Clinical trial: colectomy after rescue therapy in ulcerative colitis - 3-year follow-up of the Swedish-Danish controlled infliximab study.

BACKGROUND: The long-term efficacy of infliximab as rescue therapy in steroid-refractory ulcerative colitis is not well described. AIM: To examine the long-term efficacy of infliximab as a rescue therapy through a 3-year follow-up of a previous placebo-controlled trial of infliximab in acute steroid-refractory ulcerative colitis. METHOD: In the original study, 45 patients were randomized to a single infusion of infliximab 5 mg/kg or placebo, and at 3 months, 7/24 patients given infliximab were operated vs. 14/21 patients given placebo. Three years or later, patients were asked to participate in a clinical follow-up. RESULTS: Another seven patients underwent colectomy during follow-up: five in the infliximab group and two in the placebo group. After 3 years, a total of 12/24 (50%) patients given infliximab and 16/21 (76%) given placebo (P = 0.012) had a colectomy. None of eight patients in endoscopic remission at 3 months later had a colectomy compared with 7/14 (50%) patients who were not in remission (P=0.02). There was no mortality. CONCLUSION: The benefit of rescue therapy with infliximab in steroid-refractory acute ulcerative colitis remained after 3 years. The main advantage of infliximab treatment occurred during the first 3 months, whereas subsequent colectomy rates were similar in the two groups. Mucosal healing at 3 months influenced later risk of colectomy.

Salmonella in Black-headed gulls ( Larus ridibundus); prevalence, genotypes and influence on Salmonella epidemiology.

During a period of 3 years, 1998-2000, 1047 faecal swabs from Black-headed gulls were sampled at one location in Southern Sweden. Salmonella spp. was found in 28 individuals (2.7%) and the dominating serotype found was S. Typhimurium (83%). Twenty-five per cent of the Salmonella-infected gulls were later recaptured and re-sampled. We found that Salmonella infection in Black-headed gulls was of short duration, and that infection in this bird species was predominantly expressed as carriage without disease manifestations. All S. Typhimurium isolates were subjected to antibiotic resistance profiling and molecular characterization by pulsed-field gel electrophoresis and IS200 polymerase chain reaction. The S. Typhimurium gull isolates were compared to human and domestic animal isolates of the same serotype and phage type. We found genetic relatedness of S. Typhimurium DT195 isolates from gulls, domestic animals and humans, indicating that Black-headed gulls might play a role in the spread of S. Typhimurium in Sweden.

Psychological factors in irritable bowel syndrome: a population-based study of patients, non-patients and controls.

BACKGROUND: It has been suggested that psychopathology in irritable bowel syndrome (IBS) patients is a function of patient status rather than of the disease. Although there are many studies comparing IBS patients, IBS non-patients, and controls with each other, no previous study has recruited all three groups from a representative community sample and had all subjects diagnosed by a physician. In the present study we aimed to compare psychological factors in IBS patients, IBS non-patients, and normal controls in a sample recruited from the population. METHODS: Subjects aged 18-45 years were recruited from a random sample of the normal population. Seventeen (2 M and 15 F) IBS patients were matched by sex and age with IBS non-patients and normals. Measures of personality traits, interpersonal distress, and temporary psychological distress were used. A physician diagnosed all 51 subjects in order to exclude possible gastrointestinal diagnoses other than IBS. RESULTS: Controls often differed from IBS non-patients and patients on the personality, interpersonal, and psychological distress measures, while IBS non-patients and patients very rarely differed from each other. All three groups were non-alexithymic. CONCLUSIONS: The results indicate that there are psychopathological differences between normals and IBS persons (patients and non-patients), but they could not confirm that psychopathology was a function of patient status. Whether this psychopathology is a vulnerability factor for IBS, or a consequence of it, remains to be studied.

Psychological Factors in Irritable Bowel Syndrome: a Population-based Study of Patients, Non-patients and Controls.

