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Biomedical subjects

R E Pounder

Publications and source records attributed to R E Pounder.

At least 37 records · Page 2Linked to original sources
PubMed1999

Demonstration of new sites of expression of the CCK-B/gastrin receptor in pancreatic acinar AR42J cells using immunoelectron microscopy.

The CCK-B/gastrin receptor has been characterised in both normal and tumour tissues. Endocytosis of the CCK-B/gastrin receptor has recently been demonstrated and this has similarly been described for other peptide receptors. In addition, ligand and ligand-receptor translocation to the nucleus has been demonstrated for other peptides. The aim of this study was to identify the sites of expression of the CCK-B/gastrin receptor in the known CCK-B/gastrin receptor bearing pancreatic acinar AR42J cells. The specificity of the CCK-B/gastrin receptor antibody (alpha-CCKBR-Ser antibody) was demonstrated by inhibition ELISA studies, radioligand inhibition studies and immunofluorescence binding studies on AR42J cells. Western blotting and immunogold electron microscopy techniques were used to identify the receptor in AR42J cell preparations. The affinity purified alpha-CCKBR-Ser antibody was shown to be specific for the CCK-B/gastrin receptor. The receptor was expressed on the cell membrane, in the cytoplasm and within the nucleus. Isoforms of the receptor protein identified in extra-nuclear and nuclear extracts ranged in molecular weight from 58 to 66 kDa. We conclude that the CCK-B/gastrin receptor is not only expressed on the cell membrane, but also in the cytoplasm and nucleus of AR42J pancreatic acinar cells.

Animals↗
PubMed1999

Helicobacter pylori: from the benign to the malignant.

Half of the world's population is infected with Helicobacter pylori, making it a pathogen of potentially great significance. Although in the majority of cases, infection is harmless, many infected individuals develop peptic ulcer disease or gastric cancer. In developed countries, the prevalence of infection has decreased along with the incidences of duodenal and gastric ulcer and distal gastric cancer. In developing countries, H. pylori infection rates remain high, and, as life expectancy increases, the incidence of gastric cancer will increase. Recently, a working party of the World Health Organization designated H. pylori a class I carcinogen. This designation, along with the description of an H. pylori-infected animal model of gastric cancer, has strengthened the case for H. pylori eradication to prevent gastric cancer. However, concerns are growing that H. pylori eradication itself may cause harm. And, in developed countries, an increase in the rate of cancers arising near the gastroesophageal junction might be linked to the disappearance of H. pylori. Therefore, we are faced with a dilemma: Should we eradicate H. pylori to prevent cancer of the distal stomach, or should we leave it and hence avoid cancer of the proximal stomach or distal esophagus? The need for more reliable treatments further complicates the issue. So far, we cannot assume that current treatment regimens provide adequate eradication rates to justify widespread screening. Further research is needed to determine in whom, when, and how to eradicate H. pylori infection.

Drug Therapy, Combination↗
PubMed1999

Paramyxovirus infections in childhood and subsequent inflammatory bowel disease.

BACKGROUND & AIMS: Measles virus has been implicated in the etiology of both inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis. Subacute sclerosing panencephalitis (SSPE) is caused by atypical measles infection. This study investigated the patterns of infection that are risks for SSPE, early infection and a close temporal relationship between measles and another infection, as potential risks for IBD. METHODS: The data are from 7019 members of a nationally representative 1970 British Cohort Study. The ages of five childhood infections were recorded before onset of IBD symptoms. Diagnoses of IBD and insulin-dependent diabetes mellitus (IDDM), as a control disease, were identified by age 26 years. RESULTS: Mumps infection before age 2 years was a risk for ulcerative colitis (odds ratio, 25.12; 95% confidence interval, 6. 35-99.36). Measles and mumps infections in the same year of life were significantly associated with ulcerative colitis and Crohn's disease, with odds ratios of 7.47 (2.42-23.06) and 4.27 (1.24-14.46), but not with IDDM. These relationships are independent of each other as well as sex, social class at birth, household crowding in childhood, and family history of IBD. CONCLUSIONS: Atypical paramyxovirus infections in childhood may be risk factors for later IBD.

