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Aim: While collagenous colitis represents the most common form of the collagenous gastroenteritides, the collagenous entities affecting the proximal part of the gastrointestinal tract are much less recognized and possibly overlooked. The aim was to summarize the latest information through a systematic review of collagenous gastritis, collagenous sprue, and a combination thereof., Method: The search yielded 117 studies which were suitable for inclusion in the systematic review. Excluding repeated cases, 89 case reports and 28 case series were reported, whereas no prospective studies with or without control groups were identified. Further, no randomized, controlled trials were identified. The total number of patients with proximal collagenous gastroenteritides reported was 330., Results: An overview of clinical presentations, prognosis, pathophysiology and histopathology, as well as management of these disorders is presented. The prognosis of both collagenous gastritis and sprue seems not to be as dismal as considered previously. Data point to involvement of immune or autoimmune mechanisms potentially driven by luminal antigens initiating the fibroinflammatory condition., Conclusions: To reach the diagnosis it is recommended that biopsies are obtained during gastroduodenoscopies. Therapies with anti-secretory strategies, glucocorticoids, and in some cases iron supplementation are suggested, although rational treatment options from randomized, controlled trials do not exist for these rare or even overlooked disorders.

Abstract Extraintestinal manifestations occur rather frequently in inflammatory bowel disease (IBD), e.g. ulcerative colitis (UC) and Crohn's disease (CD). The present paper provides an overview of the epidemiology, clinical characteristics, diagnostic process, and management of rheumatic, metabolic, dermatologic (mucocutaneous), ophthalmologic, hepatobiliary, hematologic, thromboembolic, urinary tract, pulmonary, and pancreatic extraintestinal manifestations related to IBD. Articles were identified through search of the PubMed and Embase databases, the Cochrane Library, and the web sites of the European Agency for the Evaluation of Medicinal Products (EMEA) and the US Food and Drug Administration (FDA) (cut-off date October 2009). The search terms 'Crohn's disease', 'inflammatory bowel disease', or 'ulcerative colitis' were combined with the terms 'adalimumab', 'anemia', 'arthritis', 'bronchiectasis', 'bronchitis', 'cutaneous manifestations', 'erythema nodosum', 'extraintestinal manifestations', 'hyperhomocysteinemia', 'infliximab', 'iridocyclitis', 'lung disease', 'ocular manifestations', 'osteomalacia', 'pancreatitis', 'primary sclerosing cholangitis', 'renal stones', 'sulfasalazine', 'thromboembolism', and 'treatment'. The search was performed on English-language reviews, practical guidelines, letters, and editorials. Articles were selected based on their relevance, and additional papers were retrieved from their reference lists. Since some of the diseases discussed are uncommon, valid evidence of treatment was difficult to obtain, and epidemiologic data on the rarer forms of extraintestinal manifestations are scarce. However, updates on the pathophysiology and treatment regimens are given for each of these disorders. This paper offers a current review of original research papers and randomized clinical trials, if any, within the field and makes an attempt to point out practical guidelines for the diagnosis and treatment of various extraintestinal manifestations related to IBD.

Objective: Epithelial apoptosis rates are increased in ulcerative colitis (UC). The increased apoptosis rate could expose mucosal cells to luminal pathogens and thereby be regarded as a primary pathogenic factor in UC. On the other hand, the local inflammatory reaction could cause epithelial apoptosis secondary to the release of cytotoxic mediators. If apoptosis is a primary defect, apoptosis rates could influence the degree of spreading of inflammation and the clinical course of UC. If apoptosis is a side effect of local inflammation, apoptosis rates would be expected only to correlate with the degree of local inflammation. The aim of the study was to investigate the relationship between epithelial apoptosis and clinical characteristics of UC., Material and Methods: Twenty patients with UC (12 with active disease) and 20 control subjects were included. Freshly isolated colonic epithelial cells were cultured. Apoptosis was determined by flow cytometry. Cells were stimulated with Fas ligand. The disease was characterized by endoscopic findings, microscopic inflammation grade, surrogate markers of disease activity (hemoglobin level, white blood cell count, C-reactive protein, or albumin), and the clinical course 6 months after biopsy., Results: Epithelial apoptosis correlated with local inflammation, both macroscopic (p< 0.02) and microscopic (p< 0.008). Disease extent, disease course, or surrogate markers of disease activity did not correlate with apoptosis rate. However, increased microscopic inflammation inversely correlated with apoptosis response to the Fas ligand (p< 0.06)., Conclusions: The epithelial apoptosis rate is influenced primarily by the local inflammatory response. Colonocytes upregulate cytoprotective mediators that decrease apoptosis susceptibility during active UC.

