A pro-inflammatory genotype predisposes to Barrett's esophagus.

INTRODUCTION: Severity of mucosal inflammation is shown to be associated with Barrett's esophagus (BE) development in animals. It has therefore been postulated that a strong pro-inflammatory host response predisposes to BE. AIM: To determine the impact of cytokine gene polymorphisms on the development of BE. METHODS: The multiplex SNaPshot method was used to determine interleukin (IL)-12B (A+1188C), IL-10 (C-592A, C-819T, A-1082G), IL-8 (A-251T), IL-6 (G-174C) and IL-2 (G-330T) gene polymorphisms in 255 patients with BE and 247 patients with reflux esophagitis (RE). RESULTS: The presence of the IL-12B C-allele, which is associated with increased IL-12p70 expression, was more frequently observed in BE than in RE patients [odds ratio (OR) 1.8; 95% confidence interval (CI) 1.2-2.7; P = 0.007). The risk of BE was increased in patients in whom the IL-12B C-allele coincided with a hiatal hernia (OR 2.9; 95% CI 1.32-6.58; P = 0.008). The IL-10(-1082) GG genotype, which is associated with higher IL-10 levels, was also associated with a decreased risk of BE when it was associated with the IL-12B C-allele, indicating IL-10-dependent down-regulation of IL-12p70 expression. A combination of the IL-12B AA genotype and the IL-10 AA or AG genotypes was associated with RE (OR 1.4; 95% CI 1.05-1.85; P = 0.011). CONCLUSION: A genetic profile predisposing to a strong pro-inflammatory host response, mediated by IL-12p70 and partially dependent on IL-10, is associated with BE. This risk further increases when this genotype coincides with a hiatal hernia, suggesting that exposure to gastroesophageal reflux in the presence of a pro-inflammatory genetic background is a driving force in the development of BE.

Treatment of gastro-oesophageal reflux disease with rabeprazole in primary and secondary care: does Helicobacter pylori infection affect proton pump inhibitor effectiveness?

BACKGROUND: The presence of the gastric pathogen, Helicobacter pylori influences acid suppression by proton pump inhibitors and treatment outcome in patients with gastro-oesophageal reflux disease. AIM: To determine the influence of H. pylori infection on effectiveness of rabeprazole in primary and secondary care patients with gastro-oesophageal reflux disease. METHODS: Patients from primary and secondary care centres with uninvestigated gastro-oesophageal reflux disease (based on symptoms only) and investigated gastro-oesophageal reflux disease (endoscopically confirmed oesophagitis or endoscopy-negative reflux disease) were tested for H. pylori and treated with rabeprazole 20 mg once daily for 4-8 weeks in a non-randomized, multicentre, open-label study. Primary end-point for treatment effectiveness was complete resolution of both heartburn and acid regurgitation at 4-8 weeks; secondary end-point was quality of life as registered with the Psychological General Well-being Index. RESULTS: Data of 1787 patients could be analysed; mean duration of treatment was 36.3 days. At the evaluation visit 76.9% were heartburn-free, 77.7% regurgitation-free and 71% had complete symptom resolution. Overall Psychological General Well-being Index scores improved accordingly. Treatment was equally effective in patients with or without H. pylori infection, but more effective in patients with oesophagitis when compared with symptomatic gastro-oesophageal reflux disease. CONCLUSIONS: The effectiveness of rabeprazole in gastro-oesophageal reflux disease is not affected by the presence of H. pylori infection.

A double-blind, randomized, placebo-controlled dose-ranging study to evaluate the efficacy of alosetron in the treatment of irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome is a common gastrointestinal disorder characterized by abdominal pain and discomfort and altered bowel habit. Antagonism at the 5-HT3 receptor may be of benefit in the treatment of irritable bowel syndrome. AIMS: To evaluate the effect of 12 weeks of treatment with alosetron, a 5-HT3 receptor antagonist at doses of 0.1 mg b.d., 0.5 mg b.d. and 2 mg b.d. in irritable bowel syndrome patients. METHODS: A double-blind, placebo-controlled, parallel-group study with a 2-week screening and a 12-week treatment period was conducted. A total of 462 patients (335 female) recorded details of the severity of their abdominal pain, and bowel function daily on a diary card throughout the study. At monthly clinic visits patients recorded the severity of their abdominal pain/discomfort and diarrhoea on a visual analogue scale. RESULTS: In the total population and in the female subpopulation (but not in males) alosetron 2 mg b.d. significantly increased the proportion of pain-free days and decreased the visual analogue scale score for diarrhoea compared with placebo. Alosetron at doses of 0.5 mg b.d. and 2 mg b.d. led to a significant hardening of stool, and a reduction in stool frequency in the total population. CONCLUSION: Alosetron at a dose of 2 mg b.d. is an effective treatment for female patients with irritable bowel syndrome.

