Risk factors for ulcerative reflux oesophagitis: a case-control study.

A case-control study was undertaken to investigate the effects of smoking, alcohol consumption, use of non-steroidal anti-inflammatory and other analgesic medications and family and medical history on the risk of ulcerative reflux oesophagitis (URO). We recruited 191 cases with URO diagnosed at endoscopy, 162 hospital controls who had also undergone endoscopy and 140 community controls from the Adelaide metropolitan area. From these three groups of subjects, 134 case-community control pairs, Matched on age, sex and postcode of residence and 142 case-hospital control pairs, matched on age, sex, hospital and endoscopist, were formed. Elevated non-significant risks were found in those smoking at least 20 cigarettes per day relative to those who never smoked (relative risk = 1.9, 95% confidence interval: 0.9-3.9 in case-hospital control pairs; relative risk = 1.9, 95% confidence interval: 0.9-3.7 in case-community control pairs). There was no elevation in risk associated with the use of non-steroidal anti-inflammatory drugs, with alcohol consumption, factors related to medical and reproductive history, nor with family history except for paternal history of heartburn (relative risk = 2.5, 95% confidence interval: 1.2-5.4 in case-hospital control pairs; relative risk = 1.9, 95% confidence interval: 1.0-4.0 in case-community control pairs). With the possible exception of smoking, no other risk factors for ulcerative reflux oesophagitis related to lifestyle are apparent.

Omeprazole v ranitidine for prevention of relapse in reflux oesophagitis. A controlled double blind trial of their efficacy and safety.

The aim of this study was to compare recurrence rates of reflux oesophagitis (after endoscopic healing with omeprazole) over a 12 month period of randomised, double blind, maintenance treatment with either daily omeprazole (20 mg every morning; n = 53), weekend omeprazole (20 mg on three consecutive days a week, n = 55) or daily ranitidine (150 mg twice daily, n = 51). Patients were assessed for relapse by endoscopy (with gastric biopsy) at six and 12 months, or in the event of symptomatic recurrence, and serum gastrin was monitored. At 12 months, the estimated proportions of patients in remission (actuarial life table method) were 89% when receiving daily omeprazole compared with 32% when receiving weekend omeprazole (difference 57%, p < 0.001, 95% confidence intervals: 42% to 71%) and 25% when receiving daily ranitidine (difference 64%, p < 0.001, 95% confidence intervals: 50% to 78%). Median gastrin concentrations increased slightly during the healing phase, but remained within the normal range and did not change during maintenance treatment. No significant pathological findings were noted, and no adverse events were attributable to the study treatments. In conclusion, for patients who respond favourably to acute treatment with omeprazole 20 mg every morning, the drug is a safe and highly effective maintenance treatment for preventing relapse of reflux oesophagitis and its associated symptoms over 12 months. By contrast, weekend omeprazole and daily ranitidine were ineffective.

Structural abnormalities of the cricopharyngeus muscle in patients with pharyngeal (Zenker's) diverticulum.

Recent manometric and radiological studies suggest that the upper oesophageal sphincter has poor compliance in patients with a pharyngeal (Zenker's) diverticulum. To test the hypothesis that this phenomenon is related to structural changes within the cricopharyngeus muscle we examined, histologically, muscle strips from 14 patients with a Zenker's diverticulum and compared them with control tissue obtained at autopsy from 10 non-dysphagic individuals. The cricopharyngeus muscle from patients and controls differed from inferior constrictor muscle by virtue of type 1 fibre predominance and greater fibre size variability. Ragged red fibres and nemaline bodies are a normal finding in the cricopharyngeus. Marked differences were observed in the cricopharyngeus muscle of Zenker's patients which demonstrated fibro-adipose tissue replacement and fibre degeneration. It is concluded that these structural changes may account for the observed diminished upper oesophageal sphincter opening and dysphagia in patients with Zenker's diverticulum.