Objective: Responses and adverse events to medication vary greatly among patients with Crohn's disease (CD). The aim of this study was to investigate whether global gene expression profiles could predict such responses and possible side effects., Material and Methods: Tissue specimens from the descending colon were obtained from 32 CD patients (in 18 patients from areas without inflammation and in 14 patients from inflamed areas). Gene profiling was done using the Affymetrix Human Genome U133 Plus 2.0 GeneChip array. Hybridization data were analyzed with dChip software., Results: There were no differentially expressed genes between six patients who responded well to azathioprine and four who did not. No differences were found between 12 patients with adverse events to azathioprine and 9 patients who tolerated this drug. Sixteen patients who were not glucocorticoid-dependent had no differentially expressed genes as compared with 15 glucocorticoid-dependent patients. Six patients who responded well to infliximab had only one differentially expressed gene as compared to four patients who did not., Conclusions: DNA microarray analyses did not show differentially expressed genetic profiles from colonic mucosal cells obtained from groups of patients classified according to therapeutic criteria.

Objective: A global gene expression profile of non-inflamed colonic mucosal cells from patients with Crohn's disease (CD) and of colonic mucosal cells from controls was performed., Material and Methods: Tissue specimens from macroscopically non-inflamed descending colon were obtained colonoscopically from 33 CD patients and from 17 control subjects. All controls and 10 CD patients were medication-free at the time of colonoscopy. The Human Genome U133 Plus 2.0 GeneChip Array was used for gene profiling. Hybridization data were analysed with dChip software. Results were confirmed by real-time reverse transcriptase polymerase chain reaction (RT-PCR). Protein product expression of selected genes was assessed by immunohistochemistry using the Envision+ visualization technique., Results: The expression profile was not homogeneous with the statistical cut-point settings applied. In comparison with controls, it was found that 19 CD patients had three differentially expressed genes, two of them related to the innate immune system: dual oxidase 2 on chromosome 15 (DUOX2, fold change 4.1) and lipocalin 2 on chromosome 9 (LCN2, fold change 3.1). The third gene, regenerating islet-derived 1 alpha (REG1A, fold change 3.9), codes for a mitogenic protein; this could not be confirmed by RT-PCR. Medication-free patients had no differentially expressed genes as compared with controls. Immunohistochemistry indicated that these proteins were produced by epithelial cells (REG1A, LCN2) and leucocytes (DUOX2 and LCN2)., Conclusions: As compared with controls, non-inflamed colonic mucosal cells contain two up-regulated genes related to the innate immune system. Up-regulation of these genes, known to be induced by microorganisms, suggests either increased microflora antigenicity or an altered function in mucosal barrier defence.

Objective: Intercellular adhesion molecule-1 (ICAM-1) is important in ulcerative colitis (UC) by mediating the arrest and further migration of neutrophils. In vitro studies have shown that colonocytes from chronically inflamed colon and cultured colon cancer cells are capable of expressing ICAM-1. The aim of this study was to assess the ICAM-1 expression in human colonic tissue representing UC, Crohn's disease (CD), adenomas, and adenocarcinomas, with special attention to the epithelium., Material and Methods: Formalin-fixed and paraffin-embedded tissue from the archives of the Department of Pathology of Rigshospitalet University of Copenhagen was examined. Colonic tissue from 10 patients with UC, 10 with CD, 32 adenomas, 27 adenocarcinomas, and 10 lymph node metastases were included. The expression of ICAM-1 was assessed by using the EnVision(+)technique (DakoCytomation)., Results: Endothelial ICAM-1 was up-regulated in areas with dense lymphocyte infiltration and near crypt abscesses and ulcerations. Ulcerations were covered by a continuous layer of macrophages and epithelial cells expressing ICAM-1. Similar observations were made in the case of adenomas and adenocarcinomas, but in adenocarcinomas the epithelial ICAM-1 was more diffuse and not related solely to sites of surface destruction., Conclusions: In the colon, endothelial cells, macrophages, and epithelial cells are in certain conditions capable of expressing ICAM-1. Although the ICAM-1 expression was related to both the degree and the nature of inflammation, the data indicate increased susceptibility of cancer cells to express ICAM-1. Epithelial and macrophage ICAM-1 might be involved in the immune surveillance and the first-line defense of the diseased colon.

