BACKGROUND: Somatic mutations in K-ras and TP53 may be associated with both acetylator status and prognosis in colorectal cancer. AIMS: To determine whether cancers with somatic mutations are more frequent in fast acetylators and whether mutations or acetylator status influence prognosis after colorectal surgery. PATIENTS: One hundred consecutive subjects undergoing elective surgery for colorectal cancer. METHODS: Acetylator status was determined by polymerase chain reaction (PCR) genotyping for polymorphism in the N-acetyltransferase 2 (NAT2) gene. Mutations in K-ras (codon 12) and TP53 were determined by PCR analysis using restriction enzyme digestion and single strand conformation polymorphism respectively. Survival from colorectal cancer for up to five years after diagnosis was analysed using the Kaplan-Meier product limit estimator. Cox proportional hazards regression was used to compare survival rates after adjusting for tumour stage. RESULTS: Mutations in K-ras and TP53 were independent of acetylator status. By log rank test, survival was significantly reduced in subjects with TP53 mutations (p = 0.003) but was not significantly related to acetylator status or the presence of K-ras mutations. After adjustment for tumour stage, subjects with both TP53 and K-ras mutations had a 4.2-fold case fatality (95% confidence interval 1.5 to 11.6) when compared with that of a TP53 negative reference group. CONCLUSION: The presence of both TP53 and K-ras mutations in colorectal tumours is an adverse prognostic marker which is independent of tumour stage.

Acetylation↗

PubMed1997

An analysis of the relationship between bile duct stones and periampullary duodenal diverticula.

Previous studies have suggested a relationship between bile duct stones and periampullary duodenal diverticula. The aim of the present study was to examine this association in more detail, including step-wise logistic regression to identify independent predictors for the presence of diverticula. Clinical, endoscopic and radiological data were analysed from 794 consecutive subjects with bile duct stones; 44 with primary duct stones (without gall-bladder stones) and 750 with bile duct stones associated with current or previous gall-bladder stones. Frequencies of diverticula in subjects with bile duct stones were compared with those in age-matched controls who had undergone upper gastro-intestinal endoscopy using a side-viewing endoscope (n = 100) or who had undergone endoscopic retrograde cholangiopancreatography (ERCP) for pancreatic cancer (n = 100). The frequencies of diverticula in subjects with primary duct stones (70%) and bile duct stones with current or previous gall-bladder stones (25%) were significantly higher than in both control groups (7 and 8%, respectively). When subjects with bile duct stones were analysed by step-wise logistic regression, age and bile duct diameter were independent predictors of the presence of diverticula, but diverticula were unrelated to gender, mode of presentation, number of bile duct stones and outcome after endoscopic sphincterotomy. A significant association exists between duodenal diverticula and bile duct stones, perhaps because diverticula predispose to stone formation through the combined effects of bile stasis and bacterial contamination of bile.

Aged↗

PubMed1997

Dieulafoy's disease.

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Arteries↗

PubMed1997

Intraductal mucin hypersecreting neoplasm and the mucus-filled papilla.

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Cholangiopancreatography, Endoscopic Retrograde↗

PubMed1996

Diet, acetylator phenotype, and risk of colorectal neoplasia.

BACKGROUND: Inherited or acquired differences in metabolic pathways that activate or inactivate dietary carcinogens may influence the risk of developing cancer. A polymorphism in N-acetyltransferase classified people into fast and slow acetylators. This enzyme catalyses the formation of mutagenic products from foodstuffs, especially cooked meat and fish. Some data suggest that fast acetylators are at higher risk of colorectal cancer. We have studied the adenoma and cancer risk in relation to meat intake and acetylator status. METHODS: In a case-control study, we compared 110 patients with colorectal cancer, 89 patients with colorectal adenomatous polyps, and 110 controls. Acetylator status was assessed by the rate of acetylation of sulphamethazine given orally. FINDINGS: The fast-acetylator phenotype was associated with odds ratios of 1.1 (95% Cl 0.6-2.1) and 1.8 (1.0-3.3) for adenoma and colorectal cancer, respectively. The highest risk occurred in the youngest tertile (< 64 years) of cases (2.5 [0.7-9.4] and 8.9 [2.6-30.4], respectively). There was no difference between the sexes. The risk of adenoma or cancer increased with increasing intake of meat in fast but not in slow acetylators: covariate-adjusted odds of disease over three levels of meat consumption were 2.1 (0.9-4.7) for adenoma, 1.7 (0.9-3.5) for cancer, and 1.9 (1.0-3.7) for all tumours. INTERPRETATION: Our findings indicate that acetylator status modulates the risk of colorectal neoplasia associated with meat intake.

Acetylation↗

PubMed1994

Sympathetic suppression attenuates anomalous responses to morphine in unexplained pain after cholecystectomy.