Pharyngeal (Zenker's) diverticulum is a disorder of upper esophageal sphincter opening.

Pharyngeal coordination, sphincter opening, and flow pressures during swallowing were investigated in patients with pharyngeal (Zenker's) diverticula. Fourteen patients with diverticula and 9 healthy age-matched controls were studied using simultaneous videoradiography and manometry. Pharyngeal and upper esophageal sphincter pressures were recorded by a perfused side hole/sleeve assembly. Temporal relationships among swallowing events, extent of sphincter opening during swallowing, and intrabolus pressure during bolus passage across the sphincter were measured. The timing among pharyngeal contraction and sphincter relaxation, opening, and closure did not differ between patients and controls. Sphincter opening was significantly reduced in patients compared with controls in sagittal (P = 0.0003) and transverse (P = 0.005) planes. Manometric sphincter relaxation was normal in patients. Intrabolus pressure was significantly greater in patients than in controls (P = 0.001). It is concluded that Zenker's diverticulum is a disorder of diminished upper esophageal sphincter opening that is not caused by pharyngosphincteric incoordination or failed sphincter relaxation. Incomplete sphincter opening is likely to cause dysphagia. Increased hypopharyngeal pressures during swallowing are probably important in the pathogenesis of the diverticulum.

Optimized spectrophotometric determination of aldehyde dehydrogenase activity in erythrocytes.

We describe a reliable and sensitive semiautomated spectrophotometric assay of aldehyde dehydrogenase (ALDH; EC 1.2.1.3) activity in erythrocytes. The hemolysate can be stabilized with sucrose, and the technique involves only microliters of hemolysate on a centrifugal analyzer. The use of microcolumns to remove interfering hemoglobin is avoided, and reproducibility of the assay has been improved by manipulating the inherent lactate dehydrogenase activity of erythrocytes by adding lactate and oxalate to the reaction mixture. These modifications have decreased the analytical imprecision of the assay, allowing a better appraisal of aldehyde dehydrogenase activity in erythrocytes as a biological marker of excess alcohol consumption. Erythrocytic ALDH activity was significantly less in 40 alcoholics than in 145 teetotallers (median activity 128 vs 219 mU/g of hemoglobin, respectively; P = 0.0001), indicating the potential of this assay as a useful marker of excess alcohol consumption.

Effect of parenteral immunization on the intestinal immune response to Salmonella typhi Ty21a.

The effects of parenteral administration of a killed typhoid vaccine on the intestinal immune response to live orally administered Salmonella typhi Ty21a in human subjects was evaluated. Priming with parenteral vaccination neither enhanced nor suppressed the subsequent specific serum and intestinal immunoglobulin A (IgA) immune responses to a booster course of live oral vaccine. Neither a single oral dose of live vaccine nor a single dose of parenteral vaccine had any measurable booster effect on the observed primary intestinal IgA response to the live oral vaccine. Two booster doses of subcutaneously administered killed typhoid vaccine did result in a significant increase in the specific intestinal IgA antibody in those subjects primed with the oral live vaccine. This response was comparable in magnitude to the primary intestinal response. No evidence of this response could be found in serum IgA, although nonsignificant rises in serum IgG were evident. Previous parenteral priming had no effect on secondary immune responses to a live oral vaccine in humans. Serum immune responses were generally found to be of little value as indicators of local intestinal immunity. This study confirmed that parenteral vaccination was only able to induce an intestinal immune response following priming with live, orally administered organisms and that multiple parenteral booster doses were necessary to induce a measurable effect on intestinal immune responses.

Specific immune response in the human respiratory tract following oral immunization with live typhoid vaccine.

Specific antibody responses in the lower respiratory tract of human subjects to orally administered Salmonella typhi Ty21a are reported. These responses, predominantly of the immunoglobulin G class, were determined to be a transudate from serum. These results were supported by the similarity in responses to parenteral administration of heat-killed typhoid vaccine. Specific immunoglobulin A antibody was a poor contributor to the respiratory antibody response to either vaccine.

