Biomedical subjects
J P Neoptolemos
Publications and source records attributed to J P Neoptolemos.
Predictive diagnosis of familial adenomatous polyposis with linked DNA markers: population based study.
OBJECTIVES: To evaluate the use of polymorphic DNA probes linked to the APC gene in the presymptomatic diagnosis of familial adenomatous polyposis. DESIGN: Four DNA probes were tested on an unselected population of patients at risk of familial adenomatous polyposis. SUBJECTS: The first 47 families notified to the West Midlands familial adenomatous polyposis register. Plus five families sent to our hospital as part of the West of Britain DNA consortium. MAIN OUTCOME MEASURES: The proportion of families and family members in whom DNA testing could be used to adjust the estimate of risk. RESULTS: Only 17 families on the register (containing 46% (74/162) of the population at risk) had a suitable pedigree structure for DNA analysis. DNA was analysed in 12 of these families plus the five families from the West of Britain consortium. At least one probe was informative in 27 of the 33 subjects born with 50% risk, but the most informative probe (pi 227) was the one with the highest recombination rate (10%). Flanking markers were informative in only four of the 33 subjects. CONCLUSIONS: These findings confirm the potential for accurate predictive diagnosis of familial adenomatous polyposis with polymorphic DNA probes, but such an approach is currently limited to about one third of affected families. A combined approach to presymptomatic diagnosis, which includes DNA testing and indirect ophthalmoscopy, is advocated.
Biliary bile acid profiles in familial adenomatous polyposis.
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Influence of dietary calcium supplements on ileoanal pouch function and cytokinetics.
A double-blind cross-over study was undertaken in 16 patients after panproctocolectomy and ileoanal pouch reconstruction to compare supplementary calcium (1.5 g/day) with placebo over 2 months with a 2-week washout period. Stool frequency was recorded and the effects on pouch mucosal crypt cellular proliferation were determined using an in vitro stathmokinetic technique which measures the crypt cell production rate (CCPR) and an immunohistochemical method using the Ki67 monoclonal antibody for proliferating nuclei. The median (interquartile range) diurnal stool frequency was reduced by calcium (4 (3-5) per day) compared with values obtained before treatment (7 (5-10) per day, P less than 0.002) and with placebo (7 (6-9) per day, P = 0.002). Similarly, calcium reduced nocturnal stool frequency (1 (0-1) per night) compared with pretreatment and placebo (both 2 (1-3) per night, P less than 0.05) values. Calcium reduced the mean(s.e.m.) CCPR to 1.88(0.41) cells per crypt per hour compared with pretreatment (3.63(0.53), P = 0.01) and placebo (3.24(0.43), P = 0.002) values. Median (interquartile range) Ki67 activity was also reduced by calcium (13.2 (9.7-16.7) per cent), compared with values obtained before treatment (27.3 (14.3-30.2) per cent, P = 0.001) and with placebo (26.0 (17.2-32.0) per cent, P = 0.001). Stool frequency was significantly correlated with the CCPR (diurnal: r = 0.37; nocturnal: r = 0.31, both P less than 0.05). Nine patients used antidiarrhoeal medication while receiving placebo compared with four patients receiving calcium (P = 0.032). This study has shown that supplementary oral calcium significantly reduced stool frequency in patients with pouches, a reduction that was associated with reduced cell proliferation. The mechanisms for this effect are not known.
Reduction of mucosal crypt cell proliferation in patients with colorectal adenomatous polyps by dietary calcium supplementation.
The crypt cell production rate was measured in 14 patients with adenomatous colorectal polyps, 17 patients with colorectal cancer and 12 control subjects. The median (interquartile range) rate (cells per crypt per hour) was found to be significantly higher (P less than 0.001) in the polyp (2.45 (1.94-3.20)) and cancer (3.01 (2.35-3.68)) groups compared with controls (1.25 (0.70-1.85)). A double-blind cross-over study was performed in patients with adenomatous polyps consisting of 2 months' treatment, 2 weeks' washout, followed by 2 months' treatment with dietary calcium supplementation (1.25 g day-1) versus placebo. A significant reduction in the crypt cell production rate occurred with calcium treatment compared with the placebo (1.25 (0.6-2.25) versus 2.15 (1.58-3.08) cells per crypt per hour, P = 0.035). This study demonstrates a significant reduction in mucosal cell proliferation by dietary calcium supplementation in patients with adenomatous polyps. Such treatment may be worthy of further investigation in patients at high risk of developing colorectal polyps.