BACKGROUND: It has been suggested that psychopathology in irritable bowel syndrome (IBS) patients is a function of patient status rather than of the disease. Although there are many studies comparing IBS patients, IBS non-patients, and controls with each other, no previous study has recruited all three groups from a representative community sample and had all subjects diagnosed by a physician. In the present study we aimed to compare psychological factors in IBS patients, IBS non-patients, and normal controls in a sample recruited from the population. METHODS: Subjects aged 18-45 years were recruited from a random sample of the normal population. Seventeen (2 M and 15 F) IBS patients were matched by sex and age with IBS non-patients and normals. Measures of personality traits, interpersonal distress, and temporary psychological distress were used. A physician diagnosed all 51 subjects in order to exclude possible gastrointestinal diagnoses other than IBS. RESULTS: Controls often differed from IBS non-patients and patients on the personality, interpersonal, and psychological distress measures, while IBS non-patients and patients very rarely differed from each other. All three groups were non-alexithymic. CONCLUSIONS: The results indicate that there are psychopathological differences between normals and IBS persons (patients and non-patients), but they could not confirm that psychopathology was a function of patient status. Whether this psychopathology is a vulnerability factor for IBS, or a consequence of it, remains to be studied.

Increased rectal nitric oxide in coeliac disease after local challenge with gluten.

BACKGROUND: Coeliac disease is an inflammatory disorder characterized by reversible atrophy of small intestinal villi following the ingestion of gluten. Earlier studies indicate that the inflammatory response to gluten may occur also very distally in the gastrointestinal tract. The aim of this study was to evaluate whether rectal challenge with gluten would trigger an increased local production of the gas nitric oxide (NO), a novel marker of intestinal inflammation. METHODS: Rectal challenge with partially digested gluten was performed in 20 patients with treated coeliac disease and in 13 healthy controls. Luminal levels of NO were measured in the rectum at 0, 8 and 24 h using a chemiluminescence technique. RESULTS: In patients with coeliac disease mean rectal NO increased from 235+/-90 parts per billion (ppb) at 0 h to 4965+/-1653 ppb at 24 h (P < 0.005). In the control group there was no significant increase. One control subject responded with high NO levels at 24 h and the same individual tested positive for anti-endomysium IgA antibodies. Subsequent duodenal biopsing showed substantial villusatrophy. CONCLUSIONS: Rectal challenge with gluten results in increased luminal levels of NO in a group of patients with treated coeliac disease. Further studies are needed to evaluate the role of NO in coeliac disease and the potential usefulness of rectal NO measurements in aiding diagnosis of this intestinal disorder.

A population study on irritable bowel syndrome and mental health.

BACKGROUND: Irritable bowel syndrome (IBS) is commonly thought to be associated with psychologic distress. However, in some studies only persons who had sought medical care for IBS (IBS patients) showed an increased frequency of psychiatric symptoms, and nonpatients did not differ significantly from normal subjects. Our aims were 1) to estimate the prevalence of IBS in the population aged 18-45 years, 2) to find the proportion seeking medical care for IBS, and 3) to compare IBS subjects with normals, and IBS patients with IBS nonpatients with regard to mental health. METHODS: Questionnaires on IBS symptoms and the General Health Questionnaire (GHQ) were mailed to 5000 randomly sampled persons aged 18-45 years. The response rate was 58%. RESULTS: IBS was found in 7.4% of the men and 13.3% of the women. Those who had sought medical attention had more severe symptoms. The Likert mean score on the GHQ was 4.7 (95% confidence interval, 4.4-5.0) points higher for the IBS group than for normals (P < 0.001). There was no difference in GHQ scores between IBS patients and nonpatients. CONCLUSIONS: The results indicate that IBS per se is associated with more psychiatric distress, regardless of medical care-seeking. Seeking medical care is associated with more severe IBS symptoms.

Reversible increase in tight junction permeability to macromolecules in rat ileal mucosa in vitro by sodium caprate, a constituent of milk fat.

Intestinal tight junction function is thought to be of importance in the pathogenesis of various diseases. The regulation of uptake of macromolecules via the tight junctions is largely unknown. Effects of luminal sodium caprate (10 mM), a dairy product constituent, and cytochalasin B (30 microM), were studied in rat ileum in vitro in Ussing chambers. Both agents caused a reversible fall in potential difference and increased [51Cr]EDTA permeability. In addition, sodium caprate induced increased permeability to polysucrose (15,000 daltons) and opening of the tight junctions as visualized by transmission electron microscopy. Dose-response patterns suggested mainly dose-dependent differences between the agents. Confocal laser scanning microscopy suggested paracellular permeation of polysucrose. Luminal sodium caprate, a food constituent, can increase tight junction permeability, allowing passage of macromolecules, without affecting epithelial viability. Increased permeability to medium-sized molecules does not necessarily coincide with increased paracellular uptake of protein-sized molecules.

