A double-blind, placebo-controlled, randomized study to evaluate the efficacy, safety and tolerability of tegaserod in patients with irritable bowel syndrome.

BACKGROUND: Tegaserod has been shown to be an effective therapy for the multiple symptoms of irritable bowel syndrome (IBS) in Western and Asia-Pacific populations. This study evaluated the efficacy, safety and tolerability of tegaserod versus placebo in patients with IBS. METHODS: Patients with IBS (excluding those whose primary bowel symptom was diarrhoea) were randomized to receive either tegaserod 6 mg b.i.d. (n = 327) or placebo (n = 320) for a 12-week double-blind treatment period. The primary efficacy variable (over weeks 1 to 4) was the response to the question: 'Over the past week do you consider that you have had satisfactory relief from your IBS symptoms?' Secondary efficacy variables assessed overall satisfactory relief over 12 weeks and the individual IBS symptoms. RESULTS: Overall satisfactory relief was greater in the tegaserod group than in the placebo group. Over weeks I to 4, the odds ratio was 1.54, that is, the odds of satisfactory relief were 54% higher in the tegaserod group than in the placebo group (95% confidence interval for odds ratio (CI) (1.14, 2.08), P = 0.0049). Over weeks 1 to 12, the odds ratio was 1.78, that is, the odds of satisfactory relief were 78% higher in the tegaserod group than in the placebo group (95% CI (1.35, 2.34), P < 0.0001). A statistically significant therapeutic gain over placebo was observed for the majority of weeks from week 1 to week 12 (except weeks I and 4), with a mean therapeutic gain of 7.3 and 10.6 percentage points over weeks 1-4 and weeks 1-12, respectively. Headache was the most commonly reported adverse event (8.0% tegaserod versus 4.7% placebo). Diarrhoea was reported by 9.2% of patients on tegaserod (1.3% on placebo) and led to discontinuation in 2.8% of tegaserod patients. CONCLUSION: Tegaserod 6 mg b.i.d. is an effective, safe and well-tolerated treatment in patients suffering from IBS without diarrhoea as primary bowel symptom.

Is an increased intestinal permeability a valid predictor of relapse in Crohn disease?

BACKGROUND: An increased intestinal permeability (IP) may be a pathogenetic factor in Crohn disease (CD). Increases in IP could be an indicator of subclinical disease and precede clinical relapses. We examined whether an increased IP is a valid predictor of relapse in CD. METHODS: 27 patients with CD in remission (CDAI <150) and 22 healthy controls ingested 3.7 MBq of 51Cr-EDTA, 20 kBq of 14C-mannitol and 5 g of unlabelled mannitol in 100 ml of distilled water. The percent urine excretion (24 h) of labelled markers was determined. Patients were followed for 1 year or until relapse, defined as CDAI > 150 and > 50 from baseline. RESULTS: Median (25th-75th percentiles). The excretion of 51Cr-EDTA was 1.55% (1.13%-2.53%) for patients and 1.20% (1.11%-1.44%) for controls (P = 0.04). Three of 9 patients with a raised, and 6 of 18 patients with a normal, 51Cr-EDTA excretion relapsed (P = 1.00; Fisher's exact test). Thus, the specificity and sensitivity of the 51Cr-EDTA test as a predictor of relapse was 67% and 33%, respectively. The 51Cr-EDTA/14C-mannitol index was 0.060 (0.037-0.093) for patients and 0.045 (0.038-0.054) for controls (P = 0.06). Four of 12 patients with a raised, and 5 of 15 patients with a normal, index relapsed (P = 1.00; Fisher's exact test). Thus, the specificity and sensitivity of the index test as a predictor of relapse was 56% and 44%, respectively. For controls and patients in remission, who were tested twice, variability of and fluctuations in both the 51Cr-EDTA excretion and the index were greatest for patients. CONCLUSIONS: This study supports previous findings of an increased IP in patients with CD. Although fluctuations in the permeation of markers were pronounced in CD, neither the excretion of 51Cr-EDTA nor the 51Cr-EDTA/14C-mannitol index test were valid predictors of relapse in CD.

