Changes of gastric mucosal architecture during long-term omeprazole therapy: results of a randomized clinical trial.

BACKGROUND: The impact of long-term acid suppression on the gastric mucosa remains controversial. AIM: To report further observations on an established cohort of patients with gastro-oesophageal reflux disease, after 7 years of follow-up. METHODS: Of the original cohort randomized to either antireflux surgery or omeprazole, 117 and 98 patients remained in the medical and surgical arms, respectively. Gastric biopsies were taken at baseline and throughout the study. RESULTS: Fifty-three antireflux surgery and 39 omeprazole-treated patients had Helicobacter pylori infection at randomization. Eighty-three omeprazole-treated and 60 antireflux surgery patients remained H. pylori negative over the 7 years, and no change was observed in mucosal morphology except for a change in endocrine cell population (linear and diffuse hyperplasia, P = 0.03). During the 7-year study many patients, who were initially H. pylori infected, had the infection eradicated leaving only 13 omeprazole and 12 antireflux surgery patients still infected. In these patients, omeprazole induced a deterioration of the mucosal inflammation scores (P = 0.01) with a numerical increase of glandular atrophy. CONCLUSIONS: Long-term omeprazole therapy does not alter the exocrine oxyntic mucosal morphology in H. pylori-negative patients, but mucosal endocrine cells appear to be under proliferative stimulation; in H. pylori-positive patients there are changes in mucosal inflammation and atrophy.

Population-based molecular detection of hereditary nonpolyposis colorectal cancer.

PURPOSE: Cancer morbidity and mortality can be dramatically reduced by colonoscopic screening of individuals with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, creating a need to identify HNPCC. We studied how HNPCC identification should be carried out on a large scale in a sensitive and efficient manner. PATIENTS AND METHODS: Colorectal cancer specimens from consecutive newly diagnosed patients were studied for microsatellite instability (MSI). Germline mutations in the MLH1 and MSH2 genes were searched for in MSI(+) individuals. RESULTS: Among 535 colorectal cancer patients, 66 (12%) were MSI(+). Among these, 18 (3.4% of the total) had disease-causing germline mutations in MLH1 or MSH2. Among these 18 patients, five were less than 50 years old, seven had a previous or synchronous colorectal or endometrial cancer, and 15 had at least one first-degree relative with colorectal or endometrial cancer. Notably, 17 (94%) of 18 patients had at least one of these three features, which were present in 22% of all 535 patients. Combining these data with a previous study of 509 patients, mutation-positive HNPCC accounts for 28 (2.7%) of 1,044 cases of colorectal cancer, predicting a greater than one in 740 incidence of mutation-positive individuals in this population. CONCLUSION: Large-scale molecular screening for HNPCC can be done by the described two-stage procedure of MSI determination followed by mutation analysis. Efficiency can be greatly improved by using three high-risk features to select 22% of all patients for MSI analysis, whereby only 6% need to have mutation analysis. Sensitivity is only slightly impaired by this procedure.

Genetic analysis in Finnish families with inflammatory bowel disease supports linkage to chromosome 3p21.

In inflammatory bowel diseases (IBD), certain chromosomal candidate loci have been repeatedly identified by independent studies in different populations. To investigate the contribution of the loci on chromosomes 1, 3, 7, 12, 14, and 16 to the susceptibility of IBD in Finnish population, where the predominant feature is the excess of ulcerative colitis (UC) families compared to Crohn's disease (CD) families, we carried out linkage analyses using 93 Finnish, multiply-affected IBD families. We observed nominal evidence for linkage to chromosome 3p21, consistent with earlier reports. The lod scores peaked at D3S2432, with a maximum two-point lod score of 1.68 (P=0.0027). In addition, we studied whether risk of IBD is associated with functional variants of two positional candidate genes; the chemokine receptor CCR5 gene on chromosome 3p21 and the interleukin-4 receptor alpha-subunit gene (IL4RA) on chromosome 16. We did not find any significant correlation between a 32-bp deletion variant of CCR5 or a single nucleotide change A1902G (Gln576Arg) of IL4RA, and IBD phenotypes, with the exception that in the UC group homozygosity for the G1902 allele of IL4RA was less frequent (0.019 vs 0.049, P=0.038). In conclusion, our study, carried out in a genetically homogenous population, suggests that chromosome 3 may contain a susceptibility gene for IBD.