The human humoral immune response to Salmonella typhi Ty21a.

The short-term kinetics and the effects of different dose regimens and formulations on the humoral immune response induced in human subjects by the live attenuated typhoid vaccine Salmonella typhi Ty21a were examined. Antibody responses in jejunal fluid and serum and by specific antibody production in vitro by peripheral blood lymphocytes to S. typhi lipopolysaccharide were determined. A short vaccination schedule of three doses of 10(11) live organisms over 5 days induced significantly greater intestinal IgA antityphoid antibody responses than did two comparable doses 21 days apart. The humoral immune response was dose dependent with 10(10) and 10(11) live organisms stimulating greater intestinal immune responses than did 10(11) killed organisms. No responses were evident with either 10(9) viable organisms or with an enteric-coated preparation. In the continued development and assessment of oral typhoid vaccines, the effects of different doses and formulations and the timing of sampling on the humoral immune response should be considered.

Cigarette smoking and rate of gastric emptying: effect on alcohol absorption.

OBJECTIVE: To examine the effects of cigarette smoking on alcohol absorption and gastric emptying. DESIGN: Randomised crossover study. SETTING: Research project in departments of medicine and nuclear medicine. SUBJECTS: Eight healthy volunteers aged 19-43 who regularly smoked 20-35 cigarettes a day and drank small amounts of alcohol on social occasions. INTERVENTIONS: Subjects drank 400 ml of a radiolabelled nutrient test meal containing alcohol (0.5 g/kg), then had their rates of gastric emptying measured. Test were carried out (a) with the subjects smoking four cigarettes an hour and (b) with the subjects not smoking, having abstained for seven days or more. The order of the tests was randomised and the tests were conducted two weeks apart. MAIN OUTCOME MEASURES: Peak blood alcohol concentrations, absorption of alcohol at 30 minutes, amount of test meal emptied from the stomach at 30 minutes, and times taken for 50% of the meal to leave the proximal stomach and total stomach. RESULTS: Smoking was associated with reductions in (a) peak blood alcohol concentrations (median values in non-smoking versus smoking periods 13.5 (range 8.7-22.6) mmol/l v 11.1 (4.3-13.5) mmol/l), (b) area under the blood alcohol concentration-time curve at 30 minutes (264 x 10(3) (0-509 x 10(3)) mmol/l/min v 140 x 10(3)) (0-217 x 10(3) mmol/l/min), and (c) amount of test meal emptied from the stomach at 30 minutes (39% (5-86%) v 23% (0-35%)). In addition, smoking slowed both the 50% gastric emptying time (37 (9-83) minutes v 56 (40-280) minutes) and the intragastric distribution of the meal. There was a close correlation between the amount of test meal emptied from the stomach at 30 minutes and the area under the blood alcohol concentration-time curve at 30 minutes (r = 0.91; p less than 0.0001). CONCLUSION: Cigarette smoking slows gastric emptying and as a consequence delays alcohol absorption.

Relationships between oesophageal transit and solid and liquid gastric emptying in diabetes mellitus.

In 87 randomly selected diabetic patients (67 type 1, 20 type 2) and 25 control subjects, gastric emptying of digestible solid and liquid meals and oesophageal transit of a solid bolus were measured with scintigraphic techniques. Gastrointestinal symptoms, autonomic nerve function and glycaemic control were evaluated in the diabetic patients. Gastric emptying and oesophageal transit were slower (P less than 0.001) in the diabetic patients compared with the control subjects, and each was delayed in about 40% of them. There was a relatively weak (r = 0.32; P less than 0.01) relationship between solid and liquid gastric emptying, and no significant correlation (r = 0.11, NS) between oesophageal transit and gastric emptying of the solid meal. Scores for upper gastrointestinal symptoms and autonomic nerve function correlated weakly (r = 0.21; P less than 0.05) with both oesophageal transit and gastric emptying. Gastric emptying of the liquid meal was slower (P less than 0.05) in patients with blood glucose concentrations greater than 15 mmol/l. These results indicate that gastric emptying in patients with diabetes mellitus should be assessed by liquid as well as by solid test meals and that oesophageal transit should not be used as a predictor of generalised diabetic gastroenteropathy.

