Effect of omeprazole dose, nonsteroidal anti-inflammatory agents, and smoking on repair mechanisms in acute peptic ulcer bleeding.

BACKGROUND: Peptic ulcer bleeding (PUB) is a major cause of upper gastrointestinal bleeding. The effect of omeprazole on mucosal repair is unknown. AIMS: We studied the effect of omeprazole, nonsteroidal anti-inflammatory agents, and smoking on PUB. METHODS: There were 43 PUB patients who received regular or high dose of omeprazole for 72 h. Biopsies from antrum and corpus were taken before and after treatment. Biopsy samples from 20 celiac disease patients worked as controls. The expression of Ki-67, Bcl-2, COX-2, Hsp27, and Hsp70 was analyzed from patients and controls. RESULTS: Bcl-2 expression in PUB patients was lower than in controls. However, Bcl-2 increased significantly from 5.0 (SD 4.5) to 9.1 % (SD 6.7), p = 0.0004, in the antrum after omeprazole. In univariate analysis, a high omeprazole dose caused a more profound increase in Ki-67 expression in the corpus: 35.3 % (SD 54.8) than a regular dose: -10.1 % (SD 40.6), p = 0.022. In multivariate analysis, Ki-67 decreased significantly in the corpus between the pre- and posttreatment period (p = 0.011), while a high omeprazole dose (p = 0.0265), the use of NSAIDs (p = 0.0208), and smoking (p = 0.0296) significantly increased Ki-67 expression. Bcl-2 in the corpus increased significantly (p = 0.0003) after treatment. CONCLUSIONS: Our findings suggest that Bcl-2 may be an important factor in the pathogenesis of a peptic ulcer and PUB. In addition, high-dose omeprazole increased the expression of Ki-67, which may enhance the healing process of a peptic ulcer.

Comparison of outcomes twelve years after antireflux surgery or omeprazole maintenance therapy for reflux esophagitis.

BACKGROUND & AIMS: It is important to evaluate the long-term effects of therapies for gastroesophageal reflux disease (GERD). In a 12-year study, we compared the effects of therapy with omeprazole with those of antireflux surgery. METHODS: This open, parallel group study included 310 patients with esophagitis enrolled from outpatient clinics in Nordic countries. Of the 155 patients randomly assigned to each arm of the study, 154 received omeprazole (1 withdrew before therapy began), and 144 received surgery (11 withdrew before surgery). In patients who remained in remission after treatment, post-fundoplication complaints, other symptoms, and safety variables were assessed. RESULTS: Of the patients enrolled in the study, 71 who were given omeprazole (46%) and 53 treated with surgery (37%) were followed for a 12-year follow-up period. At this time point, 53% of patients who underwent surgery remained in continuous remission, compared with 45% of patients given omeprazole with a dose adjustment (P = .022) and 40% without dose adjustment (P = .002). In addition, 38% of surgical patients required a change in therapeutic strategy (eg, to medical therapy or another operation), compared with 15% of those on omeprazole. Heartburn and regurgitation were significantly more common in patients given omeprazole, whereas dysphagia, rectal flatulence, and the inability to belch or vomit were significantly more common in surgical patients. The therapies were otherwise well-tolerated. CONCLUSIONS: As long-term therapeutic strategies for chronic GERD, surgery and omeprazole are effective and well-tolerated. Antireflux surgery is superior to omeprazole in controlling overall disease manifestations, but post-fundoplication complaints continue after surgery.

Unkilned and large amounts of oats in the coeliac disease diet: a randomized, controlled study.

OBJECTIVE: There is evidence for the long-term safety of oats as part of a gluten-free diet in coeliac disease (CD). Oats is generally processed by kilning, which theoretically may change its antigenic properties and be the reason that it is tolerated by patients with CD. The aim of this study was to investigate the suitability of large amounts of unkilned oats, comparing its use with kilned oats in adult coeliac patients. MATERIAL AND METHODS: The study group included 13 men and 19 women with CD in remission. The goal of daily intake of oats was 100 g during one year. These patients using oats as part of their gluten-free diet were randomized to two treatment groups. One group used regular oats and the other unkilned oats. After 6 months the patients changed the treatment groups. Food intake, symptoms, histology of the small intestine and the levels of endomysial antibodies were noted. RESULTS: No marked changes were found in the duodenal biopsies, in the levels of endomysial antibodies or in the well-being of the patients. Compliance with the diet did not change during the follow-up. CONCLUSIONS: Large amounts of both unkilned and regular kilned oats are well tolerated by adult patients with CD. Oats is therefore not harmful, even in its unkilned form, which indicates that its antigenic nature is not changed by common industrial food processing in such a way that would prevent the provoking of CD.