Evaluation of the lactulose/mannitol and 51Cr-ethylenediaminetetraacetic acid/14C-mannitol methods for intestinal permeability.

BACKGROUND: We earlier compared the lactulose/mannitol and 51Cr-ethylenediaminetetraacetic acid (EDTA)/14C-mannitol methods for intestinal permeability We have now investigated an increased number of control subjects, with special regard to the influence of urinary volume, sex, age, and smoking on marker excretion, and patients with intestinal disorders, with special regard to correlations between markers. METHODS: The 0- to 6-h urinary excretion of orally administered markers was measured in 65 control subjects and in 70 patients. RESULTS: In the control group excretion of mannitol and 14C-mannitol (small-pore permeability markers) was strongly correlated to urinary volume, whereas such correlation was weak for lactulose and absent for 51Cr-EDTA (large-pore permeability markers). No sex difference in marker excretion was found, but correlation to urinary volume was more pronounced in males. There was a slightly decreasing excretion of markers with increasing age, reaching significance for 51Cr-EDTA and 14C-mannitol; their excretion ratio was unaffected. Smoking did not significantly affect marker excretion. In the patient group the excretion of large-pore markers tended to be higher and that of small-pore markers to be lower than in the control group; correlation between the large-pore markers, between the small-pore markers, and between the large-pore/small-pore marker ratios was higher than in the control group. CONCLUSIONS: Correction for urinary volume substantially reduces variability in small-pore marker excretion. Excretion of both types of markers tends to decrease with age, the large-pore/small-pore marker ratio remaining unchanged. Smoking does not affect small-intestinal permeability. 14C-mannitol is preferred to chemically determined mannitol owing to lower test variability.

Detection of naproxen-induced intestinal permeability change may be facilitated by adding a standardized meal but not by forming marker ratios.

BACKGROUND: We recently compared the intestinal permeability markers polysucrose (PS) 15,000, 51Cr-ethylenediaminetetraacetic acid (EDTA), and 14C-mannitol in healthy humans. We have now studied the ability of these markers to show non-steroidal anti-inflammatory drug (NSAID)-induced intestinal damage, with special regard to the possibility of improving discrimination versus healthy intestine by using a hyperosmolar test solution, adding a standardized liquid meal, calculating paracellular/ transcellular marker excretion ratios, or correcting excretion values for urinary volume. METHODS: Seventeen healthy volunteers ingested a solution containing PS 15,000, 51Cr-EDTA, and 14C-mannitol before and after 1 week of naproxen intake, the solution being isosmolar, hyperosmolar, or isosmolar and followed by a standardized liquid meal. Fractional urinary excretion of the substances was measured over 0-4 h, 4-8 h, and 8-12 h. RESULTS: The excretion of the paracellular permeability markers PS 15,000 and 51Cr-EDTA increased after NSAID pretreatment, whereas that of the transcellular marker 14C-mannitol was unaffected. A standardized liquid meal reduced test variability for all markers and tended to improve differentiation between diseased and healthy intestine. A hyperosmolar test solution tended to improve differentiation for 51Cr-EDTA but not for PS 15,000. Calculating a paracellular/transcellular ratio or correcting excretion values for urinary volume did not improve the differentiation. CONCLUSIONS: A standardized liquid meal may improve the capacity of permeability tests to distinguish between healthy and NSAID-damaged intestine.

Comparison of polysucrose 15000, 51Cr-labelled ethylenediaminetetraacetic acid, and 14C-mannitol as markers of intestinal permeability in man.

