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Biomedical subjects

R E Pounder

Publications and source records attributed to R E Pounder.

At least 19 recordsLinked to original sources
PubMed2002

Phase II study of anti-gastrin-17 antibodies, raised to G17DT, in advanced pancreatic cancer.

PURPOSE: The prognosis for advanced pancreatic cancer remains poor. Gastrin acts as a growth factor for pancreatic cancer. We describe the first study of the antigastrin immunogen G17DT in pancreatic cancer. Our aims were to determine the antibody response, safety, tolerability, and preliminary evidence of efficacy of G17DT in advanced pancreatic cancer. PATIENTS AND METHODS: Thirty patients with advanced pancreatic cancer were immunized with three doses of either 100 micro g or 250 micro g of G17DT. RESULTS: In the whole group, 20 (67%) of 30 patients produced an antibody response. The 250- micro g dose resulted in a significantly greater response rate of 82% compared with 46% for the 100- micro g group (P =.018). The most significant side effects, seen in three patients, were local abscess and/or fever. The median survival for the whole group from the date of the first immunization was 187 days; median survival was 217 days for the antibody responders and 121 days for the antibody nonresponders. The difference in survival between the antibody responders and nonresponders was significant (P =.0023). CONCLUSION: Patients with advanced pancreatic cancer are able to mount an adequate antibody response to G17DT. The 250- micro g dose is superior to the 100- micro g dose, and it appears to be generally well tolerated. Antibody responders demonstrate significantly greater survival than antibody nonresponders. Phase III studies are currently underway in order to determine efficacy.

Adult↗
PubMed2002

A pilot study of treatment of active ulcerative colitis with natalizumab, a humanized monoclonal antibody to alpha-4 integrin.

BACKGROUND: Alpha-4 integrins facilitate leucocyte migration across vascular endothelium. AIM: To assess the safety and efficacy of natalizumab (Antegren), a humanized antibody to alpha-4 integrin, in patients with active ulcerative colitis. METHODS: Ten patients with active ulcerative colitis, defined by a Powell-Tuck activity score > 4, received a single 3 mg/kg natalizumab infusion. The primary end-point was the change in Powell-Tuck score at 2 weeks post-infusion. RESULTS: Significant decreases in the median Powell-Tuck score were observed at 2 and 4 weeks post-infusion (7.5 and 6, respectively) compared to the median baseline score (10). Five of 10 patients achieved a good clinical response at 2 weeks and one more patient by 4 weeks, defined by a Powell-Tuck score of < or = 5. Significant improvements in quality of life scores were found at week 4. Rescue medication was required by two (20%), three (30%) and eight (80%) patients by weeks 2, 4 and 8, respectively (median, 34 days; range, 8-43 days). One patient remained in remission at 12 weeks. The median C-reactive protein at 2 weeks (6 mg/L) was lower than that pre-treatment (16 mg/L). CONCLUSIONS: A single 3 mg/kg infusion of natalizumab was well tolerated by ulcerative colitis patients. The positive efficacy demonstrated in this study merits further investigation by randomized, placebo-controlled trials.

Antibodies, Monoclonal↗
PubMed2002

Siblings and the risk of inflammatory bowel disease.

BACKGROUND: Environmental exposures in early life have been implicated in the aetiology of inflammatory bowel disease (IBD). Siblings are used as proxy markers to characterize patterns of exposure relevant to the risk of IBD. METHODS: Some 15,823 patients with ulcerative colitis and 12,668 with Crohn disease from the Swedish In-patient Register were compared with 79,546 and 63,035 controls, respectively, in a case-control study. Multiple logistic regression was used to investigate associations with older and younger siblings, and adjustment was made for sex, year of birth, mother's age, region and, additionally, father's social class. RESULTS: Older siblings are associated with a graded increased risk for ulcerative colitis (P for trend <0.001) and an adjusted odds ratio of 1.15 (95% CI 1.07-1.24) for three or more older siblings. Younger siblings are associated with a graded decreased risk for Crohn disease (P for trend <0.001) with an adjusted odds ratio of 0.83 (0.76-0.90) for three or more younger siblings. The greatest protective association with Crohn disease was seen for younger siblings born within 2 years of the subject. Older maternal age is independently associated with a decreased risk of Crohn disease, with P for trend <0.001. Additional adjustment for social class did not substantially alter the results. CONCLUSIONS: Having siblings is associated with the risk and phenotype of developing IBD, possibly through their influence on patterns of antigenic exposure in early life. The association of maternal age with Crohn disease may reflect age-related changes in maternal immune profile.

