Clinical epidemiology--how important now?
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Evidence-Based Medicine↗
Biomedical subjects
V Binder
Publications and source records attributed to V Binder.
Intestinal and extra-intestinal cancer in Crohn's disease: follow-up of a population-based cohort in Copenhagen County, Denmark.
AIM: To determine the long-term risk of intestinal and extra-intestinal malignancies in Crohn's disease patients in Copenhagen County, Denmark. METHODS: In Copenhagen County, a strictly population-based cohort of 374 patients with Crohn's disease diagnosed between 1962 and 1987 was followed until 1997 in order to determine the long-term risk of intestinal and extra-intestinal malignancies. Information on cancer occurrence was provided by the Danish National Cancer Registry and confirmed by the examination of hospital files. The observed number of cases was compared with the expected number, calculated from individually computed person-years at risk and 1995 cancer incidence rates for the background population. RESULTS: The risk of small bowel adenocarcinoma was significantly increased, independent of age and gender (standardized morbidity ratio, 66.7; 95% confidence interval, 18.1-170.7). The risk of colorectal cancer was not increased, either in the total group of patients or in patients with colonic Crohn's disease exclusively (standardized morbidity ratio, 1.64; 95% confidence interval, 0.20-5.92). Extra-intestinal cancer did not occur more frequently than expected. CONCLUSIONS: This population-based study of patients with Crohn's disease revealed no increase in colorectal cancer risk, possibly due to maintenance treatment with 5-aminosalicylic acid preparations and surgery in treatment failure. In contrast, the risk of small bowel cancer was increased more than 60-fold, but the numbers were small. The risk of extra-intestinal cancer was not increased and no lymphomas were observed.
Adenocarcinoma↗
Screening for dysplasia and TP53 mutations in closed rectal stumps of patients with ulcerative colitis or Crohn disease.
BACKGROUND: Patients who undergo colectomy due to intractable chronic inflammatory bowel disease (IBD) may keep a closed rectal stump for several years, which may be at increased risk of malignant transformation owing to residual inflammatory activity. We examined a hospital series of patients with ulcerative colitis or Crohn colitis to describe the clinical, endoscopical and histological features of the closed rectal stump and to screen for dysplasia and mutations in the TP53 tumour suppressor gene. METHODS: During rigid proctoscopy, rectal mucosal biopsy specimens and rectal lavage fluid were collected from 42 patients. Biopsy specimens were examined histologically, and genomic DNA extracted from frozen biopsies and lavage fluid was analysed for mutations in TP53 exons 4-9. RESULTS: The median disease duration was 8.5 years (range 1.3-34 years). No endoscopic or histological signs of dysplasia or carcinoma were seen and no mutations in the TP53 gene were detected in any biopsy or lavage fluid specimens. Histological moderate to severe mucosal inflammation was present in 78% (33/42) of the patients, however, and rectal stump involution was noted in 43% (18/42). CONCLUSION: No signs of malignancy or premalignant degeneration were detected in this prospective series of IBD patients with a closed rectal stump. Although this is reassuring for patients, the presence of moderate to severe inflammation in the majority of rectal stumps indicates a role for adjuvant molecular markers to improve colorectal cancer surveillance on this subgroup of IBD patients.
Adult↗
Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.
Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.
Alleles↗
[Therapeutic principles for chronic inflammatory bowel disease].
Whereas the incidence of ulcerative colitis has remained stable at around 8-9/10(5), the incidence of Crohn's disease has increased from below 1 to more than 5/10(5) per year during the last three decades. The new disease entities, collagenous colitis and lymphocytic colitis, are now covered by the term, chronic inflammatory bowel disease. The general principles of treatment of these diseases are to induce remission of outbreaks and to prevent outbreaks during remission. Available pharmaceutical products are 5-aminosalicylic acid preparations, with different delivery profiles in the gastrointestinal tract, glucocorticoids, and other immunosuppressants, especially azathioprine. New immunomodulating agents, with a specific effect on intracellular processes in the inflammatory cascade are now being developed, and infliximab, a TNF-alpha antibody, is now an accepted agent for use in severe, treatment-resistant cases of fistulising Crohn's disease. When medical treatment fails, surgical treatment is an option. In ulcerative colitis, colectomy is, in principle, curative, but it leaves the patient with either a permanent ileostomy or an ileal pouch, which serves as an artificial rectum after ileoanal anastomosis. This latter procedure has the obvious advantage of giving the patient a normal bowel continuity, but complications in the form of intractable "pouchitis" have been experienced in a small number of patients, thus necessitating removal of the pouch. Patients with Crohn's disease, who do not respond to medical treatment or present signs of stenosis in either the small or the large bowel, must be given surgical treatment, although an operation is less curative than in ulcerative colitis. Surgical resections for Crohn's disease must therefore be more conservative, so as to preserve the bowel and only remove macroscopically affected tissue.