BACKGROUND: We recently reported increased intestinal permeability to polysucrose (PS) 15000 in patients with Crohn's disease and in patients treated with non-steroidal anti-inflammatory drugs (NSAIDs). We have now compared this new macromolecular marker (14,700 D) with the conventional markers, 51Cr-labelled ethylenediaminetetraacetic acid (EDTA) (342 D) and 14C-mannitol (182 D), in healthy humans. METHODS: Twenty healthy volunteers on four occasions ingested a solution containing PS 15000, 51Cr-EDTA, and 14C-mannitol, the test solution being, respectively, isoosmolar, hyperosmolar, isoosmolar followed by a standard meal, and isoosmolar after 1 week of NSAID treatment. Fractional urinary excretion of the substances was measured over 0-4 h, 4-8 h, and 8-12 h. RESULTS: The excretion of PS 15000 was, like that of 51Cr-EDTA but unlike that of 14C-mannitol, increased by NSAID pretreatment, little affected by hyperosmolar test solution, little correlated to urinary volume, and skew with regard to frequency distribution. Despite being nominally about 40 times lower, the excretion of PS 15000 was highly correlated to that of 51Cr-EDTA but not to that of 14C-mannitol. A standard meal reduced the test variability for all three probes. CONCLUSIONS: PS 15000 may be an alternative to 51Cr-EDTA as a small-intestinal permeability marker. Inclusion of a standard meal reduces test variability.

Chronic hepatitis C in alcoholic patients: prevalence, genotypes, and correlation to liver disease.

BACKGROUND: Only one-fifth of chronic alcoholic patients develop chronic liver disease in spite of continuous alcohol abuse. Hepatitis C has been proposed to be one of several suggested factors contributing to the development of liver disease. METHODS: In 201 consecutive chronic alcoholic patients admitted to the hospital for detoxification, antibodies to hepatitis C virus (HCV) were determined, using second-generation enzyme-linked immunosorbent assay (ELISA) and recombinant immunoblot assay (RIBA) tests. Sera from patients with antibodies were tested with polymerase chain reaction (PCR) to detect HCV RNA and subsequently genotyped. RESULTS: Twenty-nine patients (14%) were positive in the ELISA and RIBA tests. HCV RNA was detected in 23 of the 29 (79%); 21 could be genotyped. Previous intravenous drug abuse was present in 18 of 29 (58%) in the positive group versus 3 of 172 (2%) in the negative group (p < 0.001), whereas the prevalence of previous blood transfusions did not differ between the groups. In one-third of the positive cases no obvious route of transmission was found. On the basis of clinical and biochemical variables and, if available, histology, altogether 6 of 29 (21%) HCV-positive patients were classified as having severe liver disease as compared with 12 of 172 (7%) HCV-negative patients (p < 0.05). HCV-positive patients with liver disease were younger than HCV-negative patients with liver disease (p < 0.05). CONCLUSIONS: Hepatitis C virus infection is common among chronic alcoholic patients in Stockholm, especially among patients with a history of intravenous drug abuse. To confirm ongoing infection, detection of HCV RNA is necessary. This infection seems to be a factor contributing to the development of liver disease in alcoholic patients.

Duodenitis--distinguishing features in a retrospective endoscopic and histological study.

Routine films of 596 upper GI endoscopies with the diagnosis of duodenitis were reviewed and a classification was made into granular (G), multi-polypoid (MP), reddened (R) and erosive (E) types. Two hundred and thirty-four histological specimens from 117 of the patients, as well as 100 specimens from 50 controls, were analyzed for villous obliteration, Brunner's gland dilatation and mucus depletion, erosion, mucosal hemorrhage and edema, atypia of the surface epithelium and gastric surface epithelial metaplasia. Inflammatory cell counts for polymorphonuclear and mononuclear cells in the epithelium, in the lamina propria together with a histological score was also made. On the basis of this study and a review of classifications of duodenitis in the literature, it is concluded that some endoscopical features like erosions and redness may represent more acute phases of duodenitis, mucosal elevations representing more hyperplastic changes and that the endoscopic classification into G, MP, R and E types seem relevant to use in clinical practice.

Change in size, shape and radiocolloid uptake of the alcoholic liver during alcohol withdrawal, as demonstrated by single photon emission computed tomography.