Adult↗
PubMed1999

Conservation of the cag pathogenicity island of Helicobacter pylori: associations with vacuolating cytotoxin allele and IS605 diversity.

BACKGROUND & AIMS: Specific regions of the cag pathogenicity island (PAI) believed to enhance the virulence of Helicobacter pylori, as well as vacuolating cytotoxin gene alleles and IS605 inserts, were investigated to define diversity within infecting strain populations from patients with peptic ulcer disease and from healthy individuals. METHODS: The H. pylori studied comprised 67 isolates from 26 subjects and 14 reference strains. Specific polymerase chain reaction assays were used to test for cagA and picB in the cagI region, the virD4 homologue in the cagII region, IS605 in the genome and in the cag PAI, the "empty site" indicating absence of the cag PAI, and different vacA gene alleles. RESULTS: Most (89%) subjects were infected by H. pylori with a contiguous cag PAI. No intermediate forms were found. IS605 was not detected within the cag PAI of any strain but was present elsewhere in the genomes of strains from 62% of subjects. Twenty individuals were infected with genotypically conserved populations of H. pylori. Six subjects had mixed infections, and in 3 of these cag(+)/cag(-) variants were present. CONCLUSIONS: The cag PAI-positive H. pylori was a feature of most infected individuals, irrespective of severity of associated disease. Combined genotyping showed that 8 individuals (31%) had mixed infections, which suggests that strain population structure may be an additional contributing factor in disease development.

Alleles↗
PubMed1999

Review article: the pharmacology of rabeprazole.

Rabeprazole sodium is a new substituted benzimidazole proton pump inhibitor with several differences compared with existing proton pump inhibitors. In vitro and animal studies have demonstrated that rabeprazole is a more potent inhibitor of H+,K(+)-ATPase and acid secretion than omeprazole, and is a more rapid inhibitor of proton pumps than omeprazole, lansoprazole, or pantoprazole. This probably reflects rabeprazole's faster activation in the parietal cell canaliculus. In human studies, once-daily doses of 5-40 mg of rabeprazole inhibit gastric acid secretion in a dose-dependent fashion. A once-daily dose of 20 mg has consistently achieved profound decreases in 24-h intragastric acidity in single and repeat dosing studies, in healthy volunteers and patients with either peptic ulcer disease or gastro-oesophageal reflux disease. Significantly greater decreases in intragastric acidity are achieved on day 1 of dosing with rabeprazole 20 mg than with omeprazole 20 mg. As with other proton pump inhibitors, rabeprazole has in vitro antibacterial activity against Helicobacter pylori, with greater activity against this organism than either lansoprazole or omeprazole. In addition to inhibiting bacterial urease activity, rabeprazole binds to several molecules on H. pylori. Clinical trials are needed to assess the clinical importance of these findings, as well as to assess whether the potential advantages of rabeprazole result in clinical benefit for patients with acid-related diseases.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1999

The colonic mesenteric margin is most susceptible to injury in an experimental model of colonic ulceration.

BACKGROUND: Crohn's disease ileal ulcers and indomethacin-induced jejunal ulceration in the rat tend to occur in the mucosa nearest to the mesentery (mesenteric margin), an area of the bowel wall that has a critical blood supply. Mercuric chloride induces caecal and colonic ulceration in the Brown Norway rat. AIM: To examine whether the mesenteric margin is more sensitive to injury by a substance known to be vasculotoxic in the caecum and colon. METHODS: Brown Norway rats received a single subcutaneous dose of either mercuric chloride 1 mg/kg or saline. The gastrointestinal tract was examined macro- and microscopically for lesions 48 h later. The vascular anatomy of the normal rat colon and caecum was also examined using the carbon ink perfusion technique. RESULTS: Mercuric chloride induced caecal and colonic ulceration preferentially along the mesenteric margin of the bowel wall. Histologically, the lesions showed mucosal necrosis and neutrophil infiltration. There was also extensive vascular degeneration/necrosis with microaneurysm formation and extensive submucosal haemorrhage. Cellular infiltration of the vasculature was not a feature. The caecal and colonic mesenteric margins in control rats were supplied by small end arteries. CONCLUSIONS: The colonic and caecal mesenteric margins are susceptible to injury by mercuric chloride, a chemical known to induce haemorrhagic vasculopathy in the rat gastrointestinal tract. The large bowel mesenteric margin may be susceptible to injury by mercuric chloride because of the critical blood supply to that side of the bowel wall.