Role of congenital hypertrophy of the retinal pigment epithelium in the predictive diagnosis of familial adenomatous polyposis.
A study was carried out to evaluate congenital hypertrophy of the retinal pigment epithelium (CHRPE) as a disease marker in a defined population with familial adenomatous polyposis (FAP). Indirect ophthalmoscopy was performed on 75 individuals from 25 known families with FAP, of whom 32 were known to be affected and 43 were at a 50 per cent prior risk of developing the disease. A further ten individuals from five families with hereditary non-polyposis colorectal cancer (HNPCC) were also tested. CHRPE was seen in 28 of the 32 affected individuals, 27 of whom met the criteria for a positive examination. Three individuals at risk of FAP also had positive examinations. Five individuals from the families with HNPCC also had CHRPE, although none met the criteria for a positive examination. Of four types of CHRPE analysed, one (small pigmented dots) was found to be more frequent in older family members (P = 0.012), suggesting that this type of lesion may proliferate with age. Compliance with ophthalmic screening was 97 per cent in families with FAP. Using a combined set of diagnostic criteria, CHRPE identified affected individuals with a specificity of at least 94 per cent and a sensitivity of 84 per cent. Results argue for a combined screening programme for FAP of DNA analysis, indirect ophthalmoscopy and bowel examination.
Dietary calcium does not reduce experimental colorectal carcinogenesis after small bowel resection despite reducing cellular proliferation.
It has been proposed that colorectal carcinogenesis is accompanied by increased mucosal cell proliferation and that the converse may also apply. To examine this thesis, the crypt cell production rate (CCPR) was measured in eight groups of rats (n = 187) that had received 1,2 dimethylhydrazine, 70% small bowel resection, supplemental dietary calcium, or a combination of these. Analysis of variance showed the following: (1) the CCPR decreased between the ileum and distal colon; (2) the CCPR decreased between 16 and 32 weeks; (3) 1,2 dimethylhydrazine and small bowel resection increased the CCPR and calcium decreased the CCPR independently of one another; (4) the CCPR interacted with 1,2 dimethylhydrazine x small bowel resection, calcium x 1,2 dimethylhydrazine and interacted between the site of bowel and calcium, 1,2 dimethylhydrazine, small bowel resection, and 1,2 dimethylhydrazine x small bowel resection (p = 0.014 to p < 0.001). The tumour yield was reduced by calcium in 1,2 dimethylhydrazine treated animals (chi 2 = 14.1, df = 3, p < 0.01) but was unaffected by calcium in 1,2 dimethylhydrazine and small bowel resection treated animals despite significant differences in the CCPR. An increase of the CCPR both preceded and accompanied colorectal carcinogenesis but reduction of the CCPR was not invariably accompanied by reduced carcinogenes.
Relation of diagnostic serum amylase levels to aetiology and severity of acute pancreatitis.
The sensitivity of diagnostic serum amylase (greater than 1000 iu/l) was assessed in 417 patients with acute pancreatitis as a result of gall stones (258), alcohol (104), or miscellaneous causes (55), of whom 111 (27%) had a clinically severe attack (including 34 deaths). On hospital admission, an amylase value diagnostic of pancreatitis was found in 96.1% of all mild cases and in 87.4% of severe cases (p less than 0.001); at 48 hours these values were 33.3% and 48.2% respectively (p = 0.026). Diagnostic amylase levels for alcoholic patients were found in 86% of mild cases on admission and in 76% of severe cases (p less than 0.001, compared with other groups). The diagnostic levels were also significantly lower at 24 hours for both the alcoholic and miscellaneous groups compared with the gall stone group (p less than 0.001). Eight of 27 (30%) patients with a serum amylase activity less than 1000 iu/l had pancreatic necrosis compared with 12 of the remaining 390 (3.1%) patients (p less than 0.001); the mortality was also significantly different (44% v 5.6% respectively, p less than 0.001). These data support the view that more sensitive tests for acute pancreatitis are needed for routine use especially in those whose disease has an alcoholic aetiology.
Faecal unconjugated bile acids in patients with colorectal cancer or polyps.