Nutritional status of newly diagnosed celiac disease patients before and after the institution of a celiac disease diet--association with the grade of mucosal villous atrophy.

No systematic studies have been carried out on the association of nutritional status with the severity of mucosal villous atrophy in newly diagnosed celiac disease patients. We examined the nutritional status of 40 adult patients with newly diagnosed celiac disease classified according to the grade of villous atrophy: partial, subtotal, and total. Nutritional status was determined by food records as well as by anthropometric and biochemical measurements. Anthropometric results did not differ among the three atrophy groups, but serum ferritin and erythrocyte folate were lower in patients with total villous atrophy than in the other groups. Most of the abnormal biochemical values were normalized during 1 y of a gluten-free diet; villous atrophy healed concomitantly. To conclude, patients with total mucosal villous atrophy at diagnosis had low erythrocyte folate and serum ferritin values, but no other major differences were found in nutritional status among celiac disease patients with different grades of villous atrophy.

Bone recovery after a gluten-free diet: a 5-year follow-up study.

The purpose of our study was to investigate the recovery of bone disease in celiac patients during 5 years of a gluten-free diet. The study group consisted of 28 newly diagnosed celiac patients (9 men, 19 women) recruited between 1990 and 1991. Six patients withdrew from the 5-year follow-up. Compliance with the gluten-free diet was good: 96% at 1 year and 82% at 5 years. During the follow-up period, the body mass index increased significantly (8%). Both in men and women, bone mineral density (BMD) values determined by dual X-ray absorptiometry (DXA) increased at the lumbar spine (2%), the femoral neck (1%), the trochanter (6%), and the Wards' area (3%) during the follow-up. The increase in BMD was found already during the first year of follow-up. After 1 year, BMD increased or remained the same in 69% of the patients at the lumbar spine and in 67% of the patients at the femoral neck, 89% of patients at the throchanter, and 67% of patients at the Wards' area. During the 5-year follow-up, these figures were 52%, 46%, 68%, and 59%, respectively. At the baseline, 19 out of 28 patients, after 1 year, 14 out of 26 patients, and after 5 years, 2 out of 26 patients had low serum 25(OH)D vitamin values (p = 0.0001). A high serum parathormone value was noticed in 6 out of 25 patients at the baseline, but after 1 year, 5 of them showed normalized values (p = 0.03). According to our results, bone disease in celiac patients is cured in most patients during 5 years on a gluten-free diet. The improvement in BMD mostly occurred already within the first year after the establishment of a gluten-free diet.

Osteoporosis in adult patients with celiac disease.

We investigated the bone mineral density (BMD) and prevalence of osteopenia and osteoporosis in adult celiac patients with varying disease states. In this cross-sectional study the data on the severity of celiac disease and BMD were collected from 77 celiac patients (28 newly diagnosed and 49 previously diagnosed celiac patients), and BMD results were compared with those of 157 control subjects matched for age, gender, and menopausal status. The celiac patients had significantly lower BMD than the control subjects at the lumbar spine (-6%) and femoral neck (-5%). The mean BMD did not differ significantly among celiac patients classified by severity of disease. Based on Z scores, 35% of the celiac patients and 17% of the control subjects had low BMDs for age at the lumbar spine (p = 0.005), whereas 31% of celiac patients and 16% of control subjects had Z scores of < or =-1 at the femoral neck (p = 0.01). Altogether, 26% of all celiac patients, but only 5% of control subjects, were classified as having osteoporosis (T score < or =-2.5 SD) at the lumbar spine (p = 0.03), whereas osteoporosis was rare at the femoral neck in both groups (3% vs. 1%, p = 1.00). Prevalence of osteopenia and osteoporosis was highest in newly diagnosed celiac patients and in patients with disease not in remission. A low 25-(OH)D vitamin concentration was a typical biochemical abnormality in our patients (64% of men and 71% of women). The main associated variables of low BMD were age (men), low serum vitamin D level, low body weight, and postmenopausal status (women). The present study suggests that celiac disease constitutes a risk factor for osteoporosis. This finding applies particularly to untreated and poorly treated patients.