Mesalazine-induced apoptosis of colorectal cancer: on the verge of a new chemopreventive era?

BACKGROUND: It is an accepted fact that non-steroidal anti-inflammatory drugs (NSAIDs) are potent inhibitors of colorectal carcinogenesis. However, the major disadvantages of NSAIDs are gastrointestinal and renal toxicity. We conducted a prospective pilot study on the effects of the safe salicylic acid derivative, mesalazine, on apoptosis and proliferation of tumour cells and on normal tissue in colorectal cancer patients. METHODS: Patients with colorectal cancer were asked to take mesalazine enemas for 14 days. Biopsies from malignant and normal tissue were taken prior to and after this treatment. Apoptosis was scored on haematoxylin/eosin-stained tissue sections, and cell proliferation was assessed by the proliferation marker Ki-67. RESULTS: Ten out of 14 patients completed the study. The apoptotic score increased significantly in the tumour samples (pre-treatment 14.6 +/- 1.3 vs. post-treatment 19.4 +/- 0.8; P < 0.03). The apoptotic index in the normal mucosa was unchanged (pre-treatment 3.1 +/- 0.4 vs. post-treatment 2.9 +/- 0.3; N.S.). The cell proliferation in malignant tissue, according to the Ki-67 score, was hardly affected by mesalazine (pre-treatment 522 +/- 38 vs. post-treatment 493 +/- 39; N.S.). There was no effect on the Ki-67 index of normal mucosa (pre-treatment 24.2 +/- 2.0 vs. post-treatment 28.3 +/- 2.0; N.S.). CONCLUSIONS: This pilot study conducted in patients with colorectal cancer clearly shows that mesalazine selectively induces apoptosis of tumour cells. On the basis of these findings, which need to be confirmed in larger studies, it may be speculated that 5-ASA could be useful in the chemoprevention of colorectal cancer.

Maintenance therapy with pantoprazole 20 mg prevents relapse of reflux oesophagitis.

BACKGROUND: Proton pump inhibitors can be effective as maintenance therapy in reducing the relapse rate of reflux oesophagitis at a dose lower than that used for acute healing. PATIENTS AND METHODS: Patients (n=396, 18-88 years old) with healed reflux oesophagitis (grade II or III before healing) were included in this multinational, prospective, parallel-group, randomized double-blind study. They took oral pantoprazole 20 mg (n=203) or 40 mg (n=193), once daily for up to 12 months. Scheduled endoscopies were performed at entry, after 6 and 12 months, or when symptoms of at least moderate intensity were perceived on 3 consecutive days; symptoms were assessed every 3 months. The primary efficacy parameter was the time until endoscopically proven relapse of reflux oesophagitis occurred; the secondary parameters included tolerability, safety and time until symptomatic relapse occurred. RESULTS: Analysis was performed using the 'all-patients-treated' approach. Endoscopic relapse rates in the 20 mg group after 6 and 12 months were 16 and 29%, respectively; in the 40 mg group, they were 7 and 19%, respectively. Symptomatic relapse rates after 6 and 12 months were 14 and 21% in the 20 mg group and 10 and 17% in the 40 mg group, respectively. Pantoprazole 20 mg and 40 mg were well tolerated throughout the study; the type and frequency of adverse events reported were similar for both treatment groups. CONCLUSION: The 20 mg dose was proven to be 'at least equivalent' to the 40 mg dose with respect to endoscopic and symptomatic relapse. The 20 mg once daily dose represents an effective and safe maintenance regimen for the majority of patients with healed reflux oesophagitis.

[Transanal endoscopic microsurgery: a good choice for local resection of rectal tumors]. / Transanale endoscopische microchirurgie: een goede mogelijkheid voor de lokale verwijdering van rectumtumoren.

