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Biomedical subjects

I L Beales

Publications and source records attributed to I L Beales.

At least 37 records · Page 2Linked to original sources
PubMed1998

Circulating antibodies to the 60-kD heat shock protein (hsp) family in patients with Helicobacter pylori infection.

Whilst the mechanism by which Helicobacter pylori causes different gastroduodenal diseases is uncertain, strains producing the cytotoxin-associated protein (CagA) have greater pathogenicity. Hsps are immunogenic molecules induced by inflammatory mediators. The aim of this study was to assess pathogenicity of hsp antibodies in H. pylori-infected patients. ELISA techniques were used to assay sera of H. pylori-positive patients with gastritis, gastric atrophy, duodenal or gastric ulcer, and H. pylori-negative controls, for antibodies to CagA and to human, mycobacterial, and in 20 sera, H. pylori (hspB) 60-kD hsp. IgA antibodies to mycobacterial hsp60 in atrophy patients were elevated compared with patients with gastritis (P < 0.05) and with H. pylori-negative controls (P < 0.0005). IgA antibodies to human hsp60 in gastric atrophy patients were elevated compared with H. pylori-negative controls (P < 0.05). Patients with atrophy (P < 0.0005) and gastritis (P < 0.05) who were CagA-positive had raised titres of anti-mycobacterial hsp60 IgA antibodies compared with controls. IgA antibody levels to hspB were positively correlated with those to mycobacterial hsp60 (mhsp60) (P < 0.05) and human hsp60 (hhsp60) (P < 0.005). IgA antibodies to hsp60 are associated with gastroduodenal disease, particularly gastric atrophy, in H. pylori-infected patients. Increased humoral responses to hsp60 could either contribute to gastric atrophy or result from greater gastric mucosal damage induced by CagA-positive strains of H. pylori.

Autoantibodies↗
PubMed1998

Interleukin 1 beta and tumour necrosis factor alpha inhibit acid secretion in cultured rabbit parietal cells by multiple pathways.

BACKGROUND: The cytokines interleukin 1 beta (IL-1 beta) and tumour necrosis factor alpha (TNF-alpha) are inhibitors of gastric acid secretion when administered systemically. AIMS: To investigate the inhibitory effect of IL-1 beta and TNF-alpha on cultured, acid secreting parietal cells in order to determine the mechanism of this inhibition. METHODS: Rabbit parietal cells were prepared by collagenase-EDTA digestion and counter flow elutriation. Acid secretory activity was assessed by aminopyrine accumulation. RESULTS: IL-1 beta and TNF-alpha inhibited basal and stimulated acid secretion in a dose dependent manner; near maximal effects were seen with both at 10 ng/ml. Inhibition was maximal with 15 minutes pretreatment but seen with up to 18 hours of preincubation. Both cytokines inhibited histamine, carbachol, gastrin, forskolin, and A23187 stimulated acid secretion but had no effect on stimulation by dibutyryl-cAMP. Inhibition of acid secretion was not accompanied by a change in radioligand binding to histamine H2 or gastrin/CCKB receptors. Pertussis toxin abolished the inhibitory effects on histamine and forskolin stimulation. The tyrosine kinase inhibitor herbimycin reduced the inhibitory effects of TNF-alpha against all stimuli but only reduced the effects of IL-1 beta against histamine and forskolin stimulation. CONCLUSIONS: IL-1 beta and TNF-alpha seem to inhibit parietal cell acid secretion by multiple pathways; the inhibition occurs at postreceptor level and involves pertussis toxin and tyrosine kinase dependent and independent pathways. Mucosal production of cytokines may be important in the regulation of gastric acid secretion.

Animals↗
PubMed1998

The histamine H3 receptor agonist N alpha-methylhistamine produced by Helicobacter pylori does not alter somatostatin release from cultured rabbit fundic D-cells.

