Charles T. Richardson

Norovirus Vaccine against Experimental Human Norwalk Virus Illness

BACKGROUND Noroviruses cause epidemic and sporadic acute gastroenteritis. No vaccine is available to prevent norovirus illness or infection. METHODS We conducted a randomized, double-blind, placebo-controlled, multicenter trial to assess the safety, immunogenicity, and efficacy of an investigational, intranasally delivered norovirus viruslike particle (VLP) vaccine (with chitosan and monophosphoryl lipid A as adjuvants) to prevent acute viral gastroenteritis after challenge with a homologous viral strain, Norwalk virus (genotype GI.1). Healthy adults 18 to 50 years of age received two doses of either vaccine or placebo and were subsequently inoculated with Norwalk virus and monitored for infection and gastroenteritis symptoms. RESULTS Ninety-eight persons were enrolled and randomly assigned to receive vaccine (50 participants) or placebo (48 participants), and 90 received both doses (47 participants in the vaccine group and 43 in the placebo group). The most commonly reported symptoms after vaccination were nasal stuffiness, nasal discharge, and sneezing. Adverse events occurred with similar frequency among vaccine and placebo recipients. A Norwalk virus-specific IgA seroresponse (defined as an increase by a factor of 4 in serum antibody levels) was detected in 70% of vaccine recipients. Seventy-seven of 84 participants inoculated with Norwalk virus were included in the per-protocol analysis. Vaccination significantly reduced the frequencies of Norwalk virus gastroenteritis (occurring in 69% of placebo recipients vs. 37% of vaccine recipients, P=0.006) and Norwalk virus infection (82% of placebo recipients vs. 61% of vaccine recipients, P=0.05). CONCLUSIONS This norovirus VLP vaccine provides protection against illness and infection after challenge with a homologous virus. (Funded by LigoCyte Pharmaceuticals and the National Institutes of Health; ClinicalTrials.gov number, NCT00973284.).

HEALING OF DUODENAL ULCER WITH AN ANTACID REGIMEN

To determine whether a large-dose antacid regimen is effective in promoting healing of duodenal ulcer, 74 patients with endoscopically proved duodenal ulcer completed a 28-day double-blind clinical trial comparing such a regimen with an inert placebo. The ulcer healed completely in 28 of the 36 antacid-treated as compared to 17 of the 38 placebo-treated patients (P less than 0.005). The antacid regimen was not more effective than placebo in relieving ulcer symptoms. Presence or absence of symptoms during the fourth treatment week was a poor predictor of presence or absence of an ulcer crater. Ulcers of placebo-treated patients who smoked cigarettes were less likely to heal than those of nonsmokers (P = 0.03). Except for mild diarrhea, no side effects of the antacid regimen were observed. We conclude that a large-dose antacid regimen hastens the healing of duodenal ulcer.

pH dependence of acid secretion and gastrin release in normal and ulcer subjects.

By use of a recently described method, which estimates the rate of gastric acid secretion by measuring the rate of sodium bicarbonate infusion needed to keep intragastric pH constant, gastric acid secretion rates and changes in serum gastrin were measured in five normal subjects while gastric pH was kept at 5.5, 4.0, 3.0, or 2.5. Preliminary experiments revealed that the method did not accurately measure acid secretion at a pH lower than 2.5. Stimulation of acid secretion was produced by gastric instillation of a solution of amino acids and cornstarch. The secretion rate with the amino acid meal was highest at pH 5.5 and was 60% of that produced by a steak meal at the same pH. As the pH of the amino acid meal was decreased, there was a stepwise reduction in acid secretion so that at pH 2.5 the rate was only half as great as at pH 5.5. The amino acid meal produced increases in serum gastrin that were also less marked than those produced by a steak meal. With amino acid stimulation, serum gastrin responses were similar at pH 5.5, 4.0, and 3.0, but no increase in gastrin could be measured when the meal was maintained at pH 2.5. A group of six patients with duodenal ulcers was compared with seven normal subjects at pH 5.5 and 2.5. Ulcer patients released more gastrin and secreted more acid at each time period at both pH values. More important, the degree of inhibition at pH 2.5 was significantly less in ulcer patients. For example, during the 2nd h after stimulation acid secretion was inhibited by only 30% in ulcer patients compared with 70% in normal subjects. These findings suggest a defect in autoregulation of gastrin release and gastric acid secretion at low pH in ulcer patients which may play a role in pathogenesis of this disease.