OBJECTIVE: To investigate the feasibility of transanal endoscopic microsurgery (TEM), a minimal access technique for the local resection of rectal tumours. DESIGN: Prospective. SETTING: IJsselland Hospital, Capelle a/d IJssel, the Netherlands. PATIENTS AND METHOD: TEM was performed in all patients between January 1996 and December 1997 with a rectal adenoma that could not be removed endoscopically, or with a rectal carcinoma and poor general condition which allowed no transabdominal surgery. TEM involves air insufflation and endosurgical resection of the tumour under direct vision. RESULTS: In all 11 tumours within approximately 4 cm from the linea anorectalis conversion was necessary due to technical problems and 1 tumour could not be visualized because of a stenosis. In all 23 other tumours TEM was performed. Mean distance from the linea anorectalis was 6.9 cm (4-12), with a mean surface of the base of the tumour of 7.7 cm2 (1-30). Mean operating time was 76 minutes (10-180). In one tumour the defect could not be completely closed, and conversion was necessary. Postoperatively one suture dehiscence and one urinary tract infection occurred. None of the patients had functional disorders. Every specimen contained all bowel layers, and in all but one, the margins were free of tumour. In 13 tumours an adenoma was diagnosed and in 10, a carcinoma. In 2 patients with carcinoma additional resection was performed. Mean follow-up was 9 months (1-23), and concerned 21 tumours. No recurrence has been observed. CONCLUSION: TEM is a good method for the local resection of rectal tumours, when located more than 4 cm from the linea anorectalis. Radical resection, containing all bowel layers, is possible, and has, as it appears, a low recurrence rate.

Aplasia and hypoplasia of the vestibulocochlear nerve: diagnosis with MR imaging.

PURPOSE: To introduce aplasia or hypoplasia of the vestibulocochlear nerve (VCN) as a possible cause of hearing loss and to identify the magnetic resonance (MR) imaging characteristics of this entity. MATERIALS AND METHODS: In seven patients with congenital deafness or unexplained sensorineural hearing loss, MR imaging enabled diagnosis of aplasia or hypoplasia of the VCN. Axial (0.7-mm) three-dimensional Fourier transformation-constructive interference in steady state (3DFT-CISS) images and parasagittal reconstruction images perpendicular on the course of the VCN were obtained. Twenty normal inner ears were also studied; their findings were compared with those of the patients. RESULTS: The facial nerve and inferior and superior vestibular and cochlear branches of the VCN were identified on the MR images in the 20 normal inner ears. Aplasia of the VCN was detected in two patients with normal labyrinths but with a severe stenosis of the internal auditory canal. A common VCN with absence of the cochlear branch was found bilaterally in two patients with a congenital malformation of the labyrinth. A common VCN with absence or hypoplasia of the cochlear branch was found in three patients with normal internal auditory canals and labyrinths. CONCLUSION: Submillimetric gradient-echo images (eg, 3DFT-CISS) should always be used to exclude aplasia or hypoplasia of the cochlear branch of the VCN in all cochlear implant candidates and patients with congenital deafness. This entity, which can occur with or without associated labyrinthine malformation, should be confirmed in two planes.

Pantoprazole and omeprazole in the treatment of reflux oesophagitis: a European multicentre study.

BACKGROUND: Pantoprazole is a new substituted benzimidazole which inhibits gastric H+,K(+)-ATPase. METHODS: In this double-blind, multicentre study, pantoprazole 40 mg once daily was compared with omeprazole 20 mg once daily in the treatment of grade II and III (Savary-Miller) reflux oesophagitis. Endoscopy was repeated after 4 weeks of treatment, and also after 8 weeks in patients unhealed at 4 weeks. RESULTS: The primary efficacy variable was ulcer healing; after 4 weeks, 81/103 (78.6%) patients in the pantoprazole group and 83/105 (79.0%) patients in the omeprazole group had healed completely. After 8 weeks, the cumulative healing rates were 94.2% and 91.4% in the pantoprazole and omeprazole groups, respectively (P > 0.05 at 4 weeks and 8 weeks). Both groups experienced rapid relief of the key symptoms: heartburn, acid regurgitation and pain on swallowing. The time course of relief of the individual symptoms was similar in both groups after 2 and 4 weeks (P > 0.05). Both treatments were well tolerated, with only three patients withdrawing owing to adverse events. CONCLUSION: Pantoprazole has been shown to be as effective as omeprazole in the treatment of reflux oesophagitis.

Two different dose regimens of cisapride in the treatment of reflux oesophagitis: a double-blind comparison with ranitidine.