Adjuvants, Immunologic↗
IBD: how important are clinical epidemiological studies?
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Humans↗
[When nursing care hurts.. It is part of daily experience to be confronted with one form ov violence or another. Student project in nursing research curriculum].
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Aged↗
Quality of life study in a regional group of patients with Crohn disease. A structured interview study.
BACKGROUND: The course and prognosis of Crohn disease has previously been described in a regional group of patients in Copenhagen County. The aim of the present study was to reveal the quality of life. as judged by the patients, and compared to age- and sex-matched healthy controls. METHODS: Out of 100 consecutive out-patients with Crohn disease, 94 patients accepted to participate together with 94 age- and sex-matched healthy controls. A modified McMaster Inflammatory Bowel Disease Questionnaire (IBDQ23) was used, excluding bowel-related questions. Medical students conducted interviews without knowing who were Crohn disease patients and who were controls. The bowel-related questions and Crohn's Disease Activity Index (CDAI) were assessed by gastroenterologists at inclusion in the study. Responses were indicated on a seven-point scale (7 best/1 worst). Mean numeric score was calculated as well as a delta score, i.e. the difference in score between a patient and the matched control. RESULTS: In 21 of 23 questions the median delta score was zero, indicating no difference between patient and control. The median total delta score was 0.4 in favour of healthy controls (P < 0.001), and significantly higher in patients in relapse, 0.9, than in patients in remission, 0.3 (P < 0.01). The median total numeric score was 5.7 for patients and 6.1 for controls. CONCLUSIONS: Although patients with Crohn disease scored significantly lower on the quality of life scale than matched healthy controls, the differences were smaller than could be expected, taking the chronic disease into consideration. Disease activity correlated with the quality of life score.
Adolescent↗
Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study.
BACKGROUND: Previous studies have shown an increased risk of inflammatory bowel disease (IBD) among relatives of patients with Crohn disease and ulcerative colitis. In the present study the probandwise concordance rates for ulcerative colitis and Crohn disease among mono- and dizygotic twins were estimated. Further we aimed to evaluate whether smoking habits might influence the concordance, and to look for clinical characteristics of concordant versus discordant twin pairs. METHODS: Among the 38,507 identified twins born in Denmark from 1953 to 1982, a questionnaire was sent to the 34,076 who previously had accepted to participate in studies. For twins reporting IBD, the diagnosis was verified by applying standard criteria to records requested from hospitals or practitioners. RESULTS: Among the 29,421 (86.3%) twins answering the questionnaire, 103 pairs had at least one twin who suffered from IBD. In the Crohn disease group five of 10 monozygotic pairs, but none of 27 dizygotic pairs were concordant. In the ulcerative colitis group three of 21 monozygotic, and two of 44 dizygotic pairs were concordant. The probandwise concordance rate among monozygotic pairs was 58.3% for Crohn disease and 18.2% for ulcerative colitis; among the dizygotic pairs the rates were 0 and 4.5%, respectively. The frequency of smokers was higher among twins with Crohn disease and lower among twins with ulcerative colitis compared to the frequency in the twin register. Furthermore, smoking habits were found to be of significance for discordance for disease. Regarding the clinical characteristics no homogenous pattern was observed within the concordant pairs and the differences between concordant and discordant pairs were not significant. CONCLUSION: The observation of a significantly higher concordance rate among monozygotic than among dizygotic twin pairs strongly points to a genetic influence on occurrence of IBD, which seems to be more pronounced with regard to Crohn disease than to ulcerative colitis. Differences in smoking habits among the members of the discordant twin pairs may influence the discordance.
Colitis, Ulcerative↗
Results of multiple diagnostic tests for Mycobacterium avium subsp. paratuberculosis in patients with inflammatory bowel disease and in controls.