Background: Cytokines are markers of acute pancreatic inflammation and essential for distant organ injury, but they also stimulate pancreatic fibrogenesis and are thus involved in the progression from acute pancreatitis to chronic pancreatic injury and fibrosis. The aim of this study was to evaluate the circulating levels of IL-6, MCP-1, TGF-beta1, IGF-1 and IGFBP-3 in patients with alcoholic chronic pancreatitis (CP)., Methods: Twelve male patients with severe CP and 11 matched controls ingested 40 g alcohol. Plasma cytokine concentrations were measured for 24 h and assessed by sandwich ELISA techniques., Results: IL-6 was higher in CP at fasting and 1, 4 and 24 h after alcohol intake (P < 0.04), and a significantly greater rise was found at 1 h compared to pre-stimulatory conditions and controls (P < 0.01). MCP-1 plasma levels in CP were significantly decreased at I h (P < 0.01) and 4 h (P < 0.001) compared to pre-stimulatory levels and controls, and a variance analysis showed significantly (P < 0.001) lower post-stimulatory levels at 1 h and 4 h both in CP and in controls. Alcohol consumption (40 g), however, did not influence plasma levels of TGF-1beta, IGF-I or IGFBP-3 in either of the two groups at the time frame applied., Conclusions: Acute alcohol intake induces a rise in the plasma levels of IL-6 in CP as compared to controls. The low circulating concentrations of MCP-1 1 and 4 h following alcohol consumption might possibly reflect that this mediator acts locally via autocrine mechanisms.

Background: A soluble form of intercellular adhesion molecule-1 (sICAM-1) shed from endothelial cells is present in the circulation. Whether the circulating molecules represent passive turnover of surface ICAM-1 or may have some active functions in the inflammatory process is unknown. Glucocorticoids (e.g. prednisolone) are cornerstones in the treatment of acute exacerbations of ulcerative colitis (UC), and influence of the leucocyte/endothelial interaction appears to be part of their mode of action. The aim of the present study was therefore to evaluate the ICAM-1-shedding through measurements of sICAM-1 concentrations during prednisolone treatment of UC patients., Methods: Prednisolone (40 mg) was prescribed to 15 patients with severe disease activity. At inclusion, and after 2 weeks of treatment, plasma sICAM-1 levels were measured using the ELISA technique., Results: The concentrations of sICAM-1 were significantly decreased during treatment from median 256.2 (ng/ml) (interquartile range 239.7-321.0 ng/ml) to 220.4 ng/ml (196.0-276.3 ng/ml) (P < 0.01). This reduction correlated with a decrease in disease activity (r(s) = 0.8; P < 0.003)., Conclusions: sICAM-1 seems to be a poor diagnostic tool, but since plasma sICAM-1 concentrations decreased during the treatment period, it might prove to be applicable as an activity marker in the individual patient.

Background: Cytokines are essential mediators of the intestinal inflammation during active episodes of inflammatory bowel disease (IBD). Interleukin (IL)-12 and IL-17 are potent immunoregulatory cytokines whose roles in the pathogenesis of IBD are unknown. The aim of this study was to evaluate the colonic expression of IL-12 and IL-17 genes in IBD., Methods: Fifty-one patients (22 with ulcerative colitis (UC), 17 with Crohn disease (CD), and 12 controls) who underwent colonoscopy were included. IBD disease activity was determined using a clinical grading scale. The degree of inflammation, as well as the content of CD4+ T cells (synthesizing IL-17) and CD68+ macrophages (synthesizing IL-12) in colonic biopsies, was determined. The amounts of IL-12 and IL-17 mRNA were assessed by RT-PCR, using GAPDH as an internal standard., Results: In colonic specimens, IL-17 mRNA expression was increased in moderately and severely active UC (P = 0.03) and in all degrees of activity in CD (P < 0.04). Levels of IL-12 mRNA were upregulated in both active UC and active CD compared to controls (P < 0.02). In cases of remission, IL-12 mRNA expression was similar to that found in control samples. Compared to controls, histological examination showed significant differences in signs of chronic and acute inflammation in UC (P < 0.01) and CD (P < 0.02), revealing a high correlation between clinical disease activity and histological scoring (r2 = 0.92, P < 0.005). Whereas CD4+ T cells were observed in lymphocyte aggregates located profound in the lamina propria, CD68+ macrophages were primarily found just underneath the surface epithelium. The density of CD4+ and CD68+ cells correlated significantly with the amounts of IL-17 and IL-12 mRNA, respectively (P < 0.05)., Conclusion: The expression of both IL-12 and IL-17 mRNA is induced in active UC and CD and may thus be involved in sustaining the intestinal inflammation in IBD. Inhibition of IL-12 or IL-17 might be future therapeutic targets in IBD.

