Statin use is associated with a reduction in the incidence of esophageal adenocarcinoma: a case control study.

The incidence of esophageal adenocarcinoma (EAC) is increasing significantly throughout the developed world. As yet, there are no proven chemopreventive strategies. In laboratory studies, aspirin, non-steroidal anti-inflammatory drugs and statins have promising chemopreventive actions. Several observational studies support a protective effect of aspirin and non-steroidal anti-inflammatory drugs, but there are only limited clinical data exploring the potential protective effect of statins. We conducted a case-control study examining aspirin and statin use in patients with EAC. Cancer cases were compared against age-sex-matched controls attending for diagnostic upper gastrointestinal endoscopy. Risk factor and drug exposure were established using standardized interviews. Logistic regression was used to compare statin exposure and correct for confounding factors. A total of 112 cases and 448 controls were enrolled. Statin use was associated with a significantly lower incidence of EAC (odds ratio 0.52, 95% confidence interval 0.27-0.92). Aspirin use was also associated with apparent protection against EAC (odds ratio 0.68, 95% confidence interval 0.28-0.92), and a significantly greater effect was seen with the combination of statin plus aspirin (odds ratio 0.27, 95% confidence interval 0.05-0.67). There was a significant trend for greater risk reduction with longer duration and higher doses of statin use. Simvastatin comprised the majority of statin use, but similar effects were seen with simvastatin and non-simvastatin agents. In this observational study, patients regularly using statins or aspirin had a lower incidence of EAC. Statins may have clinically useful effects in preventing the development of EAC.

Meta-analysis: risk of esophageal adenocarcinoma with medications which relax the lower esophageal sphincter.

Reasons for the rising annual incidence of esophageal adenocarcinoma (EAC) remain uncertain. Previous studies have given conflicting results, but some have suggested that drugs which relax the lower esophageal sphincter (LES) may increase the risk of EAC. This study is to determine systematically the risk of EAC associated with individual medications which relax the LES and compare risks with esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA). Relevant published studies were identified by systematic searching PubMed for case-control studies reporting on risk of EAC, ESCC or GCA with use of medications known to reduce LES pressure. Pooled odds ratios (ORs) were calculated for each malignancy. Data were analyzed from four case-control studies involving 9,412 participants. EAC was significantly associated with theophylline use (OR 1.55, 95% confidence interval [CI] 1.05-2.28; P= 0.03, I(2) = 0%) and anticholinergic medications (OR 1.66, 95% CI 1.13-2.44; P= 0.01, I(2) = 84%). This effect was not observed in cases of ESCC or GCA. Other drug groups including calcium channel modulators and nitrates did not increase the risk of EAC. An inverse relationship was observed between ESCC and nitrates and between GCA and benzodiazepines. The lack of increased EAC risk with many commonly used medications is reassuring. However, a significant correlation was found between EAC and the use of anticholinergics and theophyllines. This may reflect common causality between obstructive lung disease and EAC, and further studies to explore these relationships are warranted.

Leptin stimulates the proliferation of human oesophageal adenocarcinoma cells via HB-EGF and Tgfalpha mediated transactivation of the epidermal growth factor receptor.

Obesity increases the risk of developing oesophageal adenocarcinoma (OAC) as well as several other cancers. Leptin is secreted by adipocytes and serum leptin levels rise with body mass index. Leptin stimulates proliferation and inhibits apoptosis in OAC cells but the mechanisms are not fully elucidated, Transactivation of the epidermal growth factor receptor (EGFR) is an important signalling mechanism for G-protein-coupled receptors, but the relationship with leptin-type receptors has not been examined and the authors hypothesise that leptin-induced proliferation involves EGFR signalling. This study examines the effect of leptin on EGFR signalling in cultured cell lines. Leptin stimulated proliferation in four OAC lines expressing leptin receptors (OE33, OE19, BIC-1 and FLO) and this was abolished by specific EGFR inhibitors (PD153035 and AG1478). Leptin-induced proliferation was inhibited by neutralising antibodies to transforming growth factor-alpha (TGFalpha and HB-EGF) but not by anti-amphiregulin. Leptin significantly increased gene expression of HB-EGF and TGFalpha as measured by a quantitative real-time polymerase chain reaction (PCR) method but did not alter amphiregulin and EGFR gene expression. Leptin increased extracellular release of HB-EGF and TGFalpha and this was blocked by matrix metalloproteinase (MMP) inhibitors. The MMP inhibitors also abolished leptin-induced proliferation as well as leptin-induced EGFR tyrosine phosphorylation, but did not affect proliferation or EGFR activation induced by TGFalpha. The authors conclude that leptin stimulates OAC proliferation via increased gene expression of HB-EGF and TGFalpha, MMP-mediated extracellular release of HB-EGF and TGFalpha and subsequent activation of EGFR.

Soybean agglutinin stimulated cholecystokinin release from cultured rabbit jejunal cells requires calcium influx via L-type calcium channels.