Characterization of a culturable "Gastrospirillum hominis" (Helicobacter heilmannii) strain isolated from human gastric mucosa.

Spiral organisms were isolated from an antral gastric mucosal biopsy specimen from a dyspeptic patient with gastritis. Only corkscrew-shaped organisms resembling "Gastrospirillum hominis" ("Helicobacter heilmannii") but no Helicobacter pylori-like organisms were seen in histological sections. H. pylori was not cultured from specimens from this patient. On the basis of biochemical reactions, morphology, ultrastructure, and 16S DNA sequencing, the isolated "G. hominis" was shown to be a true Helicobacter sp. very similar to Helicobacter felis and the "Gastrospirillum" but was separate from H. pylori. "G. hominis" is a pleomorphic gram-negative cork-screw-shaped, motile rod with 3 to 8 coils and a wavelength of about 1 micrometer. In contrast to H. pylori, it has up to 14 sheathed flagellar uni- or bipolar fibrils but no periplasmic fibrils. "G. hominis" grows under microaerobic conditions at 36 and 41 degrees C on 7% lysed, defibrinated horse blood agar plates within 3 to 7 days and can be subcultured under microaerobic but not under anaerobic conditions on media similar to those used for H. pylori and H. felis. The small translucent colonies were, in contrast to those of H. felis, indistinguishable from those of H. pylori. "G. hominis" is, like H. pylori and H. felis, motile, is oxidase, catalase, nitrite, nitrate, and urease positive, and produces alkaline phosphatase and arginine arylamidase. Like H. pylori and H. felis, it is sensitive to cephalothin (30-microgram disc), resistant to nalidixic acid (30-microgram disc), and sensitive to most other antibiotics. The 16S DNA sequence clusters "G. hominis" together with "Gastrospirillum," H. felis, Helicobacter bizzozeronii, Helicobacter salmonii, Helicobacter nemestrinae, Helicobacter acinonychis, and H. pylori.

The diagnostic value of oesophageal radionuclide transit in patients admitted for but without acute myocardial infarction.

The use of radionuclide transit (RT) as a screening test for chest pain of oesophageal origin has been debated. The aim of this study was to determine the value of RT as a screening test for oesophageal disorders in comparison with oesophageal manometry in patients admitted with acute chest pain but without acute myocardial infarction (non-AMI patients), and to assess the frequency of oesophageal disease present in these patients. A total of 222 non-AMI patients entered the study. An extensive examination programme comprised noninvasive cardiac studies, pulmonary studies, a careful physical examination of the musculoskeletal system, and oesophago-gastric examinations including endoscopy, pH monitoring of the oesophagus and a Bernstein test. In 91% of the patients one or more diagnoses were obtained. Based on clinical and laboratory data a 'consensus' diagnosis was made. With manometry as the reference RT had a poor sensitivity (35%) but an acceptable specificity (82%). With the consensus diagnosis as the gold standard the sensitivities of both manometry and RT were poor (29%), whereas the specificity of RT, but not of manometry, was very high (97%). Gastrointestinal diagnoses were found in 57% of the patients. In conclusion, none of the applied oesophageal examinations are valuable as single screening tests. Both RT and manometry have low sensitivities. RT may be used as a cheap, noninvasive and rapid supplementary examination. When positive, it strongly supports further invasive studies of the oesophagus in non-AMI patients with unexplained chest pain.

The histopathology of human gastric mucosa inhabited by Helicobacter heilmannii-like (Gastrospirillum hominis) organisms, including the first culturable case.