Mycobacterium avium subsp. paratuberculosis has been incriminated as a cause of Crohn's disease (CD); however, studies to date have been relatively small and generally only used a single diagnostic assay. The objective of the study was to reexamine the association of M. avium subsp. paratuberculosis and CD using multiple diagnostic tests. Five methods were used to detect M. avium subsp. paratuberculosis infections in 439 inflammatory bowel disease (IBD) patients and 324 control subjects in the United States and Denmark. Most assays were adaptations of diagnostic tests for this infection performed routinely on animals. PCR for IS900, a genetic element unique to M. avium subsp. paratuberculosis, was positive significantly more often on resected bowel and lymph node tissues from CD patients (19.0%) and ulcerative colitis (UC) patients (26.2%) than from controls (6. 3%) (P < 0.05). Positive IS900 PCR results occurred more often in U. S. than in Danish IBD patients, 32.0 versus 13.3% (P = 0.025). The majority of Danish patients were bacillus Calmette-Guérin (Mycobacterium bovis BCG) vaccinated (CD, 77.5%; UC, 86.6%; controls, 83.0%) whereas none of the U.S. patients with IBD and only 2% of U. S. controls were vaccinated. Among Danish IBD patients, positive PCR findings were four times more common among subjects who were not BCG vaccinated (33.3%) than among BCG vaccinates (8.8%, P = 0.02). Culture of the same tissues tested by PCR using modified BACTEC 12B medium failed to grow M. avium subsp. paratuberculosis from patients or controls. U.S. CD patients had the highest serological evidence (enzyme-linked immunosorbent assay [ELISA] for serum antibodies) of M. avium subsp. paratuberculosis infection (20.7% of patients positive) which was higher than for all UC patients studied (6.1%) or healthy controls (3.8%, P < 0.005). Among Danish patients alone, however, no significant differences in rates of ELISA-positive results among CD, UC, or control patients were found. For 181 study subjects, both IS900 PCR and ELISA were performed. Although 11 were ELISA positive and 36 were PCR positive, in no instance was a patient positive by both tests, suggesting that these states are mutually exclusive. Evaluation of cytokine-mediated immune responses of IBD patients was complicated by the influence of immunosuppressive therapy given most IBD patients. Gamma interferon (IFN-gamma) release by peripheral blood leukocytes after M. avium purified protein derivative PPD antigen stimulation showed significantly lower responses in CD patients than in UC patients or controls in both U.S. (by ex vivo assay) and Danish (by in vitro assay) populations (P < 0.05). Interleukin-5 responses were not different among CD, UC, or control groups. Collectively, the PCR, ELISA, and IFN-gamma tests for M. avium subsp. paratuberculosis together with the unexpected observation that BCG vaccination influenced M. avium subsp. paratuberculosis detection, lead us to conclude that M. avium subsp. paratuberculosis, or some similarly fastidious mycobacterial species, infects at least a subset of IBD patients. Whether the infection is primary (causal) or secondary, it may contribute to the etiopathogenesis of IBD.
Adult↗
Genetic analyses of chromosome 12 loci in Crohn's disease.
BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) includes ulcerative colitis and Crohn's disease, both of which are multifactorial diseases involving the interaction of genetic and environmental factors. A region on chromosome 12 centred around the marker locus D12S83 has previously been associated with IBD predisposition. The aim of the study was to investigate this genetic region in an independent panel of European families affected by Crohn's disease. METHODS: A sample of 95 families with two or more affected relatives and 75 simplex nuclear families were genotyped for 19 microsatellite loci located on chromosome 12. A search for linkage and linkage disequilibrium was performed using non-parametric two point and multipoint analyses with the Analyze and Genehunter packages. RESULTS: No evidence of linkage or linkage disequilibrium was observed for any of the marker loci, including D12S83 (p=0.35 for the two point linkage test). Multipoint linkage analysis also failed to reveal positive linkage on chromosome 12. Power calculations allowed us to reject the hypothesis that the genetic region of chromosome 12 centred on D12S83 contains a susceptibility locus with a relative risk (lambda(s)) equal to or greater than 2.0 in these families. CONCLUSION: Failure to detect linkage or linkage disequilibrium in these families suggests that the chromosome 12 locus previously reported to be associated with genetic predisposition to IBD does not play a role in all European family samples. This observation is compatible with heterogeneity in the genetic basis of susceptibility to the disease and/or exposure to various environmental factors among Caucasian families.
Chromosomes, Human, Pair 12↗
Lauroyldextran and crosslinked galactomannan as coating materials for site-specific drug delivery to the colon.