The volume of the total liver and separate right and left lobes was studied before and after 1 week of alcohol withdrawal in 16 consecutive alcoholics by means of single photon emission computed tomography after intravenous injection of 99Tcm-human albumin colloid; the relative tissue distribution of radioactivity was also followed. The left liver lobe increased in volume more than the right lobe during drinking and decreased more rapidly after alcohol withdrawal. Median volume reductions during 1 week of alcohol withdrawal were: total liver 12%, left lobe 26%, and right lobe 8%, indicating that half of the reduction to values of a control group was achieved during this first week. The volume of the right but not of the left lobe was significantly correlated to body size in alcoholics and in controls. The left lobe had a lower capacity to concentrate the radiocolloid than the right lobe in alcoholics and in controls. The liver/spleen, liver/bone marrow and liver/background radioactivity concentration ratios in the alcoholics increased during alcohol withdrawal. We conclude that heavy drinking causes both an increased total liver volume and a change in liver shape, with a relatively more enlarged left than right lobe, as well as a decreased capacity to concentrate radiocolloid. These changes are rapidly reversible during abstinence from alcohol.

Small intestinal bacterial overgrowth in patients with rheumatoid arthritis.

OBJECTIVES: To examine the microflora of the upper small intestine in patients with seropositive rheumatoid arthritis (RA) using a combination of microbial cultivation and tests for microbial metabolic activity. METHODS: Twenty five patients with seropositive RA, 12 achlorhydric control subjects, and 11 control subjects with normal gastric acid secretion were investigated. Disease activity was evaluated in the patients with RA by three different indices. Eight (32%) of the patients with RA had hypochlorhydria or achlorhydria. The acid secretory capacity was determined with pentagastrin stimulation. A modified Crosby capsule was used to obtain biopsy specimens and samples of intestinal fluid from the proximal jejunum; aerobic and anaerobic microbial cultivation of mucosal specimens/intestinal fluid was carried out, and gas production and microflora associated characteristics in jejunal fluid were determined. Additionally, a bile acid deconjugation breath test was performed. RESULTS: Subjects with at least one of the following findings were considered to have bacterial overgrowth: positive bile acid deconjugation test; growth of Enterobacteriaceae; positive gas production; or low tryptic activity. By these criteria half of the patients with RA with hypochlorhydria or achlorhydria and half of the achlorhydric controls had bacterial overgrowth. Thirty five per cent of the patients with RA with normal gastric acid secretion had bacterial overgrowth compared with none of the normal controls. Disease activity indices and rheumatoid factor titres were significantly higher in patients with RA with bacterial overgrowth than in those without. CONCLUSIONS: A high frequency of small intestinal bacterial overgrowth was found in patients with RA; it was associated with a high disease activity and observed in patients with hypochlorhydria or achlorhydria and in those with normal acid secretion.

Comparison between the lactulose/mannitol and 51Cr-ethylenediaminetetraacetic acid/14C-mannitol methods for intestinal permeability. Frequency distribution pattern and variability of markers and marker ratios in healthy subjects.

Urinary excretion of lactulose and mannitol, determined by gas-liquid chromatography, was compared with that of 51Cr-ethylenediaminetetraacetic acid (EDTA) and 14C-mannitol for measurement of intestinal permeability in 28 healthy humans. The 0- to 6-h excretion values for unlabelled and labelled mannitol (marker of transcellular permeability) were normally distributed, whereas excretion values for lactulose and 51Cr-EDTA (markers of paracellular permeability) were skewly distributed, as were the lactulose to mannitol and 51Cr-EDTA to 14C-mannitol ratios. Excretion of the transcellular markers but not of the paracellular markers was significantly correlated to urinary volume; correction for urinary volume resulted in decreased test variability. Significant correlation was found between lactulose and 51Cr-EDTA excretion (p < 0.01) and between mannitol and 14C-mannitol excretion (p < 0.001) but not between the lactulose to mannitol and 51Cr-EDTA to 14C-mannitol ratios (p = 0.11). Inter- and intraindividual test variability was greater for each chemically determined marker than for the corresponding isotope-labelled marker. Similarly, variability was greater for each paracellular marker than for the corresponding transcellular marker and for each paracellular/transcellular marker ratio than for the transcellular marker alone. Variability of mannitol excretion was increased by the frequent presence of food-derived mannitol in the urine.

Cell proliferation rate and tumor volume in human osteosarcoma during exposure to methotrexate. A study on tissue transplants in nude mice.