Distribution pharmacokinetics of warfarin in the rat, a non-linear multicompartment model.

Preliminary analysis and linear two-compartment solutions of warfarin plasma concentrations recorded in the rat after intravenous bolus injections of 1, 2, 8 and 40 mg/kg of sodium warfarin revealed marked non-linearities. The half-life of total warfarin concentration in the plasma from 1-12h remained unchanged with all the doses used, but that of free warfarin was shorter with 40 mg/kg, possibly as the result of an increase in the binding of the drug to plasma proteins as the high total warfarin concentration decreased. The apparent volume of distribution generally increased with increasing dose, and differed according to the method used for its calculation. Liver warfarin data could be solved with Langmuir type saturation kinetics, but the saturation phenomena were slight in the concentration range studied. A non-linear multicompartment model was constructed, the physiological spaces of which were plasma, interstitial fluid and tissue. The binding of free warfarin to plasma proteins, interstitial fluid proteins and tissue structures was assumed to occur instantaneously, with saturable binding to plasma and interstitial fluid proteins, and a constant binding to tissues. The fluxes between the free warfarin pools of plasma and interstitial fluid as well as elimination were assumed to be linear. Following parameters were simulated simultaneously, using an analog hybrid computer: two for the above-mentioned fluxes, four for zero time drug mass distribution between plasma and interstitial fluid, and one for tissue binding. According to the best fits, warfarin is preferentially distributed into plasma, interstitial fluid and highly perfused tissues. The solution suggests that non-linearities in the pharmacokinetics of warfarin, a highly plasma protein-bound drug, first occur in plasma and interstitial fluid. Therefore, it is believed that the quantitative non-linear multicompartment approach presented in this paper might be useful in studying the kinetic behaviour of other highly plasma protein-bound drugs, too.

First pass metabolism of ethanol--a gastrointestinal barrier against the systemic toxicity of ethanol.

Both in men and rats, most of the ethanol ingested at a low dose is metabolized before it reaches the systemic circulation. Oxidation of ethanol (mainly in the stomach) accounts for the bulk of this effect. This "first pass" metabolism (FPM) may be viewed as a barrier which protects against the systemic toxicity of ethanol. This barrier can be overcome by large doses of ethanol. Its efficiency is also reduced by a decrease in gastric alcohol dehydrogenase (ADH) activity secondary to chronic alcohol consumption.

Prevalence of gastric metaplasia in the duodenal bulb is low in Helicobacter pylori positive non-ulcer dyspepsia patients.

BACKGROUND: Gastric metaplasia in duodenum is a common phenomena in duodenal ulcer patients. However, the role of gastric metaplasia in patients with non-ulcer dyspepsia is not clear. It is not known either whether Helicobacter pylori infected non-ulcer patients who are CagA-seropositive have gastric metaplasia in duodenum more often than CagA-negative patients. AIMS: To compare prevalence of gastric metaplasia in duodenum in non-ulcer dyspepsia patients according to Helicobacter pylori status. PATIENTS AND METHODS: A series of 400 unselected dyspeptic patients in primary care were investigated. Patients with no endoscopic evidence of organic disease (n=236) were enrolled in the study. Duodenal bulb and gastric biopsies were collected, as well as blood samples for Helicobacter pylori determination. RESULTS: There were no differences between CagA-seropositive and -seronegative Helicobacter pylori infected patients as far as concerns gastric metaplasia in duodenal bulb (20% vs 25%). Helicobacter pylori negative non-ulcer patients more often had gastric metaplastic changes (46%, p<0.0001) in duodenum. CONCLUSION: Helicobacter pylori infection has no major role in development of gastric metaplasia in duodenal bulb in non-ulcer dyspeptic patients. Furthermore, it does not result in positive CagA-serology, an increased risk for gastric metaplasia compared with CagA-seronegative cases.