Adult↗
PubMed2001

Control of intragastric acidity with over-the-counter doses of ranitidine or famotidine.

BACKGROUND: Histamine H2-receptor antagonists are available over the counter for the treatment of heartburn. AIM: To compare the effects of low doses of ranitidine and famotidine on intragastric acidity in a three-way crossover study. METHODS: Healthy subjects (12 male, 12 female) were dosed on three occasions with single oral doses of placebo, ranitidine, 75 mg, and famotidine, 10 mg, 1 h after lunch. The pH of gastric aspirates was then measured for 20 h. Subjects ate standard meals and snacks. Analysis of variance was used to determine the statistical significance of differences in acidity (mmol/L) during the day (12.30-22.30 hours) and night (22.30-08.30 hours). RESULTS: Ranitidine and famotidine were superior (P < 0.05) to placebo in decreasing acidity for daytime and night-time intervals. There were no significant differences in mean gastric acidity between ranitidine and famotidine during the daytime (11.37 mmol/L vs. 13.42 mmol/L, respectively) and night-time (23.57 mmol/L vs. 24.74 mmol/L, respectively). Intragastric acidity after ranitidine was significantly lower than that after famotidine in the first 2.5-h period following dosing (4.32 mmol/L vs. 9.28 mmol/L; P < 0.05). CONCLUSIONS: Lunchtime doses of ranitidine and famotidine decreased acidity during day- and night-time periods. The effect of ranitidine was significantly greater for the first 2.5 h after dosing.

Adult↗
PubMed2001

A randomized placebo-controlled trial of a humanized monoclonal antibody to alpha4 integrin in active Crohn's disease.

BACKGROUND & AIMS: alpha4 integrins are important mediators of leukocyte migration across vascular endothelium. This pilot placebo-controlled study aimed to assess the safety and efficacy of natalizumab, a recombinant humanized monoclonal antibody to alpha4 integrin, in patients with mild to moderately active Crohn's disease. METHODS: Thirty patients with active Crohn's disease (Crohn's Disease Activity Index [CDAI] > or =151 and < or =450) received a 3-mg/kg infusion of natalizumab (n = 18) or placebo (n = 12) by double-blind randomization. The study's primary endpoint was change in CDAI at week 2. RESULTS: At week 2, the CDAI decreased significantly from baseline after infusion of natalizumab (mean 45 points) but not placebo (mean 11 points). Seven (39%) natalizumab-treated patients achieved remission at week 2, compared with 1 (8%) treated with placebo. In contrast, 4 (33%) of the placebo-treated patients required rescue medication by week 2, compared with 2 (11%) natalizumab-treated patients. Significant increases in circulating B and T lymphocytes were detected only after natalizumab administration. The frequency of commonly reported adverse events did not differ significantly between groups. CONCLUSIONS: A single 3-mg/kg natalizumab infusion was well tolerated by Crohn's disease patients, although the dose used may have been suboptimal. Elevated circulating lymphocyte levels after natalizumab suggest interrupted lymphocyte trafficking. Natalizumab therapy in active Crohn's disease merits further investigation.

Adult↗
PubMed2001

Inflammatory bowel disease and laterality: is left handedness a risk?