Animals↗
PubMed1999

Laser assisted ratio analyser 13C-urea breath testing, for the detection of H. pylori: A prospective diagnostic European multicentre study.

BACKGROUND: Novel technology based on laser optogalvanic spectroscopy called the LARA (Laser Assisted Ratio Analyser) system was developed to measure 12C/13C ratios in breath samples using stable 13C isotopes, to detect Helicobacter pylori infection. AIM: To determine the sensitivity and specificity of the 13C-LARA-urea breath test in the detection of H. pylori infection in a prospective European multicentre trial; FDA-and EMEA-approved. METHODS: Consecutive dyspeptic patients underwent diagnostic gastroscopy with biopsies for culture and histopathology, to detect H. pylori infection (gold standard). Subsequently, the LARA-urea breath test was performed using either a system without a cold trap (part I) or a system with a cold trap (part II). In both instances baseline, 30-min and 60-min breath samples were collected. The optimum cut-off level for 12C/13C ratios was determined by Receiver Operator Characteristics analysis. RESULTS: In part I, 544 out of 604 patients were evaluable (low CO2: 47; withdrawn: 13). 284 out of 544 patients (52%) were H. pylori-positive according to the gold standard. The sensitivity of the LARA-urea breath test was 95% and the specificity 94%. In part II, 257 out of 272 were evaluable (low CO2: 14; withdrawn: 1). Sensitivity and specificity were 93% and 96%, respectively. CONCLUSION: The LARA-technology represents an accurate and non-invasive testing system for the detection of H. pylori infection. Its major advantages are the use of stable 13C isotope, the high throughput of samples and the easy means of collecting, storing and transporting the samples, thus making the system convenient to both patient and clinician.

Adolescent↗
PubMed1999

The effect of omeprazole dosing on the isolation of Helicobacter pylori from gastric aspirates.

BACKGROUND: Animal experiments suggest that omeprazole dosing increases shedding of Helicobacter into the gastric lumen, and hence into gastric juice. AIM: To assess the effect of omeprazole dosing on the yield of H. pylori from gastric aspirates of infected volunteers. METHODS: Six serial nasogastric aspirates, three before and three during dosing with omeprazole 40 mg b.d., were obtained for culture from 10 H. pylori infected volunteers and one uninfected volunteer. To reduce contamination, samples were diluted 1:10 with Maximum Recovery Diluent (MRD; pH 7.0) or HCl-KCl buffer (pH 2.2) prior to culture on Columbia and Dent's agar. RESULTS: Undiluted gastric juice cultures were rapidly overgrown by upper respiratory tract flora. HCl-KCl dilution resulted in isolation of H. pylori from 77% of infected subject aspirates before, and 67% of aspirates during dosing with omeprazole. The yields were significantly lower with MRD dilution, 47% and 10%, respectively. Omeprazole dosing significantly decreased the yield after MRD dilution, but not after HCl-KCl dilution. CONCLUSIONS: Decreasing intragastric acidity, by dosing with omeprazole, decreases the isolation of H. pylori from routinely processed gastric aspirates. In vitro acidification of gastric aspirates, by HCl-KCl dilution, increases the isolation of H. pylori both before and during omeprazole dosing.

Adult↗
PubMed1999

Asian ethnic origin and the risk of inflammatory bowel disease.