Polymeric IgA antibody to gliadin in the serum of patients with coeliac disease.

Secretory component (SC) binding assays which detect polymeric IgA (pIgA) in serum were used to measure serum antigliadin pIgA and total pIgA in patients with coeliac disease. Total IgA antigliadin antibody in serum and intestinal fluid was measured by enzyme linked immunosorbent assay (ELISA). The relationship of pIgA antibody to dietary gluten and the antigliadin IgA antibody in intestinal fluid was examined. Twenty-nine serum samples were assayed, twelve from patients ingesting gluten and seventeen from patients who had excluded gluten from their diet for 6 months. Eight of these were paired samples from 4 adults on and off gluten. In addition, paired samples of both intestinal fluid and serum were obtained from 7 children on and off gluten. Polymeric IgA antibody to gliadin was detected in 11 of 12 subjects on gluten but in only 3 of 17 who had excluded gluten. Three of the four adults from whom paired serum samples were obtained had pIgA antigliadin, but only while on gluten. Three of the seven children in whom intestinal and serum antibody were assayed had pIgA to gliadin, which could not be detected after exclusion of gluten, although their intestinal antibody level remained elevated. There was no change in total pIgA levels with diet although the levels were higher than those seen in normal subjects. We conclude that pIgA antibody to gliadin is frequently found in the serum of coeliac patients ingesting gluten. It disappears with gluten elimination at a time when the IgA antigliadin antibody in intestinal fluid has not altered.

Specific immune response in humans following rectal delivery of live typhoid vaccine.

The specific immune responses to the live vaccine Salmonella typhi Ty21a following rectal administration were determined in serum, peripheral blood lymphocytes, saliva and in jejunal fluid of adult human subjects. Following vaccination, all seven subjects had a detectable anti-typhoid IgA antibody response using their peripheral blood lymphocytes (p = 0.009). Significant rises in postvaccination anti-typhoid IgA antibody were observed in the jejunal fluid (p = 0.033), serum (p = 0.010) and saliva (p = 0.050) of these subjects. This study confirms that the normal rectal mucosa is an efficient route of entry to the systemic immune system for microbial agents, and therefore may provide a further possible route of immunization with attenuated bacterial vaccines.

Quantitative histological study of enteropathy associated with HIV infection.

A quantitative histological study was performed on small intestinal biopsies from eight ambulatory patients with HIV infection (AIDS/AIDS-related complex, ARC) and compared with those from 16 normal subjects. Enteropathy was assessed by measurement of villus area, crypt length and mitotic count, as well as duodenal counts of intraepithelial lymphocytes, mucosal mast cells and goblet cells. Enteropathy in subjects with AIDS/ARC was shown by reduced mean villus area of 0.363 (SD 0.081) compared with 0.500 (SD 0.064) mm2 in control subjects (p less than 0.0001), while intestinal crypts were of similar length with 239 (SD 36) compared with 225 (SD 28 microns, but mitotic count was increased to 3.8 (SD 1.2) compared with 2.4 (SD 0.8) (p = 0.01) in the same control subjects. These results indicate villous atrophy with impaired crypt hyperplasia. Duodenal cell counts showed similar numbers of mucosal mast cells, intraepithelial lymphocytes and goblet cells in AIDS/ARC patients and fifteen control subjects.

The serum polymeric IgA antibody response to typhoid vaccination; its relationship to the intestinal IgA response.