BACKGROUND: Left handedness has been associated with inflammatory bowel disease (IBD) and autoimmune diseases. AIMS: To determine whether left handedness is associated with IBD in two prospective national birth cohorts. METHODS: Subjects with Crohn's disease (CD) and ulcerative colitis (UC) were identified from two national longitudinal birth cohorts at age 26 years (1970 British Cohort Study (BCS70), born in 1970) and age 33 years (National Child Development Study (NCDS), born in 1958). Laterality was determined at age 10 (BCS70) or seven (NCDS) years, based on hand preference for writing and foot preference for kicking a ball (BCS70 only). Multiple logistic regression was used to assess the relationship of handedness with CD, UC, and IBD in the cohorts combined and adjusted for sex. RESULTS: Both cohorts combined showed increased adjusted relative odds of 2.13 (95% confidence interval (CI) 0.97--4.65; p=0.059), 2.13 (95% CI 0.92--4.91; p=0. 077), and 2.13 (95% CI 1.20--3.78; p=0.010) for CD, UC, and IBD, respectively in left handers. CONCLUSIONS: The study suggests a link between IBD and left handedness which may be genetic and/or environmental in origin.

Adult↗
PubMed2000

The initial care of newborn infants and subsequent hay fever.

BACKGROUND: Patterns of neonatal exposure to microorganisms have changed substantially over the last 100 years, and it has been suggested that this has influenced the risk of immune-mediated disease. Using a proxy measure, we tested the hypothesis that the initial handling of newborn infants, which is known to affect the pattern of exposure to microorganisms, may alter the risk of developing subsequent atopy, as indicated by hay fever. METHODS: Analysis was performed on 5,519 members of the 1970 British Cohort Study, a nationally representative birth cohort. Cohort members with hay fever were identified at intervals up to the age of 26 years. Details of neonatal care and childhood circumstances were recorded prospectively. Those who had spent their first night away from their mother in the communal infant nursery were selected as likely to have experienced atypical exposure compared with infants who remained with their mother. Adjustment was made for potential confounding factors in infancy and childhood by multiple logistic regression analysis. RESULTS: Unadjusted relative odds (with 95% CI) for developing hay fever among those spending the first night in the communal nursery, when compared with other infants who remained with the mother, were 1.48 (1.23-1.77), P<0.001. Comprehensive adjustment for the potential confounding factors, including feeding practices on the first day of life, markers of social and material circumstances, and region, did not substantially alter this relationship, with adjusted relative odds of 1.31 (1.08-1.59), P=0.005. CONCLUSIONS: While our proxy measure is associated with an increased risk of hay fever, further research is required to confirm that this is due to the pattern of infectious exposure in very early life. The results are consistent with the hypothesis that the first challenges are particularly important in the development of the newborn infant's immune system.

Adult↗
PubMed2000

Similarities between ileal Crohn's disease and indomethacin experimental jejunal ulcers in the rat.

BACKGROUND: Both Crohn's disease ileal ulcers and indomethacin-induced jejunal ulcers in the rat have a predilection for the mesenteric margin of the bowel wall. Unlike the anti-mesenteric margin, the mesenteric margin is supplied by small end-arteries that might render it more sensitive to ischaemic injury. AIM: To examine, in both situations, the histological relationship between the precise localization of small bowel ulcers and the mesenteric margin. METHODS: Ileal Crohn's disease ulcers identified in surgical resection specimens (n=5) and indomethacin-induced lesions in the rat jejunum (n=6) were examined macroscopically and histologically. RESULTS: In both the human ileum and the rat jejunum, ulcers occurred consistently along the mesenteric margin, with the most extensive mucosal injury occurring at two adjacent sites on either side of the midline of this margin. At these two sites, feeding arteries entered the muscularis propria. CONCLUSIONS: For anatomical reasons apparently related to the vasculature of the human and rodent small bowel, specific sites along the mesenteric margin are susceptible to Crohn's disease ulceration and NSAID damage, respectively.

Animals↗
PubMed2000

Endothelial changes precede mucosal ulceration induced by indomethacin: an experimental study in the rat.