Role of thought, sight, smell, and taste of food in the cephalic phase of gastric acid secretion in humans

The relative importance of thought, sight, smell, and taste of food in the cephalic phase of gastric acid secretion has not been studied systematically. We found that discussing appetizing food for 30 min (without sight, smell, or taste) increased acid secretion from 4 to 13 mmol/h in healthy human subjects (p less than 0.001) and also increased serum gastrin concentrations significantly (p less than 0.02). Discussing food resulted in an acid secretory response that averaged 66% +/- 10% of the response to modified sham feeding, which activates thought, sight, smell, and taste. Discussing topics other than food (e.g., current events, sports) did not increase acid secretion significantly. The sight of appetizing food (without smell or taste), the smell of appetizing food (without sight or taste), or the combination of sight and smell (without taste) also increased acid secretion and serum gastrin concentrations significantly. However, sight and smell were significantly less potent stimulants of acid secretion than sham feeding, with responses averaging only 23%-46% of the response to sham feeding. These studies indicate that thinking about food is a potent stimulant of gastric secretion in healthy humans. Moreover, the sight and smell of food increase gastric acid secretion and serum gastrin concentrations, probably by provoking thoughts related to food.

In vivo and in vitro evaluation of liquid antacids.

Abstract An in vivo test of the efficacy of liquid antacids given after a meal was shown to yield reproducible results. An average dose-response curve, obtained with the use of various doses of a single antacid, was different in subjects whose peak histamine response exceeded 25 mEq per hour and in those whose response was less than 16.6 mEq per hour. In individual subjects, however, the peak histamine response did not accurately predict the in vivo reduction in gastric acidity by antacid. Although the relative in vivo potency of equal volumes of four different antacids varied widely, this potency could be predicted with reasonable accuracy by means of an in vitro test, which showed the potency per milliliter of antacid to vary 17-fold among different commercial products. These experiments indicate that when antacids are prescribed, dosage should be determined by the milli-equivalents of neutralizing capacity rather than by an arbitrary volume or number of tablets of different antacids, that the variable ...

Duodenal-ulcer disease associated with elevated serum pepsinogen I: an inherited autosomal dominant disorder.

To delineate genetic factors involved in the pathogenesis of duodenal ulcer, serum pepsinogen I levels were determined by radioimmunoassay in two large kindreds with multiple members affected with duodenal ulcer. An elevated serum immunoreactive pepsinogen I concentration (greater than 100 ng per milliliter) segregated as an autosomal dominant trait in these families. Furthermore, 10 of 11 patients with clinical ulcer disease in these families had hyperpepsinogenemia. An elevated serum pepsinogen I concentration appears to be a subclinical marker of the ulcer diathesis in families with this autosomal dominant form of peptic-ulcer disease.

Studies on the mechanisms of food-stimulated gastric acid secretion in normal human subjects.

Liquid test meals were infused into the stomach and acid secretion was measured by intragastric titration at pH 5.0 Acid secretion after 500 or 750-ml sodium chloride meals was two to three times higher than basal secretion rates and was equivalent to 25-30% of the peak acid output in response to histamine. Since these meals did not cause a rise in serum gastrin concentration, it is assumed that they stimulate acid secretion by causing distention of the body and fundus of the stomach. Compared with this distention stimulus, glucose meals had no effect on acid secretion and fat-inhibited acid secretion; however, both glucose and fat caused an increase in serum gastrin concentration. Amino acids caused a much greater increase in serum gastrin concentration and enhanced acid secretion above that noted with distention alone. In contrast, albumin did not enhance the serum gastrin concentration or stimulate acid secretion to a statistically significant extent. There was a close correlation between the rise in serum gastrin concentration and rate of acid secretion after different test meals when average results for each test meal were plotted. However, there was a poor correlation between acid secretion and serum gastrin concentration when the responses of the individual subjects with a given test meal were compared. Our interpretations are: (a) Distention is an important stimulant of the acid-secretory response to a meal, and this is not mediated by gastrin release. (b) Gastrin is one but probably not the only mediator of the chemical phase of acid secretion, i.e., acid secretion noted with amino acids that cannot be explained by distention. (c) Glucose and fat also release gastrin; however, with glucose the rise in serum gastrin is too small and too transient to enhance acid secretion, and fat probably releases unmeasured inhibitors that overwhelm the effect of gastrin on acid secretion. (d) Albumin is not a stimulant of acid secretion.