OBJECTIVE: To assess whether inflammatory bowel disease (IBD) is more prevalent in young Asians than Europeans living in Great Britain. DESIGN: Longitudinal birth cohort study of all those born 5-11 April 1970 in Great Britain--the 1970 British Cohort Study (BCS70). METHODS: The relationship of a diagnosis of ulcerative colitis or Crohn's disease by age 26 years with ethnic origin was investigated among 8,432 cohort members with complete data using multiple logistic regression. We adjusted for potential confounding factors, household crowding and sex, as well as for a family history of IBD. RESULTS: Young Asians born in Britain were significantly more likely than indigenous Europeans to have a diagnosis of IBD by age 26 years, with relative odds of 6.10 (95% CI 2.14-17.33). This group of cohort members had ethnic origins in India, Pakistan or Bangladesh (although none of those from Bangladesh had IBD). This relationship remained statistically significant after adjustment for the potential confounding factors and family history of IBD. CONCLUSION: Young Asians who were born in Britain are at a significantly higher risk of developing IBD than the indigenous European population. This may reflect a greater genetic predisposition to IBD that is uncovered by exposure to environmental factors.

Adult↗
PubMed1999

Crohn's disease: the case for measles virus.

Crohn's disease has the epidemiological and pathological hallmarks of an infection with a long natural history. Its emergence in developed countries in the middle of the 20th Century represents an instant in the continuum of human evolution, indicating either a new infection or, as with poliomyelitis, a changing pattern of exposure to a common childhood pathogen. Both short- and long-term outcomes from viral infection are largely dependent upon age and dose of exposure. We and others have suggested that measles virus may be causally related to Crohn's disease, and that the associated risk is an atypical pattern of exposure. Early, intensive, and concurrent infections have been identified as risks for subacute sclerosing panencephalitis, a delayed sequelae to measles virus infection, possibly through a process of high zone immunological tolerance and persistent infection. The data for Crohn's disease suggest that persistent infection may follow early low dose exposure and low zone immunological tolerance. The changing pattern of measles virus exposure this century would be consistent with a shift towards lower dose of infection. Such an exposure would also be consistent with persistence of the virus at very low copy number within discrete foci of granulomatous inflammation. The ability of measles virus to profoundly disrupt mucosal immune responses may provide the human counterpart of the cytokine-gene knockout.

Adult↗
PubMed1998

The effects of low doses of ranitidine on intragastric acidity in healthy men.

BACKGROUND: H2-receptor antagonists are becoming widely available as over-the-counter medications for the treatment of heartburn and excess gastric acidity. AIM: To determine the effects of single low doses of ranitidine on intragastric acidity. METHODS: Intragastric pH was measured for 9 h after lunch in five studies involving 24 healthy male volunteers. Antacid was given to all subjects on day 1. They then received single oral doses of a study drug 45 min after lunch on four separate occasions: placebo and either ranitidine 25 mg, 75 mg or 125 mg were given double-blind according to a predetermined randomization schedule. RESULTS: During both of the post-dosing time periods (0-5 h and 5-9 h) there were significant decreases in integrated intragastric acidity for each ranitidine dose compared with placebo (P < 0.0001). There was a significant linear relationship between dose and integrated intragastric acidity with a greater decrease in acidity with increasing ranitidine doses (P < 0.0001). Compared with placebo, time with pH > 3 was significantly greater for ranitidine 75 mg and 125 mg (P < 0.001), but not ranitidine 25 mg. Results with the antacid were similar to placebo. CONCLUSIONS: Using low doses of ranitidine (25, 75 or 125 mg) there was a dose-related decrease in intragastric acidity for 9 h after dosing. A single dose of antacid did not decrease intragastric acidity significantly.

Adult↗
PubMed1998

Localization of the beta(beta)3-adrenoceptor in the human gastrointestinal tract: an immunohistochemical study.