The absorption of warfarin from the rat small intestine in situ.

The in situ absorption from the rat small intestine of the weakly acidic drug, warfarin (pKa 5-05), at 200 mug ml-1 in the instilled fluid with initial pH levels of 3, 5, 7 or 8 has been examined. These initial pH's in the buffer changed rapidly towards neutrality. The buffers at pH's 3 and 5 probably caused different amounts of warfarin precipitation, which resulted in different rates of warfarin disappearance from the instilled fluid which paralleled the initial rates of accumulation of warfarin in (or on) the intestinal wall. Where greater drug precipitation had probably occurred the initial rates of absorption into the plasma were slower. At the initial pH of 3 and by solubilization of warfarin with propylene glycol, the rate of absorption was similar to that from a fluid of pH 7. Propylene glycol in 15% solution did not affect the system significantly. The relatively high transfer of warfarin into octanol from buffer solution at pH 7 might indicate that the small fraction of unionized drug (1 : 100) at pH 7 is enough for remarkable transfer of this highly lipid-soluble drug.

First pass metabolism of ethanol: an important determinant of blood levels after alcohol consumption.

Alcohol consumption by rats fed ethanol-containing liquid diets is considerably greater than the measured rate of ethanol elimination from the blood, suggesting that a significant fraction of the alcohol ingested does not enter the systemic circulation. To assess the possibility of a first pass metabolism of ethanol, we compared the areas under the blood ethanol concentration curves after administration of various doses through various routes in alcohol-fed and control rats. In both groups, blood ethanol concentrations were significantly lower after intragastric than after intraportal or intravenous (femoral) administrations and, to a lesser extent, than after an intraduodenal dose. By contrast, the rise in blood acetate, a product of ethanol oxidation, was faster after intragastric administration. Moreover, absorption of the ethanol dose was virtually complete at the time of ethanol disappearance from the blood. The fraction of the dose that did not enter the systemic circulation was proportionally greater with the smaller doses. These results indicate that there is a significant first pass metabolism of ethanol which takes place in the gastrointestinal tract and particularly in the stomach, where alcohol dehydrogenase (ADH) activity is the highest. Chronic alcohol administration decreased ADH activity (probably secondary to gastric mucosal injury) and also decreased the magnitude of the first pass metabolism. The amount of ethanol ingested which does not enter the systemic circulation accounts for the apparent dissociation between alcohol consumption, blood ethanol levels and rate of blood ethanol elimination in alcohol-fed animals.

Nutrient intakes during diets including unkilned and large amounts of oats in celiac disease.

BACKGROUND/OBJECTIVES: We have shown earlier that consumption of moderate amount of oats improve intakes of vitamin B(1), fiber, magnesium and iron in celiac patients using gluten-free diet (GFD). The objective of this study was to clarify the effect of high amount of both kilned and unkilned oats on food and nutrient intakes in celiac patients in remission. Kilning as an industrial heating process is performed to preserve the main properties of oats and to lengthen its useableness. Kilning may, however, change the protein structure of oats and therefore influence on the intake of nutrients. SUBJECTS/METHODS: The study group consisted of 13 men and 18 women with celiac disease in remission. The patients who were earlier using moderate amount of oats as part of their GFD were randomized to consume kilned or unkilned oats. After 6 months, the patients changed the treatment groups. The goal of daily intake of oats was 100 g. Food records and frequency questionnaire were used to follow nutrient intakes. RESULTS: Type of oats did not affect the amount of oats used. In the group using kilned oats, the intake of vitamin B1 and magnesium and in the group of unkilned oats that of magnesium and zinc increased significantly during the first 6 months (P

Cardiac autonomic regulation during gastroscopy.

