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Biomedical subjects

A Dubois

Publications and source records attributed to A Dubois.

At least 19 recordsLinked to original sources
PubMed1996

Transient and persistent experimental infection of nonhuman primates with Helicobacter pylori: implications for human disease.

Helicobacter pylori can establish chronic infection in the human gastric mucosa, and it is a major cause of peptic ulcer disease and a principal risk factor for gastric cancer. This creates a need for H. pylori infection models that mimic the human condition. To test the suitability of rhesus monkeys as infection models, H. pylori-free animals were inoculated intragastrically with mixtures of H. pylori strains, bacteria recovered from colonized animals were typed by arbitrarily primed PCR, and host inflammatory and immunologic responses were monitored. Among five H. pylori-free animals inoculated with a mixture of two human strains plus one monkey strain, one became persistently infected and one became only transiently infected. The recovered bacteria matched the monkey input strain in DNA fingerprint. A subsequent trial using two new human isolates and three animals that had resisted colonization by the monkey strain resulted in persistent infection in one animal and transient infection in two others. Antral gastritis, anti-H. pylori serum immunoglobulin G, and atrophy all increased, but with patterns that differed among animals. We conclude that (i) rhesus monkeys can be infected experimentally with H. pylori, (ii) individuals differ in susceptibility to particular bacterial strains, (iii) infections may be transient, and (iv) the fitness of a particular strain for a given host helps determine the consequences of exposure to that strain.

Animals↗
PubMed1995

Comparative disposition, receptor affinity, and teratogenic activity of sulfon arotinoids.

To investigate the relationship between sulfon arotinoid biotransformation and teratogenic activity, the potency of the ethyl (Ro 15-1570) and methyl (Ro 14-9706) arotinoid sulfones and their in vivo disposition in pregnant hamsters were studied. Administration of Ro 15-1570 was teratogenic, but Ro 14-9706 showed no such activity. Total absorbed doses of the ethyl and methyl sulfones (measured as maternal plasma AUC) were very similar. Total delivered dose of Ro 14-9706 to liver and lung was 120-160% that of Ro 15-157, and Ro 14-9706 was transferred in greater amounts to the embryo as well. Placenta AUC for parent sulfon arotinoids was 160-250% that in the embryo. Plasma analyses by HPLC suggested that the ethyl sulfone was oxidized and appeared in maternal plasma as the corresponding sulfinic (Ro 14-9572) and sulfonic (Ro 14-3899) acids, amounting to 10% and 16%, respectively, of the mean maternal ethyl sulfone Cmax value. The concentrations of sulfinic and sulfonic metabolites were always less than the analytical limit of detection in placenta and embryo after maternal ethyl sulfone intubation. Neither the sulfinic nor the sulfonic acid were ever detected in maternal circulation, placenta, or embryo after methyl sulfone intubation. Comparisons of their binding affinities found that neither the ethyl nor the methyl arotinoid sulfone could act as a ligand for cellular retinoic acid-binding protein (CRABP), nor could these compounds bind retinoid nuclear receptors (RAR). Transcriptional activation of RARs was weak and similar for both compounds. The sulfinic and sulfonic acid arotinoids bind and transactivate RARs, and bind CRABP with efficiencies similar to all-trans-retinoic acid. Furthermore, they are active in cultured limb bud chondrocytes. The results suggest that the methyl sulfone (in accord with its lack of activity in cultured limb bud chondrocytes) is of no toxicologic significance in hamster embryo--even after relatively high delivered dose. Teratogenicity of the ethyl sulfone (which shows marked inhibition of chondrogenesis in cultured limb bud) does not appear to depend on measurable concentrations of these sulfinic/sulfonic acid metabolites in the hamster embryo.

Abnormalities, Drug-Induced↗
PubMed1995

Effect of radiation and radioprotection on small intestinal function in canines.