Analysis of the risk factors and their combinations in acute gastroduodenal ulcer bleeding: a case-control study.

OBJECTIVE: Traditional non-steroidal anti-inflammatory drugs (NSAIDs) including ASA for thrombosis prophylaxis (ASA-TP), for pain medication (ASA-P) or non-ASA NSAIDs (NANSAIDs), Helicobacter pylori infection, CagA strains of H. pylori and smoking are reported risk factors for peptic ulcer bleeding (PUB), but the combined and the dose effects of these factors are controversial. The aim of this study was to estimate the significance of these risk factors and their combinations in PUB. MATERIAL AND METHODS: PUB patients (n = 94) were compared with an age- (+/- 5 years) and gender-matched control group of non-ulcer patients (n = 94) attending elective endoscopy. A questionnaire on the possible risk factors (previous gastric and duodenal ulcer, use of ASA-TP, ASA-P, NANSAIDs, warfarin, alcohol and smoking) was completed. H. pylori infection was determined as positive if histology and/or urease tests were positive. CagA antibodies of IgG class were determined using an immunoblot method. RESULTS: H. pylori infection (odds ratio (OR) 8.8), the use of ASA-P (OR 3.5), ASA-TP (OR 4.07), NANSAIDs with > or =1 defined daily dose (OR 6.56), smoking > or =20 cigarettes daily (OR 6.43) and previous duodenal ulcer (DU) (OR 8.96) were independent risk factors for PUB. At least two risk factors were present in 65% of PUB patients. CagA strains were detected in 97% of the H. pylori-positive cases and in 96% of the respective controls. ASA, ibuprofen, ketoprofen and smoking were dose-dependent risk factors for PUB. CONCLUSIONS: Previous DU, H. pylori, the use of any ASA and smoking explained the majority of the PUB episodes. CagA strains of H. pylori were not associated with PUB. Two-thirds of the PUB patients had at least two risk factors, but their combination did not potentiate the risk.

No observed local immunological response at cell level after five years of oats in adult coeliac disease.

OBJECTIVE: Our earlier 5-year follow-up study produced the first evidence to show the long-term safety of oats as part of a coeliac diet. The objective of the present study was to clarify its applicability by analysing local cellular immunological responses after 5 years' consumption of oats by adult coeliac patients. MATERIAL AND METHODS: Forty-two coeliac patients took part in an earlier oats intervention study for 6-12 months. Twenty-two of these patients originally consumed oats as part of their gluten-free diet. During the 5-year follow-up 10 patients had felt uncertain about the safety of long-term consumption of oats and gave up this part of their diet. Finally, 12 of the 22 patients consumed oats for the whole 5-year period. The control group consisted of the remaining 20 coeliac patients using a strict, conventional, gluten-free diet without oats. Intraepithelial CD3, alphabetaTCR (alphabetaIEL) and gammadeltaTCR (gammadeltaIEL) T cells were counted after specific staining of small intestinal biopsy specimens. RESULTS: There were no differences in the densities of CD3, alphabetaIEL and gammadeltaIEL T cells between the oat and the control groups. CONCLUSIONS: Long-term use of oats included in the gluten-free diets of patients with coeliac disease does not stimulate an immunological response locally in the mucosa of the small intestine.

Sedation, topical pharyngeal anesthesia and cardiorespiratory safety during gastroscopy.