Intercellular adhesion molecule-1 (ICAM-1) mediates the firm adhesion of leukocytes to endothelial cells. In ulcerative colitis (UC), ICAM-1 is suggested also to be involved in the further migration of leukocytes toward the epithelial lining, and in colonic tissue it has been reported to be expressed by cell types other than endothelial cells. This study aimed at determining the ultrastructural localization of ICAM-1 on cells belonging to the colonic mucosa from patients with UC. Colonic biopsies from 3 UC patients and 3 control subjects were examined ultrastructurally by immunogold labeling of ICAM-1. ICAM-1 was expressed on the luminal cell membranes of endothelial cells in both controls and inflamed and noninflamed UC colon, although the density was significantly increased in UC (p < .0001). Labeling was observed on the basal endothelial cell membranes and on macrophages and plasma cells in inflamed UC colon only. Epithelial cells did not express ICAM-1. ICAM-1 appears to be constitutively upregulated on the luminal endothelial membrane in UC, and the expression on basal endothelial membranes in active UC only suggests that ICAM-1 is more extensively involved in the leukocyte migration than previously acknowledged.

Background: Factors influencing the directed migration of neutrophils into colonic tissue in ulcerative colitis (UC) are poorly described. ICAM-1 has recently been shown to possess chemotactic properties, and the aim of this study was to evaluate the involvement of beta 2 integrins in this ICAM-1-mediated migration., Methods: The chemotactic effect of ICAM-1 on neutrophils isolated from 13 UC patients and 17 healthy volunteers was studied in microchemotaxis chambers. Physiological concentrations of ICAM-1 (0.05-500 pM) were separated from neutrophils by nitrocellulose filters, and cell migration was evaluated using the leading front technique. beta 2 integrins on neutrophils were blocked with antibodies to CD11a, CD11b, CD11c and CD18, and migration towards ICAM-1 was examined., Results: Migration towards ICAM-1 was equal for UC and control neutrophils, showing a bell-shaped ICAM-1 dosemigratory response curve with peak migration at 5 pM ICAM-1 (30.0 microns; interquartile range 22.9-35.7; P < 0.001). Blockade of the CD11 subunits on control cells inhibited the chemoattractant effect of ICAM-1 by 43.6%-58.0%, whereas the migration was decreased by only 20% in UC under similar blocking conditions (P < 0.01). Anti-CD18 mAbs had no effect. Inhibition of protein kinases with staurosporin only slightly decreased the ICAM-1-mediated migration, whereas incubation with staurosporin and CD11 antibodies showed additive effects on UC neutrophils and synergistic effects on control cells. No quantitative differences in beta 2 integrin expression were detected between control and UC neutrophils., Conclusions: The chemotactic property of ICAM-1 was shown to be CD11-dependent and UC neutrophils were found to be less dependent on CD11/ICAM-1-mediated migration than were control neutrophils.

Background: Interleukin-8 (IL-8) is an important cytokine for recruitment and activation of polymorphonuclear neutrophils (PMNs), cells that are abundant in the intestinal lesions of ulcerative colitis (UC) and Crohn's disease (CD). The present investigation was conducted to evaluate intestinal IL-8 concentration and IL-8 gene expression in parallel in inflammatory bowel disease (IBD) patients and a non-inflammatory control group., Methods: The intestinal concentration of IL-8 was measured with a sandwich enzyme-linked immunosorbent assay (ELISA) technique (detection limit, 17.4 pg/mg protein), and relative quantitation of IL-8 mRNA transcript levels was done with a reverse transcription polymerase chain reaction (RT-PCR)-based method. Biopsy specimens from 66 humans who underwent colonoscopy--28 with UC, 18 with CD and colonic involvement, and 20 non-inflammatory disease-specific controls who subsequently were found to fulfill the diagnostic criteria for irritable bowel syndrome (IBS)--were included. None had received glucocorticoids within 3 months., Results: Using a one-tailed variance analysis, a significant concordance between increasing IL-8 protein concentrations and disease activity was found both in UC and CD (P < 0.001), and only trace amounts were detected in IBS biopsy specimens. No differences were found between the two groups of UC and CD patients (P > 0.05), and no differences were found between quiescent IBD and IBS (P > 0.05). However, the PCR method showed IL-8 mRNA in 8 of 18 CD patients (44.4%; 95% confidence limits, 21.5-69.2%) and 7 of 28 UC patients (25.9%; 95% confidence limits, 11.1-46.3%), as compared with 0 of 20 IBS (P < 0.005). Increased IL-8 mRNA levels were found only in active CD, which was not the case in UC. No correlation was found between intestinal IL-8 ELISA and IL-8-mRNA levels (r = 0.24, P > 0.05)., Conclusions: The observed correlation between disease activity and expression of the IL-8 gene in active CD colitis but not in UC and the increased IL-8 protein concentrations in affected intestinal segments of IBD as compared with the non-inflamed IBS indicate a possible transient IL-8 gene expression or altered mRNA stability in UC and CD, as is well known for other cytokines, such as IL-2. If so, it may form the basis of new therapeutic regimens for IBD like IL-10.