We conducted a double-blind study comparing two dosage regimens of a prokinetic drug, cisapride (10 mg q.d.s. and 20 mg b.d.), with a low dose of a H2-receptor antagonist (150 mg ranitidine b.d.) in the treatment of 155 patients with reflux oesophagitis as determined by endoscopy. The active treatment took 8 to 12 weeks depending on whether complete healing was found at endoscopy. Improvement in oesophagitis grades from baseline to endpoint was observed in 68% of patients in the 10 mg cisapride q.d.s. group, 83% in the cisapride 20 mg b.d. group and 81% in the ranitidine group (N.S.). At endpoint, the percentages of endoscopically cured patients with initial grades I or II were 52% for 10 mg cisapride q.d.s., 71% for 20 mg cisapride b.d. and 80% for ranitidine (N.S.). The proportional improvement of the overall reflux symptom score (60%) also showed no significant difference between the three groups. In the treatment of mild reflux oesophagitis (grades I and II) similar results can be expected from 20 mg cisapride b.d. and 150 mg ranitidine b.d. As the results of the two dosage regimens of cisapride were not different, the 20 mg twice daily regimen is preferred because it will improve patient compliance. It is concluded that in reflux oesophagitis grades I and II, the efficacy of 20 mg cisapride b.d. and 150 mg ranitidine b.d. are broadly similar.

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.

Effects of highly selective vagotomy on gastric myoelectrical activity. An electrogastrographic study.

Changes in gastric myoelectrical activity following highly selective vagotomy were studied in 12 patients by means of electrogastrography (EGG) using cutaneous electrodes. Measurements were made before, 10 days after, and six months after operation. Eight patients undergoing cholecystectomy served as controls. Preoperatively all controls and patients had normal recordings. In the cholecystectomized patients no significant changes were found postoperatively. Ten days after highly selective vagotomy the normal initial postprandial dip in gastric ECA frequency and the subsequent increase in frequency and power were not seen. Tachygastrias were observed in three patients. Six months after operation the normal frequency and power responses to a test meal had returned, but both the fasting and postprandial ECA frequencies were raised significantly. It is concluded that highly selective vagotomy is associated with abnormalities in myoelectrical activity, in particular in the postprandial state, most of which are reversible with time.

[HIV-2 infection in a Portuguese woman with an AIDS-dementia complex living in The Netherlands]. / HIV-2-infectie bij een in Nederland wonende Portugese vrouw met een AIDS-dementiecomplex.

The case history is presented of the first patient with a fatal HIV-2 infection in The Netherlands, a Portuguese woman aged 51 yr. The infection resulted in AIDS, the AIDS-dementia complex and death. Her partner, a retired Cape Verde sailor, also proved to be infected with HIV-2. Epidemiology, virology and clinical manifestations of HIV-2 infection are discussed.

Electrogastrographic study of gastric myoelectrical activity in patients with unexplained nausea and vomiting.

Using cutaneous electrodes an electrogastrographic study was made of gastric myoelectrical activity in both the fasting and postprandial states in 48 patients with unexplained nausea and vomiting and in 52 control subjects. A gastric emptying study, using a radio-labelled solid phase meal, was carried out in 30 of these 48 patients. A follow up study was done after one year. In 48% of the patients abnormal myoelectrical activity was found which was characterised by: instability of the gastric pacemaker frequency; tachygastrias in both the fasting and postprandial states; the absence of the normal amplitude increase in the postprandial electrogastrogram. This last characteristic was correlated with a delayed gastric emptying of solids. The present study shows that with electrogastrography in a heterogeneous group of patients with unexplained nausea and vomiting a subgroup can be discerned with abnormal myoelectrical activity. Our findings suggests that this abnormal myoelectrical activity is related to these symptoms.

Electrogastrographic characteristics of interdigestive migrating complex in humans.

Interdigestive myoelectric activity and mechanical activity were studied simultaneously by means of cutaneous electrodes (electrogastrography) and intraluminal pressure recording, respectively, in 10 healthy male volunteers. The aims of the present study were 1) to describe the characteristics of the electrogastrogram during the different phases of the interdigestive migrating complex (IMC) in healthy subjects and 2) to determine to what extent these characteristics can be used to identify the different phases of the IMC. The electrogastrograms were analyzed visually and by running-spectrum analysis. It was concluded that in humans the gastric frequency present in the electrogastrogram appears to be less stable during motor activity than during motor quiescence, in particular during phase III, but far more stable than its canine counterpart. A small but consistent drop in gastric frequency was observed in the changeover from motor quiescence to phase II motor activity. The power of the gastric frequency increased with increasing motor activity, except during phase III. A characteristic frequency and power behavior during phase III could only be recognized in a minority of the IMCs. In general, electrogastrography cannot, given the present state of the art, be used to precisely identify the different phases of the IMC.