The aim was to determine the prevalence of Helicobacter heilmannii-like organisms in human gastric biopsies and the associated histology compared with that of Helicobacter pylori-bearing gastric biopsies. Furthermore, the feasibility of culturing H. heilmannii was examined. A consecutive series of 727 gastric biopsies from 650 patients were prospectively scrutinized for H. heilmannii. Their distribution pattern was recorded as well as the affiliated morphology of the gastric mucosa. Additional biopsies from some of the patients were examined microbiologically. Four cases (0.6%)(95% confidence intervals: 0.01-1.2%) of the examined material harboured H. heilmannii. The bacterial burden was graded as sparse in three cases, moderate in one case. The distribution pattern was patchy; thus, in no case did all biopsies from one endoscopy comprise H. heilmannii. Adhesion to epithelial cells was infrequent. A mild gastritis, active in three cases, characterized all biopsies. Lymphoid aggregates occurred in biopsies from three patients. Micropapillary tufting of the epithelial layer and intestinal metaplasia were not apparent. Culture studies proved successful in the one of the four cases assayed. In conclusion the morphology of H. heilmannii-bearing mucosa deviates from that of H. pylori-associated mucosa by the absence of epithelial damage in the former. This observation can in part be explained by the predominant location of H. heilmannii at a distance from the epithelium in contrast to the conspicuous H. pylori adhesion to epithelial cells, coupled with a usually low bacterial burden and patchy occurrence of H. heilmannii as opposed to the generally more heavy infestation with H. pylori.

[The long-term prognosis of patients with acute chest pain of various origins]. / Langtidsprognosen for patienter med akutte brystsmerter af forskellig oprindelse.

A total of 204 patients with acute chest pain, but without myocardial infarction (non-AMI) were included. In 56 a definite diagnosis was obtained within 24-48 hours of admission. The remaining 148 patients underwent a comprehensive examination program. Ischaemic heart disease (IHD) was diagnosed in 64 patients, 81 had gastro-oesophageal disorders, 58 chest wall disorders, nine pericarditis, five pulmonary embolism, four pneumonia/pleuritis, three pulmonary cancer, two dissecting aortic aneurysm, one aortic stenosis and one herpes zoster. During 33 months of follow-up, 31 of the 64 patients with IHD had a cardiac event (cardiac deaths, non-fatal AMI, bypass surgery or PTCA) whereas only three events occurred among the 140 patients without IHD (p < 0.00001). However, the frequency of readmissions and of recurrent episodes of chest pain were similar in the three major diagnostic groups (NS). It is concluded that the high risk subset of a non-AMI population can be identified by means of non-invasive cardiac examination. The remainder who have other diagnoses are at low risk. However, the morbidity is high with frequent readmissions and recurrent episodes of chest pain, and the need for development of strategies with regard to diagnosis and treatment of these patients is emphasized.

Specific neutrophil hyporesponsiveness in chronic Helicobacter pylori infection.

The release from mucosal neutrophils of reactive oxygen species (ROS) is believed to be an important part of the pathogenesis of Helicobacter pylori-associated gastritis and duodenal ulcer. In this study, bacterial sonicates prepared from 1 reference and 29 patient strains were used to stimulate ROS release from peripheral blood neutrophils. In 29 H. pylori-positive patients, the neutrophil response toward the homologous strain was absent. In contrast, a significant response was observed toward the reference strain. In addition, on stimulation of neutrophils from 29 patients without H. pylori infection, ROS release was significant. The stimulatory effect on neutrophils by FMLP was comparable in the 2 groups. It is concluded that a specific neutrophil hyporesponsiveness in ROS release toward the homologous R. pylori strain exists. This feature has, to our knowledge, not been described previously for neutrophil responses to any human pathogen.

The diagnoses of patients admitted with acute chest pain but without myocardial infarction.