BACKGROUND: The mechanisms underlying the suppression of somatostatin dependent reflexes in Helicobacter pylori infection are not fully determined. The H pylori product N alpha-methylhistamine and inflammatory mediators such as tumour necrosis factor-alpha (TNF-alpha) may be responsible for the alterations in somatostatin release. AIMS: To examine the effect of N alpha-methylhistamine on somatostatin release from cultured somatostatin-secreting D-cells. METHODS: Rabbit fundic D-cells were obtained by collagenase-EDTA digestion and enriched by centrifugal elutriation and cultured for 40 hours. The effects of N alpha-methylhistamine on somatostatin release soon after stimulation (two hours) and after more prolonged exposure (24 hours) were assessed. RESULTS: N alpha-Methylhistamine (1 nM-1 microM) had no effect on basal or carbachol or adrenaline stimulated release over two hours. Similarly with prolonged exposure no effect on somatostatin cell content or release was identified. In contrast, TNF-alpha (24 hours) led to a dose dependent fall in both somatostatin content and release. CONCLUSIONS: N alpha-Methylhistamine had no direct inhibitory effects on D-cells, but TNF-alpha both significantly reduced the cellular content and inhibited release. Inflammatory cytokines, rather than N alpha-methylhistamine, are therefore likely to be responsible for directly inhibiting D-cell function in H pylori infection.

Animals↗
PubMed1998

Pathogenic mechanisms in Helicobacter pylori infection.

The likelihood of clinical disease is affected by the strain of Helicobacter pylori, and whether gastritis extends to the gastric corpus. Plentiful acid from a healthy corpus may cause duodenal ulcers while corpus gastritis and acid hyposecretion are associated with gastric cancer.

Genes, Bacterial↗
PubMed1997

Stimulation of IL-8 production in human gastric epithelial cells by Helicobacter pylori, IL-1beta and TNF-alpha requires tyrosine kinase activity, but not protein kinase C.

Production of interleukin 8 (IL-8) is believed to be important in the pathogenesis of the gastritis seen in Helicobacter pylori infection. The aim of this study was to investigate the roles of protein kinase A (PKA), protein kinase C (PKC), protein tyrosine kinase (PTK) and intracellular calcium in the induction of IL-8 production by gastric epithelial cells. AGS gastric epithelial cells were stimulated with H. pylori, tumour necrosis factor alpha or interleukin 1beta together with activators or inhibitors of the relevant kinases. IL-8 production was measured by enzyme-linked immunosorbent assay. Helicobacter pylori, tumour necrosis factor alpha and interleukin 1beta produced a dose-dependent increase in IL-8 production. The increase with all three was significantly reduced by the tyrosine kinase inhibitors herbimycin A and genistein. Activation of PKC by phorbol myristate acetate was also an effective stimulus to IL-8 production and this was blocked by PKC depletion or inhibitors. Protein kinase C inhibition did not reduce the stimulation produced by H. pylori or the cytokines. Stimulation of PKA with forskolin or dibutyryl cyclic adenosine monophosphate or inhibition with H89 had no effect on IL-8 production. The calcium ionophore A23187 was a weak, PKC dependent, stimulant of IL-8 production. The production of IL-8 in AGS cells is stimulated via tyrosine kinase and protein kinase C dependent pathways. Stimulation by H. pylori, tumour necrosis factor alpha and interleukin 1beta requires tyrosine kinase activity.

Calcium↗
PubMed1997

Misoprostol-associated platelet aggregation dysfunction and increased gastrointestinal blood loss.

We report a case where an acquired deficit in platelet aggregation was associated with the use of misoprostol and contributed to increased gastrointestinal blood loss. A 70-year-old man presented with chronic gastrointestinal blood loss secondary to widespread telangiectases. Investigations showed prolonged bleeding time and severely impaired platelet aggregation in vitro. Withdrawal of misoprostol resulted in resolution of the prolonged bleeding time and improvement in the platelet dysfunction. We conclude that misoprostol can lead to impaired platelet function and may exacerbate blood loss.

Aged↗
PubMed1997

Helicobacter pylori stimulates granulocyte-macrophage colony-stimulating factor (GM-CSF) production from cultured antral biopsies and a human gastric epithelial cell line.