The relationship between the IgA antibody response in serum (total and polymeric IgA) and intestinal secretions was examined in volunteers subjected to oral and parenteral typhoid vaccination. After oral vaccination (three doses of 10(11) live Ty21a vaccine given at 48-hr intervals), serum pIgA antibody to typhoid lipopolysaccharide (LPS) was detected in seven of the 14 subjects (46.4 +/- 59 U/100 microliters, mean +/- SD). However, all 14 showed a significant intestinal IgA response (993 +/- 2516 and 9349 +/- 6754 U/mg pre- and post-vaccine; t = 5.25, P = 0.0002). The level of pIgA antibody declined rapidly, whereas intestinal IgA antibody levels remained elevated. Serum pIgA antibody was also found after parenteral immunization (two doses of 5 X 10(8) heat-killed bacteria given 14 days apart to six subjects), but an intestinal IgA antibody response was detected in these individuals only after a subsequent course of the oral vaccine given 1 month after initial parenteral immunization. Changes in serum pIgA antibody followed those of total serum IgA antibody rather than those of intestinal antibody. The results indicate that a serum pIgA response can be induced by an antigenic stimulus delivered either orally or parenterally, whereas an intestinal IgA response is induced only by a local antigen stimulus. The regulation of serum pIgA and intestinal IgA appear to be independent.

The effect of cyclosporin A in delaying maturation of the small intestine during weaning in the rat.

As maturation of the small intestine has similar features to an immunologically mediated reaction, we studied the effect of the immunosuppressive agent, cyclosporin A (CyA), on the development of the small intestine during weaning in the DA x PVG rat. Intestinal development was measured by villus area, crypt length, crypt cell production rate (CCPR), and disaccharidase activity. Rat pups received either cyclosporin A (7.5 mg/kg daily subcutaneously) or polyethoxylated castor oil (Cremophor, drug vehicle) subcutaneously from 12 days of age. Cremophor- and CyA-treated litters were killed at 18, 20, 22, 24, and 26 days of age. CyA-treated animals had retarded weight gain, lower mesenteric lymph node and spleen weights, fewer intraepithelial lymphocytes, and reduced systemic secretion of rat mucosal mast cell protease II. CyA treatment retarded any increase in villus area, crypt length and CCPR until day 26 of age. Lactase activity was retained longer, and sucrase and maltase induction was delayed. We conclude that CyA retarded normal development of the small intestine, but some maturation still occurred at the end of weaning.

Gastric and oesophageal emptying in patients with type 2 (non-insulin-dependent) diabetes mellitus.

Gastric emptying of a digestible solid and liquid meal and oesophageal emptying of a solid bolus were measured with scintigraphic techniques in 20 randomly selected Type 2 (non-insulin-dependent) diabetic patients receiving oral hypoglycaemic therapy and 20 control subjects. In the diabetic patients, the relationships between oesophageal emptying, gastric emptying, gastrointestinal symptoms, autonomic nerve function and glycaemic control were examined. The percentage of the solid meal remaining in the stomach at 100 min (p less than 0.001), the 50% gastric emptying time for the liquid meal (p less than 0.05) and oesophageal emptying (p less than 0.05) were slower in the diabetic patients compared to the control subjects. Scores for upper gastrointestinal symptoms and autonomic nerve dysfunction did not correlate significantly (p greater than 0.05) with oesophageal, or gastric emptying. The 50% gastric emptying time for the liquid meal was positively related (r = 0.58, p less than 0.01) to the plasma glucose concentration at the time of the performance of the gastric emptying test and the lag period, before any solid food emptied from the stomach, was longer (p less than 0.05) in subjects with plasma glucose concentrations during the gastric emptying measurement greater than the median, compared to those with glucose concentrations below the median. These results indicate that delayed gastric and oesophageal emptying occur frequently in Type 2 diabetes mellitus and that delayed gastric emptying relates, at least in part, to plasma glucose concentrations.