OBJECTIVE: The purpose of this study was to describe the frequencies of various diagnoses in patients admitted with acute chest pain, but without acute myocardial infarction, and to evaluate a non-invasive screening programme for these patients. PATIENTS: A total of 204 consecutive non-acute myocardial infarction patients were included. Fifty-six had a definite diagnosis within 48 h, whereas 148 patients underwent an examination programme including pulmonary scintigraphy, echocardiography, exercise electrocardiography, myocardial scintigraphy, Holter monitoring, hyperventilation test, oesophago-gastro-duodenoscopy, 3 h monitoring of oesophageal pH, oesophageal manometry, Bernstein test, physical examination of the chest wall and thoracic spine, bronchial histamine provocation test and ultrasonic examination of the abdomen. RESULTS: According to predefined criteria, 186 patients (91%) had at least one diagnosis, 144 had one, whereas 39 had two, and three patients had three diagnoses. In 18 patients no diagnosis was obtained. The diagnoses belonged mainly to three groups: (1) ischaemic heart disease (n = 64); (2) gastro-oesophageal diseases (n = 85); (3) chest-wall syndromes (n = 58). Less frequent diagnoses included pulmonary embolism, pleuritis/pneumonia, lung cancer, aortic stenosis, aortic aneurysm and herpes zoster. CONCLUSIONS: The high risk subset of a non-acute myocardial infarction population can be identified by means of a clinical evaluation and non-invasive cardiac examinations. Among the remainder, pulmonary embolism, gastro-oesophageal diseases and chest-wall syndromes should be paid special attention. A careful physical examination of the chest wall and upper endoscopy seems to be the most cost-beneficial examination to employ in this subset.

[Measurement of intestinal permeability]. / Intestinal permeabilitetsmåling.

The intestinal epithelium has the dual functions of being an absorptive organ and acting as a barrier to the permeation of potentially harmful compounds and organisms. The theory behind measurement of intestinal permeability in human studies as well as selected studies of intestinal permeability are presented. Intestinal permeability studies as diagnostic, prognostic, sequential and screening parameters are illuminated- and the importance of changed intestinal permeability in the pathogenesis and maintenance of disease is discussed. Measuring of intestinal permeability can be used as both a prognostic and diagnostic tool, and maybe also as a screening parameter. The method may in the future turn out to be an important tool in the management of various diseases.

Long-term risk of death, cardiac events and recurrent chest pain in patients with acute chest pain of different origin.

The purpose of the study was to describe the prognosis of patients with acute chest pain of different origin, but without myocardial infarction (non-AMI). A total of 204 patients were included. In 56, a definite diagnosis was obtained within 24-48 H of admission. The remaining 148 patients underwent the following examinations: exercise test, myocardial scintigraphy, echocardiography, Holter monitoring, hyperventilation test, oesophago-gastro-duodenoscopy, oesophageal manometry, oesophageal pH monitoring, Bernstein test, physical chest wall examination, bronchial histamine test, chest X-ray and ultrasonic upper abdominal examination. Ischaemic heart disease (IHD) was diagnosed in 64 patients, 81 had gastro-oesophageal disorders, 58 chest wall disorders, 9 pericarditis, 5 pulmonary embolism, 4 pneumonia/pleuritis, 3 pulmonary cancer, 2 dissecting aortic aneurysm, 1 aortic stenosis and 1 herpes zoster. During follow-up of 33 months, 31 of the 64 patients with IHD had a cardiac event (cardiac deaths, non-fatal AMI, bypass surgery or PTCA), whereas only 3 event occurred among the 140 patients without IHD (p < 0.00001). However, the frequency of readmissions and of recurrent episodes of chest pain were similar in the 3 major diagnostic groups (NS). To conclude, the high-risk subset of a non-AMI population can be identified by means of non-invasive cardiac examination. The remainder who have other diagnoses are at low risk. However, the morbidity is high with frequent readmissions and recurrent episodes of chest pain and the need for development of strategies with regard to diagnosis and treatment of these patients are emphasized.

Localized tuberculosis of the oesophagus: a rare condition.

This report describes the case of a male patient with progressive dysphagia, epigastric pain, odynophagia, generalized weakness and a mid-oesophagus ulceration in which biopsies showed acid-fast bacilli and histological evidence of tuberculosis. Culture of the biopsies and the sputum revealed mycobacterium tuberculosis. There were no respiratory symptoms, and radiographs did not reveal evidence of pulmonary tuberculosis. The patient responded well to antituberculous therapy and he is alive and well 7 years later, without any signs of relapse. The involvement of the oesophagus as the only demonstrable localization of tuberculosis is an extremely rare condition, which should always be considered as differential diagnosis in dyspepsia of unknown origin.