Lauroyldextran (LD) and crosslinked galactomannan (XGM) were investigated as microbiologically degradable film coating materials for site-specific drug delivery to the colon. LD was used with degrees of substitution between 0.12 and 0.40, and swelling in aqueous media between 195 and 50%, XGM-batches showed swelling between 309 and 520%. Theophylline tablets were coated in a Hüttlin Kugelcoater with coating quantities of 4-17 mg/cm2. Sprayable coating formulations were obtained with 4% aqueous dispersions of XGM or 4% dispersions of LD in a 1:1 mixture of 1-propanol and water with 10% glycerol (based on the polymer) as a plasticizer. Theophylline dissolution was monitored in a USP XXIII paddle dissolution apparatus with buffer pH 5.5. After 4 h, which is an average small intestine transit time, colon conditions were simulated by adding galactomannanase or dextranase, respectively. Results showed similar dissolution rates for all XGMs and high-swelling LDs during the first 4 h and a relatively quick disintegration after enzyme addition. Both parameters decreased with increasing coating quantities. Dissolution from low-swelling lauroyldextrans was very low but no disintegration was observed after enzyme addition. The disintegration rate was found to be proportional to the square root of the enzyme activity. All swollen materials exhibited low mechanical stability. XGM coatings, especially at higher coating quantities, showed small transient ruptures at the edges not caused by enzyme addition. This behaviour was explained by internal stress due to the high degree of swelling. In principle, materials of both types proved to be suitable as degradable coating materials. The ideal zero-dissolution before and quick disintegration after enzyme addition, however, was not realized with the present materials.
Biodegradation, Environmental↗
Arthritis and the gut.
Mild arthritis/arthralgia is the most frequent extraintestinal manifestation in inflammatory bowel disease (IBD) and has been reported to occur in 10-35% of patients in different studies. A classification of peripheral arthropathy in relation to inflammatory bowel disease has recently been proposed. Type 1: pauciarticular, asymmetrical, preferably large joints, and related to IBD activity. Type 2: polyarticular, symmetrical, preferably small joints, and occurring independently of IBD activity. While this classification requires the presence of synovitis, arthralgia without swelling or other objective signs are of equal frequency but are not covered by this system. In this issue of the journal, Thomas et al. report a prospective study, incorporating strict endoscopic and histological criteria for pouchitis, which elucidates the correlation to arthropathy. Both pouchitis and symptoms of the joints occurred more frequently in ulcerative colitis patients than in patients with familial polyposis. Surprisingly, arthropathy was not more frequent among patients with pouchitis than among patients without pouchitis in this study. Extraintestinal manifestations of the joints are thus not likely to be a reactive arthritis secondary to pouchitis, which would have been an obvious explanation. Preoperative occurrence of extraintestinal manifestations from the joints does not seem to be predictive for the outcome of an ileo-anal pouch anastomosis and especially development of pouchitis. The arthritic symptoms were generally mild and not disabling.
Antibodies, Antineutrophil Cytoplasmic↗
[Inflammatory bowel diseases in children].
From an incidence cohort diagnosed during 1962-1987 we identified all patients with onset of IBD before the age of 15 in order to describe the course and to compare course and prognosis with adult onset IBD. The mean incidence of IBD among children below 15 years was 2.2/10(5), 2.0 for ulcerative colitis (UC), and 0.2 for Crohns disease (CD). At diagnosis, UC children had more extensive disease compared to adults (p < 0.05). Abdominal pains were also more frequent. The cumulative colectomy probability was 6% after one year and 29% after 20 years, not different from adults. Regarding disease activity, it was found that 60-70% of UC patients were in remission in the first 10 years of disease, for CD about 50% were in remission. One UC patient developed carcinoma of the sigmoid colon. Time between onset and development of carcinoma was 12 years. For CD no differences in clinical appearance at diagnosis and course between children and adults were found. No deaths occurred among CD patients. Three CD patients were found to have severe growth retardation already at diagnosis. In conclusion, the incidence of IBD is low in childhood. At diagnosis children with UC have more widespread disease than adults. Children with CD do not differ in clinical presentation, course or prognosis compared to adult onset CD. However, growth retardation is a problem among CD patients.
Adolescent↗
Preliminary applicability tests of different methacrylic acid copolymers, type C NF, particularly relevant to spreading and film formation.
