percutaneous liver biopsy seems a safe and reliable method in patients with chronic liver disease associated with impaired coagulation and/or ascites needing histological evaluation.

Adult↗