With routine use of obstetric ultrasonography, fetal low-grade hydronephrosis is commonly detected, but may resolve spontaneously after birth. Two cases are presented to illustrate that in some cases such findings can express intermittent hydronephrosis caused by aberrant renal vessels. Renal deterioration later in childhood may be a consequence.

Background: The prognosis of patients with ulcerative colitis (UC) has previously been described with regard to mortality, cancer occurrence, and need for colectomy on the basis of an annual follow-up of a regional cohort of UC patients in Copenhagen County diagnosed in 1962-87. The objective of this study was to examine the prognosis with regard to spread of disease and to evaluate possible prognostic factors with regard to spread of disease and colectomy by multivariate regression analysis., Methods: An inception cohort of 1161 patients with UC was examined by actuarial analysis and by multivariate regression analysis of a subgroup of 467 patients diagnosed in 1979-87., Results: The probability for further progression of proctosigmoiditis, evaluated by sigmoidoscopy and radiology, was 53% after 25 years. The probability for regression was 76.8% for substantial colitis and 75.7% for pancolitis after 25 years. Multivariate regression analysis showed that the occurrence of the symptoms abdominal pain and diarrhoea was prognostically unfavourable with regard to the progression from proctosigmoiditis. Age influenced the regression probability in extensive disease. With regard to colectomy the following variables influenced the prognosis: fever, general condition, serum albumin, mucopus in stools, and diarrhoea at onset., Conclusions: Disease extent in UC is not static but changes with time in approximately half of the patients. This finding should have implications for the follow-up. Ulcerative proctitis should be considered the same disease as UC and needs the same long-term follow-up.

A distinguishing feature of inflammatory bowel disease (IBD) is its apparently spontaneous, chronic relapsing course. Despite extensive research over several decades the etiology of IBD remains unknown, but evidence has accumulated to suggest that the mucosal inflammatory response may be caused by (i) a defective mucosal barrier function resulting in an abnormally increased exposure to luminal antigens and toxins, (ii) an appropriate immunologic response to an unusual infection, antigen or toxin, or (iii) an inappropriate immunological response to ubiquitous antigens or stimuli. In recent years, the identification of established and potential mediators of inflammation has expanded to include eicosanoids, platelet activating factor, biogenic amines, kinins, complement-derived peptides, chemotactic peptides, cytokines, neuropeptides, and reactive metabolites of oxygen and nitrogen. Thus, the study of the inflammatory process has become ever more complex. Until the predisposing and trigger factors have been identified the achievement of a more rational and effective approach to therapy in IBD relies on interruption of the mechanisms responsible for excess mediator formation. As summarized in this review on the role of soluble mediators of inflammation, several Danish gastroenterologists have been profoundly engaged in basic and clinical research in the past 25 years to place some pieces of the confusing puzzle of IBD.

Activated polymorphonuclear leukocytes (PMNs), which are found in the inflammatory lesions of chronic inflammatory bowel disease, produce tissue-destructive oxygen-derived free radicals. The influence of 5-aminosalicylic acid (5-ASA), its acetylated metabolite (Ac-5-ASA), sulfasalazine (SAZ), and olsalazine (OLZ) (5-ASA dimer linked by an azo group) in pharmacologically relevant concentrations (0.1-10 mM) were tested on PMN superoxide production with either the receptor-specific agent formyl-methionyl-leucyl-phenylalanine (fMLP) or the protein kinase C activator phorbol myristate acetate (PMA). Inhibition of receptor-specific superoxide production occurred at 0.07, 0.32, and 0.63 mM (IC50 values) for 5-ASA, SAZ, and OLZ, respectively. No inhibitory effects of SAZ and OLZ were observed when PMA was applied as stimulus for PMN superoxide production. The results indicate that the signal to which PMNs respond by generating superoxide is primarily due to calcium release from intracellular stores. They further suggest that SAZ and OLZ may affect the oxygen-derived free radical production in human PMNs by unspecific cytotoxicity or by interference with the nicotinamide adenine dinucleotide phosphate, reduced (NADPH) oxidase system, whereas 5-ASA itself is a free radical scavenger.