GOALS: In a prospective, double-blind study, we examined the effects of routine sedation and pharyngeal anesthesia on cardiorespiratory parameters during gastroscopy. BACKGROUND: Intravenous sedation and topical pharyngeal anesthesia are used to alleviate the discomfort during upper gastrointestinal endoscopy. Cardiorespiratory changes during gastroscopy are common. STUDY: Two hundred fifty two consecutive outpatients undergoing gastroscopy were assigned into 4 groups: (1) sedation with intravenous midazolam and placebo throat spray (midazolam group), (2) placebo sedation and pharyngeal anesthesia with lidocaine throat spray (lidocaine group), (3) placebo sedation and placebo throat spray (placebo group), and (4) no intravenous cannula nor throat spray (control group). Arterial oxygen saturation (SaO2), systolic and diastolic blood pressure and continuous electrocardiogram were recorded before, during, and after the endoscopic procedure. RESULTS: Gastroscopy increased heart rate in all study groups. Premedication with intravenous midazolam or lidocaine spray alleviated this rise (P<0.001, repeated measures analysis of variance) and decreased the incidence of tachycardia. Similarly, sedation with midazolam or topical pharyngeal anesthesia decreased the rise in systolic blood pressure (P<0.001). Midazolam produced lower SaO2 values during gastroscopy compared with lidocaine, placebo or control groups (P<0.001). However, episodes of desaturation (SaO2

HLA genotyping is useful in the evaluation of the risk for coeliac disease in the 1st-degree relatives of patients with coeliac disease.

OBJECTIVE: Coeliac disease (CD) is a common disease with a strong heredity. About 10-20% of 1st-degree relatives of probands develop CD. Relatives should be screened for CD, because if not treated, CD exposes patients to numerous complications. The heterogeneity of symptoms and the lifetime-spanning risk of CD render the timing of CD antibody and/or gastroscopy screenings difficult. As CD susceptibility has been shown to be strongly associated with the HLA alleles DQA1*0501 and DQB1*0201 (together encoding the DQ2 heterodimer) and DRB1*04 (associated with the DQ8 heterodimer), our aim was to investigate whether HLA genotyping might be useful in the identification of 1st-degree relatives of CD patients who do not need further screening for CD. MATERIAL AND METHODS: The study comprised 54 Finnish CD families including 54 CD probands and 382 living 1st-degree relatives. All subjects who were willing to participate were screened for CD (duodenal and skin biopsies; endomysial, reticulin and gliadin antibodies). The DQA1*0501, DQB1*0201 and DRB1*04 allele frequencies of CD patients and the 1st-degree relatives were determined. RESULTS: Altogether 17.6% (5.9% of the parents, 15.7% of the siblings, 25.8% of the offspring) of the investigated 1st-degree relatives (n = 245) did not carry any of the alleles studied. All of the CD patients (n = 136) with the exception of one (0.7%) carried at least one of the alleles investigated. CONCLUSIONS: By using the HLA genotyping a considerable proportion of 1st-degree relatives of CD probands could be excluded from further screening for CD.

Gene dose effect of the DQB1*0201 allele contributes to severity of coeliac disease.

OBJECTIVE: Coeliac disease (CD) susceptibility has been shown to be associated with the HLA alleles DQA1*0501 and DQB1*0201. This HLA-associated risk has been estimated to account for 29-40% of the genetic component of CD. Conflicting data have been published on the gene dose effect of these HLA alleles on the risk and severity of CD. In this study the aim was to investigate the association between the number of HLA risk alleles and the severity of CD. MATERIAL AND METHODS: Fifty-four Finnish CD families, including 144 CD patients mainly diagnosed in adulthood (94.4%), were enrolled in the study. The association between the number of DQA1*0501 and DQB1*0201 alleles and villous atrophy, symptoms and laboratory parameters at the time of diagnosis, and the association with villous atrophy after one year of treatment on a gluten-free diet were studied. RESULTS: The homozygosity for the DQB1*0201 allele was associated with a more severe form of CD assessed by more severe villous atrophy (p=0.011), younger age (p=0.036), more severe diarrhoea (p=0.048) and a lower level of blood haemoglobin at the time of diagnosis (p=0.010). Furthermore, the homozygosity for the DQB1*0201 allele was associated with a slower recovery of villous atrophy after a gluten-free diet (p=0.041). In contrast, the DQA1*0501 allele did not have a significant association with the severity of CD. CONCLUSIONS: Our results demonstrate a gene dose effect of the DQB1*0201 allele on the clinical heterogeneity of CD and on the rate of recovery from villous atrophy in patients on a gluten-free diet.

The effect of regular and high doses of omeprazole on the intragastric acidity in patients with bleeding peptic ulcer treated endoscopically: a clinical trial with continuous intragastric pH monitoring.