BACKGROUND: Activation of human and non-human colonic beta(beta)3-adrenoceptors causes smooth muscle relaxation. beta3-Adrenoceptor agonists protect against experimental indomethacin-induced jejunal ulceration. The mechanism of protection may involve spasmolytic/vasodilatory agonist activity. The precise localization of beta3-adrenoceptors in the human gut is not known. AIM: To localize the beta3-adrenoceptor within the human gastrointestinal tract using the immunohistochemical technique. METHODS: Human beta3-adrenoceptors were immuno-localized in paraffin sections of human oesophagus (OS), stomach (ST), duodenum (DU), ileum (IL), sigmoid colon (SC), rectum (R) and gall-bladder (GB) using the rabbit polyclonal antibody anti-P12. Staining was graded , ++, + and 0. Immunostaining of SC was also done with pre-incubation of anti-P12 with P12 peptide. Western blotting of anti-P12 on human and murine IL and SC isolated membrane proteins was performed. RESULTS: All epithelia, vascular endothelial cells and ganglia scored 0. Smooth muscle of the vasculature, muscularis propria, muscularis mucosae and mucosa was graded, respectively, as follows; OS ( , , ,-), ST (++, , ++, ++), DU (++, , , +), IL (++, ++, ++, +), SC ( , ++, ++, ++), R (++, ++, +, +), GB ( , , -, 0). Pre-incubation of anti-P12 with P12 peptide almost abolished SC smooth muscle positivity. Western blot analysis using anti-P12 on human, but not murine, IL and SC membrane proteins revealed a single 5 5 kDa band, a size consistent with the predicted size of a partially glycosylated form of the human beta3-adrenoceptor. CONCLUSIONS: This immunohistochemical study has localized the beta3-adrenoceptor to vascular and nonvascular smooth muscle in the human gastrointestinal tract. These findings support a role for the beta3-adrenoceptor in the control of blood flow and motility in the human gastrointestinal tract.

Amino Acid Sequence↗
PubMed1998

Reversal and protection against indomethacin-induced blood stasis and mucosal damage in the rat jejunum by a beta3-adrenoceptor agonist.

BACKGROUND: In the rat, indomethacin causes jejunal villous shortening, microvascular distortion, and blood stasis prior to ulceration. The beta3-adrenoceptor agonist CL316,243 (CL) prevents both the early histological changes and ulceration. AIM: To test the hypothesis that the beta3-adrenoceptor agonist CL316,243 exerts its protective effect by prevention and/or reversal of blood flow changes in the rat jejunum exposed to indomethacin. METHODS: In anaesthetized rats, jejunal villous blood flow was measured in surface capillaries using fluorescence microscopy. Stasis of superficial capillary blood flow was induced by combined topical and i.v. indomethacin (100 microg/mL, 2.8 x 10(-4) M). To examine the effect of CL on blood stasis, CL was applied either i.v. (1 mg/kg) or luminally (100 microg/mL, 2.5 x 10(-5)M) at the onset of stasis. Prophylactic protection was assessed by giving i.v. CL simultaneously with indomethacin. Results were compared with controls which received luminal saline applied at blood stasis. The effect of i.v. CL (1 mg/kg) alone, or luminal CL (100 microg/mL) alone on basal villous blood flow was also examined. The small intestines were perfusion-fixed with 10% formol saline, and removed for histology, n = 5 for all groups. RESULTS: Luminal CL given at stasis reversed indomethacin-induced stasis within 10 min, whereas i.v. CL did not. Pretreatment with i.v. CL prevented the onset of stasis. Basal blood flow was raised slightly only by luminal CL. CONCLUSION: The beta-adrenoceptor agonist CL316,243 can protect against indomethacin-induced blood stasis in rat jejunal villi.

Adrenergic beta-Agonists↗
PubMed1998

A placebo-controlled trial to assess the effects of 8 days of dosing with rabeprazole versus omeprazole on 24-h intragastric acidity and plasma gastrin concentrations in young healthy male subjects.