The incidence of Crohn's disease increased sixfold from 1962 to 1987 in the county of Copenhagen. The mean annual incidence for 1979-87 was 4.1 per 10(5) inhabitants. The increase was found equally in both sexes, with an approximately 40% higher incidence in women. The maximal incidence was found in the 15- to 24-year age group, being 12.8 per 10(5) per year for women and 6.0 per 10(5) per year for men, as mean of the period 1979-87. The prevalence at the end of the study was 54 per 10(5) inhabitants, 46 per 10(5) in men and 63 per 10(5) in women. The clinical appearance of the disease at the time of diagnosis was remarkably similar during the study period with regard to both the localization of disease and the clinical symptoms and signs. A slightly higher percentage of the patients, however, were in high disease activity at diagnosis in the later years of the study.

The incidence of ulcerative colitis was estimated during the period 1962 to 1987 in the county of Copenhagen. Within this area of approximately 550,000 inhabitants, 1161 patients were diagnosed. The mean annual incidence for the period was 8.1 per 10(5) inhabitants. There were significant increases in incidence in the early 1970s and in the early 1980s, both of which were followed by significant decreases. A bimodal age distribution was found in men, with incidence peaks in young adult life and late in life. In women a peak incidence was found in the young adult age group. The interval from onset of symptoms to diagnosis in terms of years remained unchanged over the period, with a median of 1 year (range, 0-37 years). The extent of disease at diagnosis was total colon in 18% of the patients, a substantial part of the colon in 36%, and distal colon in 44%--with no changes during the study period. The distribution of different localizations did not differ among age groups except for a tendency towards more extensive disease in young patients, below 20 years of age. The disease activity in the 1st year was fulminant in 9.1% of the cases, moderate to high in 70.7%, and low in 20.2%, with a tendency towards higher activity in patients diagnosed late in the study period. The prevalence of ulcerative colitis increased steadily during the study period, reaching a value at the end of the study (31 December 1987) of 161 per 10(5) inhabitants.

Circulating human neutrophil granulocytes (PMNs) from patients with rheumatoid arthritis (RA) have earlier been described to possess an enhanced capacity for production of certain 5-lipoxygenase-derived metabolites of arachidonic acid (AA), 5-hydroxyeicosatetraenoic acid (5-HETE) and leukotriene B4 (LTB4). In the present investigation the endogenous AA metabolism of synovial fluid PMNs of RA patients was studied and compared with that of the corresponding circulating PMNs. Synovial fluid PMNs prelabelled with 14C-AA released significantly less radioactivity than circulating PMNs when stimulated with calcium ionophore. Furthermore, synovial fluid PMNs produced significantly smaller amounts of both 5-HETE and LTB4 than circulating PMNs from the same patients, whereas no such difference was observed in the LTB4 catabolites or the cyclo-oxygenase products. More information dealing with the complex way in which arachidonic acid is metabolized in diseased RA joints may provide future rational approaches in the treatment of this chronic inflammatory disease.

Circulating neutrophils were investigated in 15 patients with Crohn's disease (CD), 15 with ulcerative colitis (UC), and 15 healthy volunteers. Dose-response curves for chemotaxis in Boyden chambers were analysed for sensitivity to leukotriene B4 (LTB4), its 20-hydroxy-LTB4 (20-OH-LTB4) and 20-carboxy-LTB4 (20-COOH-LTB4) catabolites, and 5- and 15-hydroxyeicosatetraenoic acids (HETEs). Positive controls included: complement 5a (C5a), formy-L-methionyl-L-leucyl-L-phenylalanine (f-Met-Leu-Phe), and casein. Control chemotaxis test were performed at concentrations yielding optimal responses in leucocytes of healthy volunteers. Chemotaxis to suboptimal concentrations of LTB4 1.0 and 3.2 nmol/l, and 5-HETE 316 nmol/l, was markedly depressed in patients with chronic inflammatory bowel disease (CIBD). Analyses of individual dose-response curves revealed an underlying decreased sensitivity to LTB4 in 11 out of 30 patients, to 5-HETE in 10 out of 30 patients with a corresponding decrease of median sensitivity to LTB4 and 5-HETE in both CD and UC. Peak responses to LTB4, 5-HETE, f-Met-Leu-Phe, and casein were identical in the three groups tested, whereas the C5a values were significantly depressed in both groups of patients (p less than 0.05). The potency of LTB4 exceeded that of 5-HETE by a factor of approximately 100 whereas 20-OH-LTB4 was nearly as potent as LTB4. 20-COOH-LTB4 and 15-HETE did not activate chemotaxis of human neutrophils. These findings are suggestive of a competitive inhibition of receptors with heterogeneity for LTB4 and 5-HETE.(ABSTRACT TRUNCATED AT 250 WORDS)