OBJECTIVE: To examine the regulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) production by gastric epithelial cells in Helicobacter pylori infection. DESIGN: The effect of H. pylori infection on gastric GM-CSF production was assessed using short-term culture of antral biopsies. The mechanism of GM-CSF induction was investigated using a gastric epithelial cancer cell line. METHODS: Production of GM-CSF was assessed by enzyme-linked immunosorbent assay. The mechanism of stimulation of GM-CSF production was examined by co-culture of AGS carcinoma cells with H. pylori and specific stimulants and inhibitors. RESULTS: Biopsies from H. pylori-negative patients in the basal state did not produce GM-CSF. However, over 24 h in the presence of the active phorbol ester, phorbol myristate acetate (PMA), significant release of GM-CSF was seen. H. pylori-positive biopsies produced significantly more GM-CSF in both the unstimulated and PMA-stimulated state than H. pylori-negative biopsies. Constitutive release of GM-CSF from cultured human gastric AGS cells could be significantly enhanced by co-culture with live H. pylori or the addition of interleukin-1 beta, tumour necrosis factor alpha and PMA, but not by exposure to forskolin. The protein kinase C inhibitor staurosporine abolished the stimulatory effect of PMA on AGS cells, whereas the protein-tyrosine kinase inhibitor herbimycin A prevented the stimulation of GM-CSF production seen with H. pylori and both cytokines. CONCLUSION: H. pylori enhances GM-CSF production by gastric epithelia. H. pylori appears to stimulate gastric epithelial cells directly to produce GM-CSF and this stimulation involves a tyrosine kinase dependent step. Induction of GM-CSF may play a role in the initiation and perpetuation of gastric inflammation in H. pylori infection.

Adenocarcinoma↗
PubMed1997

Helicobacter pylori infection and tumour necrosis factor-alpha increase gastrin release from human gastric antral fragments.

OBJECTIVES: To investigate the mechanism of the hypergastrinaemia associated with Helicobacter pylori infection by examining the effect of H. pylori infection and the cytokine tumour necrosis factor-alpha (TNF-alpha) on gastrin release from human antral fragments. DESIGN: In-vitro experimental study. METHODS: Human antral biopsy fragments were cultured for 6 h with and without TNF-alpha (20 ng/ml) and the gastrin released over the following 2-h stimulation period measured by radioimmunoassay. The integrity of the paracrine feedback loop inhibiting gastrin release was tested by concurrent administration of cholecystokinin (CCK). RESULTS: H. pylori-positive fragments were associated with significantly greater bombesin-stimulated gastrin release (increased by 40%, P < 0.05) and less inhibition produced by CCK administration (decreased by 55%, P < 0.05), than H. pylori-negative fragments. TNF-alpha treatment of H. pylori-negative fragments significantly enhanced bombesin-stimulated gastrin release (by 82%, P < 0.01) and diminished inhibitory feedback by CCK (by 53%, P < 0.05). CONCLUSION: H. pylori infection is associated with enhanced gastrin release from human antrum and TNF-alpha produces a similar effect. Proinflammatory cytokines generated in the antrum in response to the infection are likely to play a significant role in the hypergastrinaemia of H. pylori infection.

Bombesin↗
PubMed1997

Effect of N alpha-methyl-histamine on acid secretion in isolated cultured rabbit parietal cells: implications for Helicobacter pylori associated gastritis and gastric physiology.