The unconjugated faecal bile acid profiles of 14 patients with colorectal cancer, nine patients with polyps and 10 controls were compared using gas liquid chromatography, controlling for such confounding variables as cholecystectomy, gall stones and hepatic function. Patients with adenomatous polyps had a higher concentration of faecal bile acids (5.23 mumol/g, 2.16-13.67 (median, range) v 1.96, 0.91-6.97; p = 0.016) lithocholic acid (2.41, 0.88-3.22 v 1.07, 0.38-2.03; p = 0.013) and total secondary bile acids (5.23, 2.16-13.4 v 1.96, 0.73-6.63; p = 0.02) compared with control subjects. Patients with colorectal cancer had an increased (p = 0.029) proportion of secondary faecal bile acids (mol%) compared with controls (100, 96.5-100 v 95.19, 81.73-100) and the ratios of the primary bile acids, cholic and chenodeoxycholic acid, to their respective derivatives (secondary bile acids) were significantly lower in cancer patients compared with control and patients with polyps (p = 0.034 to 0.004). This study lends further support to the theory that bile acids may play a role in the development of polyps and colorectal cancer.
The use of DNA from paraffin wax preserved tissue for predictive diagnosis in familial adenomatous polyposis.
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Long-term results of choledochoduodenostomy.
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Induction of cholangiocarcinoma in the Golden Syrian hamster using methylazoxymethyl acetate.
The Golden Syrian hamster, which has a bile acid profile similar to that of humans, is often used as an experimental model for cholangiocarcinoma. Unfortunately, most chemical carcinogens result in other tumour types also being induced which can be disadvantageous. In the present study, we describe the development of cholangiocarcinoma associated with precursor lesions of bile duct proliferation and dysplasia which occurred following a single i.v. dose of methylazoxymethyl acetate (10, 20 or 40 mg/kg body weight). Moreover, no other tumours were induced. This model may, therefore, prove useful in investigating the steps involved in the carcinogenesis of cholangiocarcinoma.
Oncogenes, growth factors, and prognostic indicators in colorectal cancer.
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Dietary and erythrocyte fatty acids in experimental colorectal carcinogenesis.
The influence of dietary fat on the erythrocyte stearic:oleic acid ratio was investigated in an experimental model of colorectal cancer. One hundred male Wistar rats were divided into four separate dietary groups: A (5% saturated fat), B (20% saturated fat), C (5% n-6 unsaturated fat) or D (20% n-6 unsaturated fat). Colorectal tumours were induced by intraperitoneal injection of azoxymethane (n = 60) and control animals received saline (n = 40). Animals were killed after 26 weeks and erythrocyte fatty acid profiles were determined by gas liquid chromatography. Although there were no differences in the incidence of adenoma formation in the four dietary groups, there was a significantly lower incidence of carcinomas in rats fed a 5% or 20% unsaturated fat diet when compared with either a 5% (P less than 0.05) or a 20% saturated fat diet (P less than 0.01). Multivariate analysis of fatty acid profiles demonstrated that both the type and quantity of dietary fat had a highly significant influence on the fatty acid profile of erythrocytes. The stearic:oleic acid ratio varied considerably between the four dietary groups but was only significantly lower in tumour bearing animals compared with controls in group B (20% saturated fat diet).
Colon perforation during colonoscopy: surgical versus conservative management.
A survey of endoscopy units in the West Midlands, UK, was undertaken to ascertain the management of colonic perforation during colonoscopy. Fifteen perforations were reported from a total of 17,500 colonoscopies performed in 14 units (a rate of 0.09 per cent). In seven patients the diagnosis was suspected or diagnosed immediately and in the remaining eight 2-72 h later. Four patients with associated pathology (carcinoma, Crohn's disease, ulcerative colitis and a polyp) had resection and primary anastomosis. Seven patients had a simple oversew, four of these having had a delayed diagnosis. In four cases the site of perforation was not identified, but only one patient had conservative treatment. Three patients had drainage and a defunctioning colostomy. There was no significant morbidity following treatment. It is recommended that patients who have had a good bowel preparation should be treated conservatively unless there is a large perforation or an underlying carcinoma.
Human hepatic peroxisomes with crystalloid cores associated with urate oxidase activity.
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The place of endoscopy in the management of gallstones.
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Changes in serum lipids after exercise and on exposure to altitude.
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