OBJECTIVE: In peptic ulcer bleeding (PUB), pH level >4 is considered necessary to prevent dissolving of a formed fibrin clot. The effect of regular or high doses of omeprazole on the intragastric pH in patients with acute PUB was studied. METHODS: In our earlier study, after endoscopic therapy, PUB patients were randomized to receive a regular dose of intravenous omeprazole (20 mg; i.e. 60 mg/3 days) or a high dose of omeprazole (80 mg bolus + 8 mg/h; i.e. 652 mg/3 days). Of these 142 analysed and reported patients, 13 PUB patients also had intragastric pH monitoring for these 3 days; seven of these patients had a regular dose and six received a high dose of omeprazole. RESULTS: The mean 24-h intragastric pH (regular versus high dose) on day 1 was 4.9 +/- 1.6 versus 6.3 +/- 0.5 (P = 0.035), on day 2 was 4.9 +/- 1.8 versus 6.7 +/- 0.3 (P = 0.001), and on day 3 was 5.7 +/- 1.1 versus 6.7 +/- 0.5 (P = NS). The medians of the intragastric pH were 6 versus 6.5 (P = 0.082) on day 1, 5.8 versus 6.8 (P = 0.001) on day 2, and 6.2 versus 6.8 (P = 0.17) on day 3. The proportion of time when pH <4 on day 1 was 29.2 +/- 34.1 versus 5.4 +/- 5.7% (P = NS). CONCLUSIONS: A regular dose of omeprazole raises the mean and median 24-h intragastric pH >4 in patients with PUB. This reduction in the acidity together with endoscopic therapy is probably sufficient to maintain haemostasis. A high dose of omeprazole keeps the pH almost constantly >6.

Is routine sedation or topical pharyngeal anesthesia beneficial during upper endoscopy?

BACKGROUND: Upper endoscopy is an invasive procedure. However, the benefits of routinely administered sedative medication or topical pharyngeal anesthesic are controversial. The aim of this study was to clarify their effects on patient tolerance and difficulty of upper endoscopy. METHODS: A total of 252 patients scheduled for diagnostic upper endoscopy were randomly assigned to 4 groups: (1) sedation with midazolam and placebo pharyngeal spray (midazolam group), (2) placebo sedation and lidocaine pharyngeal spray (lidocaine group), (3) placebo sedation and placebo pharyngeal spray (placebo group), and (4) no intravenous cannula/pharyngeal spray (control group). The endoscopist and the patient assessed the procedure immediately after the examination. Another questionnaire was sent to the patients 2 weeks later. RESULTS: Patients in the midazolam group rated the examination easier and less uncomfortable compared with those in the other groups. The differences were especially evident in the questionnaires completed 2 weeks after the examination ( p < 0.001). Lidocaine did not significantly improve patient tolerance. However, endoscopists found the procedure easier in patients in the lidocaine group compared with the midazolam ( p < 0.01) and control groups ( p < 0.01) but not the placebo group. CONCLUSIONS: Routine administration of midazolam for sedation increased patient tolerance for upper endoscopy. However, endoscopists found intubation to be more difficult in sedated vs. non-sedated patients. Topical pharyngeal anesthesia did not enhance patient tolerance, but it did make upper endoscopy technically easier compared with endoscopy in patients sedated with midazolam without topical pharyngeal anesthesia, and in patients who had no sedation or pharyngeal anesthesia, but not in patients who received placebo sedation and placebo pharyngeal anesthesia.

Genomewide search and association studies in a Finnish celiac disease population: Identification of a novel locus and replication of the HLA and CTLA4 loci.

It has been reported that celiac disease (CD) is strongly associated with the HLA-DQ2 alleles DQA1*0501 and DQB1*0201. However, this association only accounts for a portion of the genetic component of CD. Several non-HLA loci and candidate genes that potentially contribute to CD susceptibility have been reported, but have not been confirmed. The aim of this study was to identify loci that contribute to disease susceptibility in a CD population from Finland. We performed a genomewide linkage scan and identified two regions of significant linkage to CD (6p and 2q23-32) and one region of suggestive linkage (10p). We also performed targeted typing and analyses that replicated the associations of the HLA and CTLA4 loci.