Over a 13-year period, the course of 109 pregnancies in 68 women with Crohn's disease was studied. A total of 76 children were delivered. There were no gemellary deliveries, and none of the children had congenital malformations. Pregnancy entailed no increased risk of an exacerbation of the bowel disease. As compared with the reference population and with women with ulcerative colitis, the total material showed an increased risk of premature delivery and spontaneous abortion, but a further analysis showed that this was due only to an increased risk in women with active disease at the time of conception and in women who had undergone bowel resection during pregnancy. Birth weight and birth length corresponded to those in the reference population. The frequency of neonatal hyperbilirubinaemia was not higher in children of mothers with Crohn's disease than in children of healthy mothers. Treatment with sulphasalazine, salazosulphadimidine, and corticosteroids did not influence the course of pregnancy or the frequency of neonatal jaundice or malformations. Consequently, in Crohn's disease a pregnant woman should be given the same medical treatment as when not pregnant. Generally, the women should be advised preferably to conceive at a time when their bowel disease is inactive. The risk groups should be followed up with frequent obstetrical examinations throughout pregnancy.

Bacteriological studies of uncontaminated upper jejunal fluid were performed in 85 normal subjects. Fifty-three per cent of the samples were sterile (less than 10(1) CFU/ml). In 10% of the cases the total number of microorganisms exceeded 10(5) CFU/ml. The main groups of microorganisms isolated were Streptococcus sp ('Viridans group'), Lactobacillus sp., Veillonella parvula, Actinomyces sp., Haemophilus sp., Corynebacterium sp., and Candida albicans, each found in more than 10% of the subjects. Only the Streptococcus sp. exceeded 10(5) CFU/ml, and enterobacteria were found in 5% of the subjects, the number not exceeding 10(3) CFU/ml. No other typical members of the lower gastrointestinal tract were isolated. The number of subjects harbouring bacteria and the distribution of bacterial species were the same in both sexes and in different age groups.

It has been proposed that the presence of elevated serum titres against various Bacteroides species among patients with chronic inflammatory bowel disease (CIBD) may yield aetiological, pathogenic, or prognostic information. Using a crossed immunoelectrophoretic method, we investigated circulating antibodies against four Bacteroides species in 122 patients with CIBD (80 with ulcerative colitis (UC) and 42 with Crohn's disease (CD)) and in 32 patients with the irritable colon syndrome. In this cross-sectional study we found raised titre scores (greater than 0) among 26% of the patients with CD, among 46% of the patients with UC, and among 34% of the patients with the irritable colon syndrome. These differences are not significant. There were no correlations between the antibody titres and the duration of the disease, the clinical disease activity, or the site of the disease. Furthermore, the antibody titres yielded no prognostic information as to the necessity of surgery--that is, colectomy and/or small-bowel resection.

The complications of non-tropical sprue were registered in 100 patients seen during an 18-year period. The patients had a significantly higher mortality than the age- and sex-matched general population. They had an increased incidence of malignancies, predominantly malignant lymphomas and carcinomas of the gastrointestinal tract. The disease must be considered a premalignant condition.

Enemas containing 1000 mg 5-ASA were administered to patients with active distal colitis in three separate studies: as a single dose in a neutral solution (pH 7.4); as a single dose in a slightly acidic, buffered suspension (pH 4.8); and as multiple doses once a day for 10 days with the acidic enema. 5-ASA was relatively rapidly absorbed from the neutral solution, resulting in plasma concentrations of 5-ASA sometimes two to three times higher than those found after peroral salazosulphapyridine (SASP) treatment. In contrast, absorption from the acidic enema was reduced and/or prolonged, giving plasma concentrations similar to those found during oral SASP treatment. After repeated doses of the acidic enema, plasma concentrations after an enema resembled those seen after the single dose. Urinary excretion was significantly lower, suggesting a reduced fraction of absorption at steady-state conditions. No side effects were observed, and no local irritation was reported. An acidic buffer suspension with 5-ASA seems to be safe for use as enema and deserves further clinical testing for treatment of distal ulcerative colitis.