Development of a PCR-based technique for detection of Helicobacter pylori.

A primer-set was designed for specific detection of genes that encode for 16S rRNA of Helicobacter pylori, using direct polymerase chain reaction (PCR). The primers were selected in the hypervariable regions, derived from a complete small subunit 16S rRNA sequence of the reference strain H. pylori CCUG 17874. The primer-set amplified a 537 base pair (bp) sequence specifically from chromosomal H. pylori DNA. Amplification of purified chromosomal H. pylori DNA was achieved at concentrations as low as 1 femto gram (fg), equivalent to 5 bacteria. Furthermore, as few as 1 lysed H. pylori cell was detected by this PCR technique. The specificity of the primers was 100%, since purified chromosomal DNA was detected from all 32 various H. pylori isolates, whereas no other bacteria species were detected, whether related to Helicobacter or not. The 16S rDNA primers successfully detected H. pylori in antral biopsy specimens collected from infected patients.

Effect of intravenous infusion of omeprazole and ranitidine on twenty-four-hour intragastric pH in patients with a history of duodenal ulcer.

The effect on intragastric pH of two different dose regimens of continuous intravenous infusion of omeprazole (4 or 8 mg/h after a bolus of 80 mg), and ranitidine (0.25 mg/kg/h after a bolus of 50 mg) was studied in 10 patients with duodenal ulcer disease in symptomatic remission. The pH was monitored over 24-hour periods during fasting in a cross-over, randomised design including a baseline period. With the high omeprazole dose it was possible to maintain a pH > or = 4 in all patients but 1 and 6 of the patients also maintained a pH > or = 6. The lower dose of omeprazole seemed to be somewhat less effective. Continuous infusion of ranitidine was as efficient as the higher omeprazole infusion although with a tendency to decreased pH levels towards the end of the 24-hour period. Thus, in order to obtain consistently high pH levels of 4-6 over a prolonged period a continuous infusion of omeprazole, an 80-mg bolus plus a continuous infusion of 8 mg/h seem to be needed.

Treatment of severe obesity with a highly selective serotonin re-uptake inhibitor as a supplement to a low calorie diet.

Inhibitors of serotonin (5HT) re-uptake have generally been successful in inducing modest but statistically significant weight reductions in clinical trials. Citalopram is a new, highly selective inhibitor of 5HT re-uptake. It is effective and safe in relieving major depression at doses up to 60 mg daily. In our study, 72 severely obese subjects (BMI > 44 kg/m2) were instructed in a 4500 kJ carbohydrate-rich (50%) diet. The initial two week run-in diet+placebo period was followed by a 12 week double-blind period of diet+citalopram or placebo. There were seven withdrawals during the initial two weeks. Of the remaining 65 patients, 45 were randomized to 60 mg citalopram daily and 20 received placebo. A trend towards a higher frequency of nausea at week 6 was noted in the citalopram group. Weight loss during the initial two weeks was 2.01 kg. In the following 12 weeks, mean weight loss was 3.78 kg in the citalopram group vs. 2.64 kg in the placebo group (P = 0.29), reductions occurring almost entirely during the initial four weeks of the treatment period. We conclude that citalopram is of no clinical value in the treatment of obesity when added to a 4500 kJ diet.

[Do pregnant women need supplementation of folic acid?]. / Behøver gravide tilskud af folinsyre?

Neutral tube defects (NTDs) occur at an incidence of about 0.01 per cent, and in Denmark 40-50 new cases are recorded annually. Although the metabolism of folic acid increases during pregnancy, the dietary supply is marginal. Finding in recent studies suggest that folic acid supplementation as prophylactic treatment of gravidae reduces the incidence of NTDs. Folic acid prophylaxis is already being recommended as a general policy, with treatment starting before conception.