Studies on the Role of Cephalic-Vagal Stimulation in the Acid Secretory Response to Eating in Normal Human Subjects

These experiments were performed to determine the importance of cephalic-vagal stimulation in the acid secretory response to eating in normal human subjects. Cephalic stimulation was induced by a modified sham feeding (MSF) technique, during which subjects chewed and expectorated appetizing food. The response to MSF was compared with that to gastric distention with 600 ml NaCl, glucose, or food. In addition, we measured the extent to which cephalic stimulation augments acid secretion that has been stimulated simultaneously by these other mechanisms. Our conclusions are as follows: (a) cephalic stimulation accounts for approximately one-third of the acid secreted when all mechanisms act simultaneously (food-distention plus MSF); (b) within the limits imposed by the maximal secretory capacity, the response to MSF is approximately the same, regardless of whether acid secretion is otherwise unstimulated or is stimulated simultaneously by gastric distention with NaCl, glucose, or food; and (c) gastric distention prolongs the response to cephalic stimulation.

Abnormal Gastric Function in Longstanding, Insulin-Dependent Diabetic Patients

We evaluated gastric function in 8 longstanding, insulin-dependent diabetic patients with nausea and recurrent vomiting, as well as in 10 asymptomatic diabetic patients and 11 nondiabetic subjects. Gastric vagal function was assessed by measuring the gastric acid secretory response to sham feeding. Normal subjects secreted 17.2 ± 3.1 meq/hr, whereas diabetic patients with, or without, vomiting secreted 5.4 ± 1.4 and 6.4 ± 2.0 meq/hr, respectively (P From these studies we conclude that many patients with longstanding insulin-dependent diabetes have (a) reduced acid secretory responses to sham feeding, suggesting vagal neuropathy; (b) normal acid secretory responses to infused food, despite an enhanced serum gastrin response; and (c) delayed gastric emptying. These abnormalities occur both in diabetic patients with nausea and vomiting and in asymptomatic diabetic patients.

Effect of Atropine on Vagal Release of Gastrin and Pancreatic Polypeptide

We studied the effect of several doses of atropine on the serum gastrin and pancreatic polypeptide responses to vagal stimulation in healthy human subjects. Vagal stimulation was induced by sham feeding. To eliminate the effect of gastric acidity on gastrin release, gastric pH was held constant (pH 5) and acid secretion was measured by intragastric titration. Although a small dose of atropine (2.3 mug/kg) significantly inhibited the acid secretory response and completely abolished the pancreatic polypeptide response to sham feeding, this dose of atropine significantly enhanced the gastrin response. Higher atropine doses (7.0 and 21.0 mug/kg) had effects on gastrin and pancreatic polypeptide release which were similar to the 2.3-mug/kg dose. Atropine (0.78 and 2.3 mug/kg) without sham feeding significantly inhibited basal acid secretion and also led to significant increases in serum gastrin above basal levels. The gastrin response to sham feeding with 2.3 mug/kg atropine was significantly greater than the sum of the gastrin responses to sham feeding alone and to 2.3 mug/kg atropine alone, indicating potentiation of vagal gastrin release by atropine. We conclude: (a) Unlike vagally mediated gastric acid secretion and pancreatic polypeptide release which can be blocked by atropine, vagal gastrin release is potentiated by atropine. This observation suggests the existence of a vagal-cholinergic pathway which normally (i.e., in the absence of atropine) inhibits gastrin release. (b) Because atropine (without sham feeding) increased basal gastrin levels, it is likely that the cholinergic pathway which inhibits gastrin release is active even when the vagus nerve is not stimulated by sham feeding.