The intention of this study was to show under which conditions a film forming methacrylic acid copolymer coating excipient, corresponding to the requirements of pharmacopoeia, but obtained from different sources, can be substituted without severe problems. The mechanical properties of the film coats were investigated by dynamic-mechanical thermo-analysis (DMTA) experiments to determine with respect to the glass transition the storage modulus E', the loss modulus E'', and the loss factor tan delta. Further determinations concerned the surface tensions of the different coating dispersions. This attribute plays an important role in spreading, distribution and coalescence of the film forming preparations. Finally by a series of small experimental fluidized bed batches cores containing a model drug were coated with the different methacrylic acid copolymers. The resistance of these coated tablets in 0.1 N HC1 as well as their dissolution rates in artificial intestinal juice were tested. The coatings proved themselves so similar that in this case substitutions of products of different provenance are possible. The determinations of surface tension and the DMTA measurements seem to be useful and reliable preliminary applicability tests.
Caffeine↗
[Mycobacterium paratuberculosis--an etiological agent in Crohn disease?].
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Animals↗
Inflammatory bowel diseases with onset in childhood. Clinical features, morbidity, and mortality in a regional cohort.
BACKGROUND AND METHODS: In a geographically derived incidence cohort diagnosed from 1962 to 1987 we identified all patients with onset of inflammatory bowel diseases (IBD) before the age of 15 years, to describe the clinical course and to compare the course and prognosis with those of adult-onset IBD. RESULTS: The mean incidence of IBD among children below 15 years was 2.2/10(5), 2.0 for ulcerative colitis (UC) and 0.2 for Crohn's disease (CD). At diagnosis children with UC had more extensive disease than adults (P < 0.05). Abdominal pain was also more frequent. The cumulative colectomy probability was 6% after 1 year and 29% after 20 years, not different from that of adults. More females underwent colectomy. With regard to disease activity, apart from the year of diagnosis 60-70% of UC patients were in remission in each of the first 10 years of disease; for CD about 50% were in remission. One patient with UC developed carcinoma of the sigmoid colon. Time between onset of UC and development of carcinoma was 12 years. For CD no differences in clinical appearance at diagnosis and course between children and adults were found in relationship to surgery. No deaths occurred among CD patients. Three CD patients were severely growth-retarded already at diagnosis. CONCLUSION: The incidence of IBD is low in childhood. At diagnosis children with UC have more widespread disease than adults. Childhood-onset CD does not differ in clinical presentation, disease course, or prognosis from adult-onset CD. However, growth retardation is a problem among male CD patients.
Abdominal Pain↗
Familial occurrence and inheritance studies in inflammatory bowel disease.
A number of studies have demonstrated aggregation of cases of ulcerative colitis or Crohn's disease in families, and of cases of both diseases within the same families, suggesting that patients share a genetic background. Perhaps because of differences in the selection of patients, study design and diagnostic criteria, different patterns of occurrence of inflammatory bowel disease (IBD) have been found among relatives of patients with these disorders. In recent years, however, several studies have been carried out, aiming by epidemiological methods to reveal (1) the frequency of familial occurrence of IBD among patients with ulcerative colitis and Crohn's disease, and (2) the prevalence of IBD among 1(0) relatives to patients with these diseases. Results from these studies show a relatively uniform pattern of family occurrence in about 10% of patients with ulcerative colitis and Crohn's disease, and a prevalence among 1(0) relatives of about 10 times that of the background population. A twin study reported a significantly higher concordance rate for Crohn's disease than for ulcerative colitis in monozygotic twins. By use of complex segregation analyses in 3 different studies, a very similar model of inheritance was found to fit for ulcerative colitis, namely a major dominant or additive gene with a low penetrance. For Crohn's disease the best-fitting model was a major recessive gene, with a high penetrance. This difference strongly supports the concept of ulcerative colitis and Crohn's disease as two separate disease entities. The occurrence of both diseases within the same families in certain members of the affected families is difficult to explain. The search for distinct associations of HLA genes with inflammatory bowel disease has shown a positive correlation between DR2 and ulcerative colitis and a negative association with DR4 and DRw6, compared with ethnically matched controls. In contrast, in Crohn's disease a positive association with the combination of DR1 and DQw5 alleles was revealed, thus indicating genetically different disease susceptibility for the two disorders. In general, however, no consistent pattern has been revealed from studies of association of HLA-A or -B antigens or blood group and serum protein markers. In two French families with several members affected with Crohn's disease no evidence for an HLA haplotype association could be revealed. Possible inherited markers of ulcerative colitis or Crohn's disease have been sought but without convincing success. Increased intestinal permeability, presence of anticolon antibodies and presence of antineutrophil leukocyte antibodies have been proposed, but not proved. Thorough studies are now needed of multimember families with disease for linkage studies to identify loci which contribute to increased liability. Such studies are in progress in different centres.
Adolescent↗