Prevalence of antibodies against heat-stable antigens from Helicobacter pylori in patients with dyspeptic symptoms and normal persons.

Heat-stable antigens from Helicobacter pylori were investigated for the detection of serum IgG, IgA and IgM antibodies against H. pylori by an ELISA technique. Antibody titers against H. pylori were measured in 167 dyspeptic patients, of whom 96 were H. pylori positive confirmed by culture or microscopy, and in 482 controls (0-98 years). Increased IgG antibody titers were found significantly more often in dyspeptic patients with active chronic gastritis than in patients with normal morphology, as well as in H. pylori-positive patients as compared to H. pylori-negative patients, independent of the endoscopic findings. The heat-stable antigens were compared with acid glycine-extracted antigens and a high degree of concordance was found in the results obtained with the two antigen preparations. The differences in the IgA antibody titers against H. pylori between H. pylori-positive and H. pylori-negative dyspeptic patients were significant and may be useful to confirm a borderline IgG result. No differences were found in IgM antibody titer between H. pylori-positive and -negative patients. The greatest age-dependent increase in IgG and IgA antibody titers was found in children, and if a lower cut-off level is used for children than for adults, as has been proposed, the proportion of people with increased antibody titers against H. pylori would be almost constant from the age of between five and 10 years until the time between 61 and 80 years. Comparison of H. pylori IgG antibodies with IgG antibodies against Campylobacter jejuni and total antibodies against cytomegalovirus (CMV) showed a greater similarity between H. pylori and C. jejuni (R = 0.51) than between H. pylori and CMV (R = 0.22). This may possibly be caused by cross-reactions between H. pylori and C. jejuni. The H. pylori heat-stabile antigen seems not to be very different from other crude H. pylori antigens like acid glycine-extracted antigens, but purification and characterization of the antigens are needed to improve antibody assays.

[Acute recurrent chest pain originating in the esophagus. A review]. / Akutte og recidiverende brystsmerter udløstsmeter udløst fra esophagus.e En overightkikel.

In half of the patients admitted for observation for acute myocardial infarction, this diagnosis is disproved. Gastro-oesophageal reflux and/or disturbances of oesophageal motility are the cause of the thoracic pain resulting in hospitalization in 16-34% of these patients. In 13-59% of the patients with chronic recurrent thoracic pain without demonstrable ischaemic cardiac disease (IHD), oesophageal disease is, similarly, considered to be the cause of the pain. It is not possible to distinguish whether the pain is caused by oesophageal disease or IHD on the basis of the history, but the differential diagnosis is important as patients with pain on account of oesophageal disease have a good prognosis as regards mortality. The physical and mental conditions of the patients may be improved if the correct diagnosis is established and treatment instituted. Methods of examination to demonstrate oesophageal disease are described. On account of the frequency of the condition and the extent of the methods of examination, a programme of investigation is proposed for patients suspected of having thoracic pain due to oesophageal disease.

Effect of cisapride on relapse of reflux oesophagitis, healed with an antisecretory drug.

Maintenance treatment with cisapride was evaluated in 298 patients in whom reflux oesophagitis had been healed with antisecretory drugs. Initially, 34% of the patients had grade-I oesophagitis, 33% had grade II, and 33% had grade III. The patients were treated with 20 mg cisapride twice daily or placebo for 6 months or until endoscopic relapse was shown if this occurred earlier. Survival analysis showed that cisapride significantly prolonged the time to endoscopic relapse in grade-I patients (P = 0.02). The intergroup difference in symptomatic relapse in all patients was also significant (P = 0.010). The effect of cisapride was less clearcut in grade II or III, and/or in patients healed with omeprazole. Factors associated with early relapse were placebo therapy, prior omeprazole therapy, duration of pre-trial symptomatic period, and initial endoscopic severity grade. Adverse experiences were limited; diarrhoea was reported by 9% of the cisapride patients.