BACKGROUND: Indomethacin has been shown to damage the villous microvasculature concomitant with alterations in villous blood flow in the rat. AIM: To test the hypothesis that alterations in blood flow result from ultrastructural damage to microvasculature endothelium. METHODS: In anaesthetized rats, jejunal villi were exteriorized in a chamber and blood flow in surface capillaries visualized by fluorescence microscopy. Villi were exposed both luminally and systemically to indomethacin (100 microg/mL) for 10 min or until blood slowing or stasis had occurred in superficial capillaries (n=3 per group). Control animals received both a luminal and intravenous vehicle for 45 min (n=3). The small intestines were vascular perfusion-fixed with 1.5% glutaraldehyde and studied by transmission electron microscopy. RESULTS: All controls appeared to be ultrastructurally normal. A 10 min exposure to indomethacin had no effect upon the epithelium but resulted in mild endothelial vacuolization and the development of small finger-like projections into the lumen of villus surface microvasculature. At the point of blood slowing, villus tip epithelium was again normal but the endothelial vacuolization and finger-like projections became more obvious. The endothelial projections and vacuolization became severe at the point of blood stasis; this also coincided with epithelial degeneration. CONCLUSION: This study shows that villus surface microvasculature is the earliest site of morphological damage after indomethacin exposure.

Animals↗
PubMed2000

Beta(beta)3-adrenergic receptors in human pancreatic islet and duodenal somatostatin neuroendocrine cells.

BACKGROUND: We previously localized beta3-adrenergic receptors immunohistochemically in human gastrointestinal smooth muscle and incidently found a population of human pancreatic islet cells and duodenal epithelial neuroendocrine cells that also expressed beta3-adrenergic receptors. AIM: To identify the nature of the islet and duodenal cells that stained positive for beta3-adrenergic receptors. METHODS: Paraffin sections of human pancreas and duodenum and Chinese hamster ovary cells transfected with the human beta3-adrenergic receptor were immuno-stained for beta3-adrenergic receptors using an affinity-purified rabbit polyclonal antibody (anti-P12) raised against a 15 amino acid sequence (P12) of the human receptor. Immunohistochemical staining for the receptor was carried out in the presence and absence of P12 peptide and both somatostatin 14 and 18 peptides. beta3-adrenergic receptor-stained sections were also double-immunostained with anti-insulin, -glucagon, -somatostatin and -pancreatic polypeptide antibodies. RESULTS: A subpopulation of human pancreatic islet cells and duodenal epithelial cells expressed positive cytoplasmic beta3-adrenergic receptor immunostaining. Using distribution and double-staining techniques, these cells were found to be somatostatin-positive D cells but not A or B cells. The positive staining of D cells with anti-P12 antibody was inhibited by prior incubation of the antibody with P12 peptide but not somatostatin-14 or -28 peptides. Pancreatic vascular smooth muscle and duodenal vascular and non-vascular smooth muscle also stained with anti-P12 antibody. Transfected Chinese hamster ovary cells showed positive membrane staining. CONCLUSION: We have identified a population of neuroendocrine cells in the human pancreas and duodenum that express beta3-adrenergic receptors. These cells appear to be somatostatin D cells.

Animals↗
PubMed2000

A placebo-controlled study to assess the effects of 7-day dosing with 10, 20 and 40 mg rabeprazole on 24-h intragastric acidity and plasma gastrin in healthy male subjects.

AIM: To compare the effects of rabeprazole 10, 20 and 40 mg o.d. on 24-h intragastric acidity and plasma gastrin concentration in a randomized, double-blind placebo-controlled trial. METHODS: Twenty-four healthy male volunteers were studied on the 7th day of morning dosing with either placebo or rabeprazole 10, 20 or 40 mg in a crossover fashion. On day 7, hourly intragastric acidity was measured for 24 h from 08.00 hours by gastric aspiration. Plasma gastrin concentrations were also measured hourly from 08.00 to 24.00 hours, and 2-hourly thereafter. RESULTS: Compared with placebo, rabeprazole 10, 20 and 40 mg produced significant dose-related decreases in intragastric acidity (median 24-h integrated acidity=697, 186, 129 and 82 mmol h/L, respectively). This was associated with significant elevation of plasma gastrin concentration (median 24-h integrated gastrin=141, 1184, 1484 and 1763 pmol.h/L, respectively). Rabeprazole 40 mg resulted in significantly decreased acidity compared with both 10 and 20 mg, and in longer times for which intragastric pH was maintained at > 3 (19. 2 h vs. 17.3 h and 17.5 h) and > 4 (17 h vs. 14.2 h and 15.2 h), but was accompanied by significantly increased plasma gastrin. There was a consistent trend for greater antisecretory activity for 20 mg compared with 10 mg, but these differences did not reach statistical significance. The interindividual variability in antisecretory response was greatest with 10 mg. CONCLUSIONS: Rabeprazole 10, 20 and 40 mg produce significant, profound dose-related inhibition of gastric acid secretion. Taking into account reciprocal increases in plasma gastrin and the interindividual variation in antisecretory response, 20 mg appears to be the preferred dose for routine clinical use.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2000