We have studied the mechanism of soybean agglutinin (SBA) mediated cholecystokinin (CCK) release in enriched cultured cholecystokinin-secreting cells. 12-O-Tetradecanoylphorbol-13-acetate 1 mM significantly stimulated release of CCK-like-immunoreactivity (CCK-LI) by 55%+/-17% (p < 0.05), which was blocked by the protein kinase C inhibitor staurosporine 100 nM. Forskolin 10 mM stimulated CCK-LI by 82%+/-12% (p < 0.05) and this was inhibited by somatostatin 1 nM. 1-Phenylalanine 20 mM and Bay K 8644 1 mM stimulated CCK-LI by 69%+/-22% and 60%+/-19% respectively (p < 0.05), these responses were completely abolished by the L-type calcium channel antagonist verapamil 10 mM. SBA 10 and 100 microg/ml stimulated CCK-LI by 65%+/-22% and 74%+/-24% respectively (p < 0.05). The effect of SBA was inhibited by verapamil and N-acetylgalactosamine. We conclude that SBA stimulates CCK-LI through calcium flux via L-type calcium channels.

Effect of PACAP-27 on 14C-aminopyrine accumulation in isolated rabbit parietal cells.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is present in gastric mucosa, but its direct effect on parietal cells is unknown. We examined this using 14C-aminopyrine uptake in elutriated rabbit cells. PACAP-27 had no effect on basal cells but significantly increased the response to histamine (10(-4) M) at 10(-9) M and to carbachol (10(-4) M) in the presence of ranitidine (10(-4) M) at 10(-7) M and 10(-8) M. PACAP (6-38), an antagonist of PACAP, inhibited the effect of PACAP-27 on carbachol-stimulated cells. Vasoactive intestinal peptide had no significant effect. In conclusion, PACAP-27 has a direct additive effect on stimulated rabbit parietal cells in vitro.

Efficacy of Helicobacter pylori eradication therapies: a single centre observational study.

BACKGROUND: Many Helicobacter pylori eradication regimens have been described. There are little data reporting their efficacy or integration in routine clinical practice. The overall results of eradication therapy in a cohort of patients are described and an algorithm for management outlined. METHODS: 469 patients receiving eradication therapy in routine clinical practice were evaluated. The successes of individual regimes as first, second and third line therapy were determined. RESULTS: Overall success after one, two and three courses of therapy were 73% (95% confidence intervals 69-77%), 94% (91-96%) and 98% (97-99%) respectively. 10 different regimens, including many non-recommended ones were used as primary therapy. Ranitidine bismuth citrate-amoxicillin-clarithromycin triple therapy (94.8%, 90-99%) was significantly more effective than any other combination as primary therapy, including all proton pump inhibitor based triple therapies. Quadruple therapy with bismuth chelate-proton pump inhibitor-tetracycline and a nitroimidazole (70%, 52-88%) and ranitidine bismuth citrate-based triple therapy (73%, 56-90%) where more effective second line combinations than proton pump inhibitor-triple therapies (37.5%, 12-58%). Third line therapy directed by the results of sensitivity testing improved eradication compared to further empirical antibiotics. The use of a proton pump inhibitor with clarithromycin and a nitroimidazole as initial therapy was associated with a significantly worse overall eradication rate than other combinations. CONCLUSIONS: Helicobacter pylori eradication rates can be maximised by using ranitidine bismuth citrate-clarithromycin-amoxicillin containing triple therapy, followed by bismuth and nitroimidazle containing second-line therapy, with third line combinations directed by sensitivity testing. Proton pump inhibitor-clarithromycin-metronidazole combinations should be avoided.

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.

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.

Helicobacter pylori increases gastrin release from cultured canine antral G-cells.

OBJECTIVE: To investigate the mechanisms underlying the hypergastrinaemia of Helicobacter pylori by examining the effects of H. pylori on basal and stimulated gastrin release from cultured canine G-cells. METHODS: Canine antral G-cells were prepared by collagenase-EDTA digestion and cultured for 40 h. G-cells were then cultured for a further 24 h with two different H. pylori sonicates before basal and bombesin-stimulated gastrin release were measured by radioimmunoassay. RESULTS: Treatment of G-cells with both H. pylori sonicates significantly enhanced basal gastrin release (by 17-27%) and bombesin-stimulated gastrin release (by 115-133%). This effect was independent of cagA and vacuolating cytotoxin status. Control treatment with Escherichia coli sonicate had no effect on gastrin release. There was no change in the cellular content of gastrin. CONCLUSIONS: Incubation of antral G-cells with H. pylori constituents enhances subsequent basal and bombesin-stimulated gastrin release. Direct contact between H. pylori and G-cells in the gastric antrum may be responsible for the hypergastrinaemia seen with the infection.

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.

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.

Drinking among medical students: a questionnaire survey.

To assess the prevalence of drinking among medical students a questionnaire on smoking, exercise, drinking, and weight was distributed among the students available. A total of 260 replies were received from an estimated available population of 350 students (134 men and 126 women). The mean alcohol consumption obtained by a quantity-frequency measure was 20.5 units/week for male students and 14.6 units/week for female students. Retrospective diary reports showed mean (SE) consumptions of 18 (2) units/week for men (n = 134) and 11 (1) units/week for women (n = 126). Consumption among the men closely matched consumption among men matched for age in the general population. Women, however, drank more than women matched for age. Male and female medical students exceeded the suggested maximum for their sex in equal proportions. Quantity-frequency data showed that 31 (23%) men drank over 35 units/week and 28 (22%) women drank over 21 units/week. Of the 59 students exceeding these limits, 51 responded positively to a standard screening questionnaire for alcohol abuse. Forty students reported that they might have a drinking problem, and 138 reported that alcohol had affected their academic performance at some time; 17 of these were affected frequently. The students suggested sensible maximum consumption figures for health education. Smoking was associated with heavy drinking, especially among the women. These results suggest that some medical students are compromising their future health and their academic performance through excessive drinking.

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.