BACKGROUND: Gastroscopy is sometimes associated with adverse cardiovascular events. AIMS: We evaluated the effects of sedation and pharyngeal anaesthesia on cardiac autonomic regulation during gastroscopy. PATIENTS: Two hundred thirteen outpatients undergoing gastroscopy. METHODS: The patients were assigned to 4 groups: (1) sedation with intravenous midazolam and placebo throat spray (midazolam group), (2) placebo sedation and pharyngeal anaesthesia with lidocaine (lidocaine group), (3) placebo sedation and placebo throat spray (placebo group), and (4) no intravenous cannula nor throat spray (control group). Continuous electrocardiogram was recorded. Heart rate variability was assessed; the powers of low frequency (0.04-0.15 Hz) and high frequency (0.15-0.40 Hz) components as well as total power (0.0-0.4 Hz) were calculated. RESULTS: Gastroscopy was associated with a decrease in high frequency normalized units, increases in low frequency normalized units and low frequency/high frequency ratio indicating activation of sympathetic and withdrawal of vagal modulation. Sympathetic activation resulted in a decrease in total power and all components of heart rate variability. The decrease was most prominent in the midazolam treated patients (p<0.001 vs the lidocaine group and p<0.01 vs placebo and control groups during the postendoscopy phase). CONCLUSION: Gastroscopy induces a shift towards dominance of the sympathetic modulation of the heart. Premedication with midazolam potentiates this shift.

Elevated expression of hyaluronan and its CD44 receptor in the duodenal mucosa of coeliac patients.

AIMS: Since hyaluronan (HA) metabolism is disturbed in some malignant tumours and in inflammatory diseases, we analysed HA and its receptor CD44 as well as the expression of the Ki67 nuclear protein, a marker of cell proliferation, in histological sections of duodenal biopsies of coeliac disease patients and controls. METHODS AND RESULTS: The study group consisted of 52 patients with coeliac disease in remission, 40 patients with newly diagnosed disease and 10 healthy control subjects. HA was detected with a specific biotinylated probe prepared from cartilage aggrecan and link protein, and CD44 with an antibody recognizing all forms of CD44 and another specific for its v6 variant. For the expression of the nuclear protein, monoclonal antibody MIB-1 was used. The percentage of HA-positive cells in surface epithelium was higher in newly diagnosed patients (13%) compared with patients in remission (11%) and controls (2%). In addition, HA intensity in the lamina propria was decreased in the newly diagnosed patients. In patients with active disease, 22-26% of the surface epithelium was CD44+, whereas the corresponding figure in patients in remission was 5%, and that of controls 1%. The more intensive MIB-1 labelling in the duodenal epithelium of coeliac patients without treatment was normalized after gluten-free diet. CONCLUSIONS: The HA-positive coat on surface epithelium seen even in patients in remission suggests persistent or even permanent changes in the epithelial permeability barrier in coeliac disease.

pH-dependency in diffusion of some weakly acidic drugs, warfarin, sulfaethidole, and barbital, into organic phases.

The diffusion of three weakly acidic drugs (warfarin, sulfaethidole, and barbital) in cyclohexane-buffer and n-octanol-buffer systems was studied by two different methods; shaking and model cell type of experimentation. At low pH values the drugs moved generally more readily into the organic phases than at higher pH. Moreover, when the shaking method was used the drugs moved readily to the n-octanol phase even at higher pH levels. Lecithin improved the diffusion at low more than at high pH levels. Thus, the results varied according to the organic phase selected and the method used. Poor correlation was found between some results of this study and previously reported results of in situ absorption from the rat gastrointestinal tract of the same drugs. The results do not support the assumption that phospholipids may have a role in the absorption of ionized moieties.