BACKGROUND: Helicobacter pylori has been shown to produce the unusual metabolite N alpha-methyl-histamine. This compound is known to be a potent agonist at inhibitory histamine H3 receptors. There is increasing evidence implicating this receptor in the control of gastric acid secretion but the mechanism for this remains to be clarified. AIMS: To investigate the effect of N alpha-methyl-histamine on the acid secretory activity of parietal cells and to determine the mechanism for such effects, thus helping to determine the role of this compound in the pathophysiology of H pylori infection. METHODS: Rabbit parietal cells were isolated and enriched by collagenase-EDTA digestion and centrifugal elutriation. Following culture on Matrigel coated plates, acid secretion was assessed by 14C aminopyrine accumulation. RESULTS: N alpha-methyl-histamine (100 microM) was as potent as histamine (100 microM) in stimulating acid secretion. This effect was reversed by ranitidine indicating it was mediated via the H2 receptor. N alpha-methyl-histamine potentiated the effects of both carbachol (increased by 280%) and gastrin (by 350%) (p < 0.01). N alpha-methyl-histamine had no inhibitory actions on forskolin or carbachol stimulated acid secretion suggesting that there is not an inhibitory H3 receptor located directly on the parietal cell. CONCLUSIONS: Bacterially produced N alpha-methyl-histamine directly stimulates acid secretion by parietal cells and this may contribute to the increased acid secretion that contributes to duodenal ulceration.

Aminopyrine↗
PubMed1996

Tumour necrosis factor alpha stimulates gastrin release from canine and human antral G cells: possible mechanism of the Helicobacter pylori-gastrin link.

There is evidence that gastric Helicobacter pylori (Hp) infection promotes duodenal ulceration by releasing gastrin. We therefore asked how Hp releases gastrin. Tumour necrosis factor alpha (TNF-alpha) is up-regulated in Hp gastritis and stimulates hormone release from pituitary cells, so we tested its effect on primary cultures of canine antral G cells and human antral fragments. TNF-alpha pretreatment (100 ng mL-1) of canine G cells significantly increased both basal (by 89%: P < 0.01) and bombesin-stimulated (by 39% P < 0.05) gastrin release. A similar pattern of increase was seen following TNF-alpha (20 ng mL-1) pretreatment of human antral fragments: basal gastrin release was increased by 38% (P < 0.05) and bombesin-stimulated by 26% (P < 0.05). This effect persisted during immunoblockade with anti-somatostatin antibody S6. We propose that TNF-alpha provides the link between Hp infection and gastrin release and thus contributes to duodenal ulceration.

Animals↗
PubMed1996

Truncated glucagon-like peptide-1 and oxyntomodulin stimulate somatostatin release from rabbit fundic D-cells in primary culture.

The ability of the proglucagon-derived peptides oxyntomodulin and truncated glucagon-like peptide-1 (7-36)amide to stimulate somatostatin release from cultured rabbit fundic D-cells was assessed. Significant stimulation of somatostatin release was seen with both peptides at 10 nM. Potentiation of the stimulatory action of cholecystokinin was seen with both peptides at both 100 pM and 10 nM. The paracrine release of somatostatin from fundic D-cells may explain the acid inhibitory actions of the enteroglucagons. The different small bowel-derived peptides may interact at the level of the D-cell to regulate gastric acid secretion.

Animals↗
PubMed1996

Antibodies to CagA protein are associated with gastric atrophy in Helicobacter pylori infection.

Strains of Helicobacter pylori which express the product of the cytotoxin associated gene A(CagA) are associated with duodenal ulceration. Also there is evidence that the presence of serum IgG antibodies to CagA is associated with an increased risk of gastric cancer of the intestinal type. Gastric atrophy is a precursor of intestinal-type gastric cancer so we have investigated whether antibodies to CagA are associated with gastric atrophy. In H. pylori infected patients, IgG antibodies to CagA were present in 24/38 (63%) of non-ulcer patients with atrophy compared with 13/40 (33%) of patient-controls with neither atrophy nor ulcer (P < 0.02). CagA antibodies were also more prevalent in patients with duodenal ulcers; 15/20 (75%) or gastric ulcers 5/5 (100%) than in the patient-controls (P < 0.005 and < 0.02 respectively). These results show that circulating IgG antibodies to CagA are associated with gastric atrophy, as well as peptic ulcer disease. Atrophy is a precursor of gastric cancer so support the hypothesis that certain strains of H. pylori are more likely to cause gastric cancer.

Adult↗