Radiation with doses > 7.5 Gy damages the canine intestinal mucosa, and pretreatment with WR2721 reduces this damage. However, the effects of radiation and of WR2721 on in vivo intestinal transport are unclear. Therefore, we determined canine survival, intestinal transport, and mucosal histology following unilateral abdominal irradiation. Isoperistaltic ileostomies were prepared in 23 dogs under general anesthesia and aseptic conditions. After a three-week recovery period, animals were given either placebo or WR2721, 150 mg/kg intravenously, 30 min prior to 10 Gy cobalt-60 abdominal irradiation. Ileal transport and histology were determined in both groups before exposure and one, four, and seven days after irradiation. Seven-day survival was significantly improved by pretreatment with WR2721 (91% vs 33%, P < 0.02). On day 4, both mucosal integrity and net intestinal absorption were significantly better (P < 0.05) after WR2721 than after placebo. Thus, radiation-induced damage to the ileal mucosa is accompanied by a reduction in net ileal absorption of water and electrolytes in vivo. In addition, pretreatment with WR2721 improves animal survival while reducing ileal damage and improving intestinal absorption.

Amifostine↗
PubMed1995

Cloning and characterization of hemolytic genes from Helicobacter pylori.

Strains of Helicobacter pylori, the bacterium associated with gastritis, peptic ulcer disease, and gastric cancer in humans, express different degrees of hemolysis on agar containing erythrocytes (RBC). Here we report the isolation and characterization of six recombinant clones from a genomic library of H. pylori ATCC 49503 that confer on Escherichia coli the ability to lyse sheep RBC. DNA hybridizations indicated no sequence homology among these hemolytic clones. Hybridization mapping of them to an ordered H. pylori cosmid library identified their separate chromosomal locations. One clone hybridized to two regions separated by approximately 200 kb. The specificities of the hemolytic activities of these clones were tested with RBC from humans, monkeys, cattle, horses, guinea pigs, rabbits, and chickens as well as with RBC from sheep. One clone conferred the ability to lyse RBC from five species, a second clone allowed the lysis of RBC from four of these species, three other clones allowed the lysis of RBC from three of these species, and the sixth clone allowed the lysis of RBC from just two species. We propose that some or all of the genes that confer these various hemolytic activities contribute to pathogen-host tissue interactions and that the different specificities seen here are important for H. pylori infections of humans of different genotypes or disease states.

Cloning, Molecular↗
PubMed1995

Seroepizootiology of Helicobacter pylori gastric infection in nonhuman primates housed in social environments.

We determined the seroepizootiology of Helicobacter pylori infection in rhesus monkeys. Plasma was obtained from 196 animals (age range, 1 to 22 years) that were housed in social environments, either in indoor gang cages, in outdoor corrals, or in free-ranging forested conditions. Plasma immunoglobulin G levels were determined with a specific enzyme-linked immunosorbent assay, and the cutoff immunoglobulin G value for H. pylori seropositivity was determined from a study of 25 monkeys whose infection status was assessed by light microscopy and culture. One-year-old animals of both genders in all housing conditions had the lowest rate of positivity (60% in monkeys 1 year old versus 81% in monkeys 2 to 10 years old, P = 0.026). In addition, females tended to have higher rates of positivity than males. Seroconversion during a 1-year observation period occurred in 7 (28%) of 25 seronegative animals. Seroreversion occurred in 3 (4%) of the 78 positive animals; all 3 of these animals had received antimicrobial agents during the year. These observations demonstrate that the epizootiology of H. pylori infection in rhesus monkeys may serve as a model for human infection.

Animal Husbandry↗
PubMed1994

Physiological role of cholecystokinin on gastric emptying and acid output in dogs.