The growth inhibitory effect of methotrexate (MTX) on osteosarcoma cells was studied in dysthymic nude mice bearing tumor transplants obtained from a patient before (PRE-CHEM) and after (POST-CHEM) preoperative chemotherapy for osteosarcoma of the distal femur. Cell proliferation was analyzed by autoradiographic evaluation of the fraction of labeled cells after continuous administration of 3H-thymidine for seven days. Histomorphometric analysis of the tissue distribution of cells in the partly ossified tumors was performed. The PRE-CHEM sarcoma transplants showed a significant reduction of labeled interphases from 52 to 1.7 percent upon daily MTX treatment of the mice as compared to controls. In contrast, MTX treatment did not inhibit cell proliferation in the POST-CHEM tumor transplants in which approximately 70 percent of the cells were labeled. Tumor volume increased by 65 and 54 percent in the MTX-treated PRE- and POST-CHEM groups, respectively. During the same eight-day period, control transplant volume increased by 30 percent (PRE-CHEM) and 20 percent (POST-CHEM). Tumor cell densities in the MTX-treated groups were reduced by a factor of approximately 11 in the PRE-CHEM transplants and by a factor of approximately 1.5 in the POST-CHEM transplants. The results show that in this patient the osteosarcoma cells had changed their responsiveness to MTX during the preoperative chemotherapy period. In both the MTX-sensitive and non-sensitive tumor lines, exposure to MTX induced increased tumor volume by increasing the extra cellular matrix volume, irrespective of the neoplastic cell proliferation rate. This effect of MTX was most pronounced in the MTX-sensitive tumor line. These results indicate that in the clinical situation it is difficult to judge the response to chemotherapy even from morphologic parameters.

Microdialysis of 5-S-cysteinyldopa from interstitial fluid in cutaneous human melanoma transplanted to athymic mice.

Microdialysis was investigated as a tool for the determination of the extracellular concentration of the pigment metabolite 5-S-cysteinyldopa in human melanoma transplanted to athymic mice. Histology of the tumour with the microdialysis probes in situ showed no tissue damage. With probes equipped with polycarbonate membranes (20 kD) extraction (relative recovery) was approximately 50% at pH 4.0 and flow rates of 1 microliter/min, but at pH 7.0 recoveries were markedly lower, particularly from serum. In a first series of human melanomas transplanted to athymic mice low concentrations of 5-S-cysteinyldopa were detected in only two out of ten dialysates and were not detected in the other eight. Utilizing devices constructed for comparison of membrane characteristics in vitro we found about 4-fold higher recoveries with cuprophane and polyamide membranes than with polycarbonate membranes. Therefore newly constructed microdialysis probes (CMA/11) with cuprophane membranes were tested in vitro and gave recoveries of 38-48% from Ringer-Acetate solutions and 22-31% from serum, and the pH effects were low. When these probes were utilized in a second series of melanomas transplanted to athymic mice, 5-S-cysteinyldopa could easily be quantified in 10/10 experiments. A steady-state level of the dialysate 5-S-cysteinyldopa concentration was reached after 45 min.

Effect of heavy drinking and alcohol withdrawal on markers of carbohydrate metabolism.

A number of biochemical markers were monitored in 38 male alcoholic patients at admittance and one week later. In patients with a drinking period of greater than 3 weeks the median fasting B-glucose decreased significantly as well as S-fructosamine concentrations. The ability of S-fructosamine to identify patients with a diabetic glucose tolerance test, expressed in terms of sensitivity and specificity, was 12 and 47%, respectively; that of HbA1c was still lower.

[Abuse of laxatives as the cause of obscure prolonged diarrhea]. / Laxermedelsmissbruk som orsak till svårförklarlig långvarig diarré.

Although concealed abuse of cathartic laxatives is probably an unusual cause of severe longstanding diarrhoea, nevertheless, it is presumably a more frequent cause of such diarrhoea than are endocrine pancreatic tumours. The patient often undergoes extensive and expensive investigations before the diagnosis can be reached if indeed it ever is. The condition is almost exclusive to women, often those employed in medical care. A psychiatric background is usual, frequently with anorectic traits. The abuse often continues even after 'disclosure' and commonly defies psychotherapy.