Early determinants of inflammatory bowel disease: use of two national longitudinal birth cohorts.

OBJECTIVE: To examine previously cited early risk factors for inflammatory bowel disease. DESIGN: The 1946 National Survey of Health & Development (NSHD) and the 1958 National Child Development Study (NCDS) are on-going, longitudinal birth cohort studies. A nested case-control design was used combining data from both cohorts; eight controls per case, matched for gender and social class, were selected randomly. METHODS: Data concerning maternal infection in pregnancy (NCDS only), childhood infection (measles, mumps and whooping cough), birth order, appendicectomy, breast-feeding and measures of poor housing conditions in childhood were analysed. In both cohorts, the member's hospital physician or medical records were used to confirm the diagnosis. RESULTS: Twenty-six cases of Crohn's disease and 29 cases of ulcerative colitis were identified. No significant association was found between the development of Crohn's disease or ulcerative colitis and any of the studied factors. There was a trend that those with Crohn's disease were more likely not to have been breast-fed (OR 0.4, 95% CI 0.15-1.03) and not to have had an appendicectomy (OR < 1.00). The opposite was true of those with ulcerative colitis (OR 2.76, 95% CI 0.86-9.81 and OR 2.34, 95% CI 0.69-7.46, respectively). The prevalence of inflammatory bowel disease was 5.12/1000 by the age of 43 years in NSHD and 2.02-2.54/1000 by the age of 33 years in NCDS. CONCLUSIONS: The prevalence of inflammatory bowel disease in these cohorts is among the highest recorded in Europe. Childhood factors may be different for those with Crohn's disease and ulcerative colitis. These cohorts will be increasingly valuable data sources.

Adult↗
PubMed2000

Measles vaccination and inflammatory bowel disease: a national British Cohort Study.

OBJECTIVE: Measles vaccination has been suggested as a risk for inflammatory bowel disease. Atypical age of measles infection has also been associated with Crohn's disease. This study was designed to examine the relationship of measles vaccination and age of measles vaccination with later inflammatory bowel disease. METHODS: A prospective population-based national birth cohort was used, of those born in 1 wk in April 1970 in Great Britain. The data are from 7616 responding members of the 1970 British Cohort Study with complete vaccination data, who were traced at age 26 yr. A diagnosis of Crohn's disease, ulcerative colitis, and diabetes mellitus (a control disease) was obtained by survey at age 26 yr, and confirmed by physicians. Vaccination data were from survey at age 5 yr. Measles and mumps infection data were obtained from the survey at age 10 yr. Adjustment was made for sex, household crowding in childhood, and father's social class at birth. RESULTS: No statistically significant association was found between measles vaccination status at 5 yr and Crohn's disease (adjusted odds ratio [OR] 0.67, 95% confidence interval [CI] 0.27-1.63), ulcerative colitis (adjusted OR 0.57, 95% CI 0.20-1.61), or diabetes (adjusted OR 0.75, 95% CI 0.33-1.74). There was a statistically significant trend (p = 0.040) with increasing age of measles vaccination for risk of Crohn' s disease, although this was based on very few cases vaccinated after age 2 yr. CONCLUSIONS: In this cohort, monovalent measles vaccination status is not associated with inflammatory bowel disease by age 26 yr. Older age at measles vaccination needs to be examined in other studies to confirm whether it is a genuine risk for Crohn's disease.

Adult↗
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↗