The course of pregnancy in 97 women with ulcerative colitis was studied over a 12-year period. During this period they had 173 pregnancies and delivered 136 children. There were two gemellary deliveries. Nine women had a spontaneous and 16 an induced abortion, of which 4 were performed on therapeutic indication. For a woman with ulcerative colitis the risk of an exacerbation of the bowel disease was 32% per year in her fertile years, whereas it was 34% per year during pregnancy. This difference is not statistically significant. As compared with women with an inactive bowel disease, women in whom the disease was active at the start of pregnancy had a small but significantly greater risk of spontaneous abortion and premature delivery. The frequency of malformations, prematurity, and neonatal hyperbilirubinaemia was not higher in the children of ulcerative colitis mothers than in those of healthy mothers. Treatment with sulphasalazine, salazosulphadimidine, and corticosteroids had no influence on the course and outcome of pregnancy. Birth length and weight of the children of mothers with ulcerative colitis equalled those for children of healthy mothers. In conclusion, pregnancy does not necessitate any change in the usual medical treatment of ulcerative colitis. Women with ulcerative colitis should be advised preferably to conceive at a time when their bowel disease is inactive. Generally, ulcerative colitis constitutes no indication for induced abortion.

Sulfasalazine is of proven therapeutic value in chronic inflammatory bowel diseases (ulcerative colitis and Crohn's disease in the colon) of mild and moderate degrees. However, owing to adverse effects (allergy, dyspepsia), this drug often has to be withdrawn. The present work analyzes, in 704 patients with chronic inflammatory bowel disease, the frequency of such side effects that over a 15-year period necessitated withdrawal of sulfasalazine (Salazopyrin). A total of 17% of the patients developed dyspeptic manifestations, whereas extraintestinal manifestations, mainly exanthema and fever, occurred in 13%. Out of 121 patients with dyspeptic troubles, 107 had Salazopyrin replaced by EN Salazopyrin (dragées), and in 102 of them dyspepsia did not recur. Salazosulfadimidine (Azudimidine) was given to 48 patients who had developed extraintestinal manifestations when receiving sulfasalazine. Only 29% of these patients developed intolerance to this drug too. Generally, dyspepsia occurred within the first days after institution of treatment, extraintestinal manifestations after 1 to 3 weeks.

The response to 5-aminosalicylic acid (5-ASA) in mild and moderately active Crohn's disease localized in the small bowel was studied in a randomized, double-blind, placebo-controlled trial in four centres. Sixty-seven patients were included, of whom 30 were treated with 1500 mg slow-release 5-ASA/day (Pentasa) for a scheduled period of 16 weeks. In the 5-ASA group 40% of the patients improved, versus 30% of the placebo-treated group ('intent to treat' basis; p greater than 0.1). Four of the patients treated with 5-ASA left the study owing to disease deterioration, versus 10 of the placebo-treated patients (p greater than 0.2). Seventeen patients were secondarily excluded, and the remaining 50 patients (23 receiving 5-ASA) were reevaluated in greater detail. No statistically significant differences in outcome were shown. Three patients (one given 5-ASA) were withdrawn from the study because of presumed side effects, but no serious adverse reactions were recorded. The present results indicate that 5-ASA, at least in the dosage used, is not superior to placebo. Nevertheless, trends towards a beneficial effect in Crohn's disease in the small bowel justify further clinical trials with a larger dosage of 5-ASA.

Fifteen adult and 19 pediatric outpatients with ulcerative colitis were studied to determine the steady-state kinetics of 5-aminosalicylic acid (5-ASA) released from salazosulfapyridine (SASP). Results of excretion in adults (mean 24-h recovery of 5-ASA, 21% in urine and 57% in feces) were compatible with those of healthy volunteers. Since mean SASP dose/kg body weight (about 50 mg/kg) and compliance (reflected in sulfapyridine recovery) were equal in adults and pediatric patients, the results of the patient groups could be compared. Near-complete azo reduction of SASP occurs in children. Absorption and excretion of 5-ASA and metabolism to acetyl-5-ASA did not differ statistically between pediatric and adult patients. However, the fecal excretion of the drug and its metabolites was significantly lower in young patients, although fecal concentrations were the same. The present results demonstrate that SASP is an excellent sustained-release drug for the delivery of 5-ASA to the lower part of the bowel system and provide a reference for comparison of 5-ASA kinetics after treatment with newer 5-ASA preparations.