Roy E. Pounder

Abnormal intestinal permeability to sugars in villous atrophy

Intestinal permeability to a monosaccharide and a disaccharide was compared by simultaneous measurement of the urinary excretion of L-rhamnose and lactulose after oral ingestion of an hypertonic solution containing both sugars. Urine samples were analysed for sugar content by quantitative thin-layer or paper chromatography. Results in thirteen patients with untreated villous atrophy were compared with those in twelve healthy volunteers. Urinary L-rhamnose excretion was significantly decreased (-40%, p less than 0.02) in patients with villous atrophy, whereas lactulose excretion was paradoxically and significantly increased (+345%, p less than 0.01). The median value of the lactulose/L-rhamnose urinary excretion ratio was sevenfold higher in the patients with villous atrophy; there was no overlap of values for patients and volunteers (p less than 0.01). It is postulated that reduced L-rhamnose urinary excretion in untreated villous atrophy is due to a decreased absorptive area in the small bowel, whereas increased lactulose excretion indicates leakiness of the abnormal mucosa to larger polar molecules.

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), Crohns 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 Crohns 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.

Smoking in adults and passive smoking in children are associated with acute appendicitis.

2,3 Appendicectomy by age 26 years was defined with a question in a postal survey in 1996: “Have you ever had appendicitis that required surgical removal of your appendix?”. Life-long smoking behaviour was also recorded. When cohort members were 5 years of age in 1975, mothers’ smoking was recorded during an interview by health visitors. The social class was based on details of the father’s occupation collected by midwives in 1970. Household crowding at age 5 years was assessed, by the persons-per-room ratio divided into 5ths of its distribution. Multiple logistic regression investigated the relation of smoking and maternal smoking behaviour with the risk of appendicitis. Adjustment was made for the potential confounding variables: sex, social class, and household crowding, which are markers for multiple lifestyle factors including smoking behaviour. 4.5 Relations of the smoking variables with appendicectomy were statistically significant (p<0·002) (table). There was a slight excess risk for females, with 6·5% reporting appendicectomy compared with 5·3% of males (p=0·059). Other potential confounding factors were not statistically significantly associated with risk of appendicectomy. Cohort members with mothers who had smoked for 5 years or longer in 1975 were at a significantly increased risk of appendicectomy, even after adjustment for the potential confounding factors and cohort members’ own smoking behaviour. When cohort members who had ever smoked are excluded from the analysis, reducing the sample to 2645, the adjusted relative odds for maternal smoking for 5 years or longer were 1·60 (95% CI 1·06‐2·43). Cohort members who smoked every day at age 26 years were significantly more likely to have had an appendicectomy than never-smokers, even after

Decrease of Intragastric Acidity in Healthy Subjects Dosed with Ranitidine 75 mg, Cimetidine 200 mg, or Placebo

This study assessed the duration of action of single doses of ranitidine (75 mg), cimetidine (200 mg), or placebo on intragastric acidity in healthy subjects. When dosed with placebo, mean daytime intragastric acidity (0–10 hr after dose) was 37.62 mmol/liter, decreasing to 17.21 mmol/liter (mean decrease 59%; P < 0.001 vs placebo) and 25.06 mmol/liter (mean decrease 35%; P < 0.001 vs placebo) when treated with ranitidine and cimetidine, respectively. Ranitidine inhibited intragastric acidity to a greater degree than cimetidine (P < 0.001). Mean nighttime (10–20 hr after-dose) intragastric acidity when dosed with placebo was 34.37 mmol/liter, decreasing to 29.06 mmol/liter (mean decrease 18%; P = 0.027 vs placebo) when dosed with ranitidine and remaining virtually unchanged at 33.85 mmol/liter (mean decrease 2%; NS vs. placebo) when dosed with cimetidine. Ranitidine inhibited acidity to a greater degree than cimetidine (P = 0.043). The inhibitory effect of ranitidine, 75 mg, on intragastric acidity can be detected from 0–15 hr after an oral dose. Cimetidine 200 mg has little inhibitory effect beyond 10 hr.

A phase II study of gastrimmune in advanced pancreatic cancer

A PHASE II STUDY OF GASTRIMMUNE IN ADVANCED PANCREATIC CANCER. Bernard T. Brett, Stephen C. Smith, Catherine V. Bouvier, Dov Michaeli, Daniel Hochhauser, Brian R. Davidson, Tom R. Kurzawinski, Tony Watkinson, Neil Van-Someren, Roy E. Pounder, Martyn E. Caplin, The Middlesex Hosp, London, United Kingdom; Royal Free and Univ Coli Med Sch, London, United Kingdom; Aphton Corp, Woodlands, CA; Royal Free Hosp, London, United Kingdom; Chase Farm Hosp, London, United Kingdom; Dept of Gastroenterology, Royal Free Hosp, London, United Kingdom.

Expression of CCK-B/gastrin receptor and endocytosis of anti-CCK-B/gastrin receptor antibody

Introduction: We have previously reported endocytosis of anti-CCK-BI gastrin receptor antibody (GR#l) by tumour cell lines. Aim: To demonstrate expression of CCK-B/gastrin receptor using RT-PCR, and confirm that uptake of anti-CCK-B/gastrin receptor antibody is dependent on expression of CCK-B/gastrin receptor. Materials and methods: GR#l is an antibody to the amino terminal end of the human CCK-BR. It was labelled with either Alexa-546 (red) or Alexa-488 (green) fluorescent marker. GR#l was added to live cells from the AR42J pancreatic adenocarcinoma cell line, as well as to fibroblast NIH3T3 cells transfected with human CCKB/gastrin receptor gene. GR#l was also added to non-transfected NIH3T3 cells as a negative control. Expression of CCK-B/gastrin receptor was demonstrated by RT-PCR. Total RNA was isolated from I . 3 X 106 cells using the Promega SV isolation system, according to the manufacturers instructions. RT-PCR was performed using l-2!Lg total RNA and the Access RT-PCR system (Promega). Specific primers were used for transcription and amplification of gastrin receptor and f3 actin as a positive control; a double round of PCR was used. Results were analysed using agarose gel electrophoresis. Results. Uptake of anti gastrin receptor antibody was seen in AR42J cells and in NIH3T3 cells transfected with gastrin receptor. No uptake was seen in non-transfected NIH3T3 cells. Using RT-PCR, mRNA for f3 actin was detected in all cell lines: mRNA for gastrin receptor was detected in AR42J cells and in transfected NIH3T3 cells, but not in non-transfected NIH3T3 cells. Conclusions. Anti gastrin receptor antibody was only taken up by cells expressing CCK-BR. This specific uptake confirms that this antibody may be a potential targeting agent in tumours expressing CCK-BR.