BACKGROUND: Rabeprazole (LY307640, E3810) is a new, potent, proton pump inhibitor. A single daily 20 mg dose significantly decreases 24-h intragastric acidity. There are no data currently available directly comparing the effect of rabeprazole on 24-h acidity with established proton pump inhibitors. AIM: To compare the effects of rabeprazole 20 mg o.m. and omeprazole 20 mg o.m. on 24-h intragastric acidity and plasma gastrin concentration in a randomized, double-blind, placebo-controlled trial, in healthy H. pylori-negative subjects. METHODS: Twenty-four healthy male volunteers, negative for H. pylori infection by serology and 13C-urea breath test, were studied on the 1st and 8th day of dosing with either placebo, rabeprazole 20 mg or omeprazole 20 mg, once each morning, in a crossover fashion. On days 1 and 8, hourly intragastric acidity was measured by gastric aspiration for 24 h from 08.00 hours. On day 8, plasma gastrin concentrations were also measured hourly from 08.00 to 24.00 hours, then every 2 h thereafter. RESULTS: A single dose of both rabeprazole and omeprazole significantly decreased 24-h intragastric acidity compared with placebo. The 24-h acidity on day 1 was significantly decreased for rabeprazole compared with omeprazole (331 vs. 640 mmol.h/L, P < 0.001), resulting in a significantly higher median 24-h intragastric pH and longer times at which intragastric pH was > 3 and > 4. On day 8 of dosing, the decrease in 24-h intragastric acidity was greater with rabeprazole than with omeprazole, but the difference was not statistically significant (160 vs. 218 mmol.h/L, P = 0.1). However, 24-h plasma gastrin concentration (1687 vs. 1085 pmol.h/L. P < 0.01) and percentage time that intragastric pH was > 3 (69 vs. 59%, P = 0.008) and > 4 (60 vs. 51%, P = 0.03) were significantly greater. CONCLUSIONS: Rabeprazole 20 mg once daily has a significantly faster onset of antisecretory activity than omeprazole 20 mg once daily. After 8 days the differences in intragastric pH > 3 and > 4 holding times persisted, but there was no significant difference in 24-h acidity.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1998

Patients consulting with Crohn's disease in primary care in England and Wales.

OBJECTIVE: To determine annual incidence and prevalence for patients consulting their GP because of Crohn's disease in England and Wales and compare demographic details with matched controls. DESIGN: We used the fourth Morbidity Statistics in General Practice study (MSGP-4) which covered 468 042 person-years during a 12-month period in 1991-92. METHODS: All GPs reporting a patient with Crohn's disease in MSGP-4 were sent a questionnaire to confirm the diagnosis and obtain supportive details (surgical, pathological, radiological and/or endoscopic). Data concerning ethnicity, social class, smoking status, living in an urban or rural environment and employment had been collected previously. Conditional logistic regression models were used to analyse the data for cases and matched controls. RESULTS: Three hundred and fifteen patients were reported to have Crohn's disease. Replies were obtained to 251 (80%) questionnaires. The diagnosis of Crohn's disease was confirmed in 184 cases (89%) and refuted in 23 cases (11%) -- details were unavailable for 44 patients. The mean age of patients was 44 years, the female:male ratio was 1.46:1, and 108 (59%) patients had required surgery. Thirty-three of 178 (18.5%) patients were diagnosed within the study period. Hence, this study detected a prevalence for consulting Crohn's disease of 54.6-59.8/100,000 and an annual incidence of 10.1-11.1/100,000 in 1991-92. No significant differences were found between cases (n = 291) and controls (n = 1682) with regard to ethnicity, social class, smoking or living in an urban/rural environment. Patients with Crohn's disease had similar employment levels as controls, but were significantly more likely to be registered as permanently sick, odds ratio 4.01 (CI 2.21-7.29). CONCLUSIONS: This national survey, including 1% of the population, suggests there are approximately 30,600 patients consulting their GP because of Crohn's disease in England and Wales, with 5700 new cases diagnosed per year.

Adolescent↗