We investigated the physiological role of cholecystokinin (CCK) on gastric emptying and acid secretion in seven conscious dogs with gastric cannulae. Two hundred milliliters of a 4% amino acid meal was given via the cannula, and both gastric emptying and acid output were measured concurrently using a dye-dilution technique. Gastric emptying of the liquid amino acid meal was exponential, and the acid output and plasma concentrations of CCK, gastrin, and somatostatin peaked within 30 min after the meal. Intravenous infusion of CCK-8 at 28 and 56 pmol/kg/hr but not 14 pmol/kg/hr increased plasma levels of the peptide and inhibited gastric emptying as well as acid output. Plasma gastrin was not affected significantly by the CCK infusion, whereas plasma somatostatin increased significantly in response to 56 pmol/kg/hr of CCK-8. Loxiglumide, 22 mumol/kg/hr, significantly enhanced gastric emptying and augmented acid output, as well as plasma gastrin response, whereas it abolished the postprandial rise in plasma somatostatin. We concluded that in dogs, CCK plays an important role in the physiologic regulation of postprandial gastric emptying of a liquid caloric meal and acid output. Its inhibitory effect on gastric acid secretion appears to be mediated, at least in part, by somatostatin.

Animals↗
PubMed1994

Natural gastric infection with Helicobacter pylori in monkeys: a model for spiral bacteria infection in humans.

BACKGROUND/AIMS: There is no generally accepted model for Helicobacter pylori infection in humans. The aim of this study was to examine the natural history and effect of treatment in rhesus monkeys and sequentially define the immune response to H. pylori in relation to treatment. METHODS: Infection and gastritis were graded blindly by histological analysis and culture of biopsy specimens harvested during gastroduodenoscopies in 26 anesthetized colony-bred monkeys. Plasma H. pylori-specific immunoglobulin (Ig) G levels were determined by enzyme-linked immunosorbent assay. RESULTS: H. pylori and Gastrospirilum hominis-like organisms were present in 13 and 9 monkeys, respectively; 3 animals harbored both organisms, whereas 4 monkeys were not infected. Gastritis score was < or = 1.5 in animals uninfected or infected only with G. hominis-like organisms and > or = 2.0 in all H. pylori-infected animals. IgG ratios were > or = 0.5 in 12 of 13 H. pylori-infected animals and in 2 of 13 H. pylori-negative animals (P < 0.001). One monkey became infected with H. pylori during the observation period, with concurrent increase of gastritis and plasma IgG levels. In untreated animals, infection, gastritis, and plasma IgG levels remained unchanged over 7-15 months. Triple therapy eradicated H. pylori at 6 months in 4 of 6 animals while suppressing gastritis and plasma IgG levels. CONCLUSIONS: Rhesus monkeys harboring H. pylori are persistently infected and have gastritis and elevated specific IgG levels, all of which may respond to appropriate therapy, whereas G. hominis infection is associated with little inflammation.

Animals↗
PubMed1994

Characterization and presumptive identification of Helicobacter pylori isolates from rhesus monkeys.

We characterized 38 Helicobacter isolates, including 22 from gastric biopsy samples obtained from 14 rhesus monkeys and single isolates from 16 monkeys in a different colony. Biochemical profiles of these isolates were nearly identical to that of Helicobacter pylori ATCC 43504. Restriction fragment length polymorphism (RFLP) analysis indicated that each infected monkey harbored one to four strains. The 17 RFLP types found among these 22 isolates differed from all seven RFLPs found among the other 16 isolates. Thus, monkeys within a given colony are more likely to be infected by Helicobacter isolates with the same or a similar RFLP than are monkeys from different colonies. A 16S rRNA gene was amplified by PCR and cloned from the Helicobacter isolate from rhesus monkey 85D08. Ribotyping with this probe demonstrated less diversity among isolates from rhesus monkeys than was reported among isolates of H. pylori from humans, as did RFLP analysis of a PCR fragment of the ureA-ureB gene cluster. The DNA sequence of the cloned 16S rRNA gene was determined and compared with sequences reported for H. pylori and other Helicobacter species. Our analysis of 127 nucleotides (corresponding with residues 1240 to 1366 of the Escherichia coli 16S rRNA gene) indicated that the Helicobacter isolate from monkey 85D08 was 99.2 to 100% homologous to isolates of H. pylori from humans but only 83.5 to 96.9% homologous with other Helicobacter species in this region of the 16S rRNA gene. These data provide strong support for the presumptive identification of these isolates as H. pylori.

Animals↗