Anomalous responses to morphine are common in patients with unexplained pain in the upper abdomen after cholecystectomy and may be linked to activation of the sympathetic nervous system. The hypothesis that sympathetic suppression would attenuate anomalous responses to morphine was tested by a randomized, cross-over trial using a standard challenge with morphine, with and without pretreatment with clonidine (300 micrograms orally, 1 h prior to the administration of morphine). In 13 of the 15 patients who completed the study, pre-treatment with clonidine decreased plasma concentrations of noradrenaline, dopamine and adrenaline by 56, 15 and 25% respectively. This was associated with a significant reduction in morphine-induced pain (p = 0.02) and nausea (p = 0.04) and attenuated increases in plasma aspartate aminotransferase (AST) activity (p = 0.03). Clonidine attenuates anomalous responses to morphine, perhaps through effects on sympathetic nervous activity or plasma concentrations of catecholamines.

Adult↗

PubMed1993

Genetic studies of human and murine giardiasis.

Wide variation has been observed in the natural history of human and murine giardiasis, which could be due to factors associated with the parasite or with the host. In humans, prolonged infections with Giardia duodenalis have been associated with hypogammaglobulinemia, protein-calorie malnutrition, and prior gastrectomy. The duration of infection or severity of symptoms may also be influenced by the humoral immune response and by other factors such as ABO blood group and HLA antigen type. Elimination of Giardia muris is impaired in hypothymic mice, B-cell-deficient mice expressing the xid gene, and in mice deficient in mast cells. Prolonged infections also occur following depletion of helper/inducer T cells and suppression of antibody production with antisera to IgM. However, quantitative or qualitative defects in immune function do not appear to account for prolonged cyst excretion in C3H/He, C3H/HeJ, and A/J mice. The defect in these strains is influenced by several genes and may involve intermediate or late stages of macrophage activation leading to impaired elimination of the parasite.

ABO Blood-Group System↗

PubMed1992

Glucose metabolism in proliferating epithelial cells from the rat colon.

1. The effects of fasting and fasting followed by refeeding on the activities of the oxidative pentose pathway (OPP) and the tricarboxylic acid cycle (TCA) in isolated rat colonocytes were estimated by the rate of production of 14CO2 from [1-14C]glucose and [6-14C]glucose, respectively. 2. Refeeding after a fast induced a 2-3-fold increase in glucose flux through the OPP and TCA cycle and the degree of change was similar in colonocytes from the proximal and distal colon. 3. Butyrate at a concentration of 40 mM inhibited the OPP by 20-30% (P less than 0.05) but had no effect on the activity of the TCA cycle. Glutamine at a concentration of 2 mM decreased the glucose flux through both the OPP and the TCA cycle by 30-50% (P less than 0.05). 4. Production of 14CO2 from the oxidation of butyrate or glucose indicated that the former was 5-7 times more active in colonocytes from fasted rats. After refeeding, however, butyrate utilization was similar to fasting values in the proximal colon but significantly lower (P less than 0.05) in the distal colon.

Animals↗

PubMed1992

Regional factors affecting proliferation in the large intestine of the rat.

Colonic neoplasia is more frequent in the distal colon than in the proximal colon in spontaneous human disease and in carcinogen-induced tumors in rodents. The possibility that this may reflect regional differences in morphology and in proliferative responses to fasting and refeeding was explored in this study in rats. Scanning electron microscopy revealed that the density of colonic crypts was 36% higher in the distal than in the proximal colon, while light microscopy revealed that distal crypts had 70% more colonocytes than proximal crypts. Thus, the number of colonocytes per unit area in the distal colon is approximately twice that in the proximal colon. Proliferation was assessed by the uptake of bromodeoxyuridine in vivo and showed that regions of the distal colon had greater suppression of proliferation during fasting than the cecum, and greater enhancement of proliferation during refeeding than that observed in the cecum or the proximal colon. Changes in proliferation associated with fasting and refeeding were accompanied by changes in the concentrations of short chain fatty acids, but the data did not support the hypothesis of a direct relationship between increasing concentrations of short chain fatty acids and enhanced proliferation. Regional differences in morphology and proliferation could be relevant to the greater susceptibility of the distal colon to neoplasia.

Animals↗

PubMed1991

Morphine responders with unexplained pain after cholecystectomy may have sympathetic overactivity.

In patients with unexplained pain after cholecystectomy, morphine often induces pain and may increase plasma aspartate aminotransferase activity because of exaggerated or prolonged rises in pressure within the biliary system. Previous studies have demonstrated that patients showing increases in aspartate aminotransferase have increases in plasma concentrations of noradrenaline and dopamine prior to and soon after induction of pain. The purpose of this study was to assess sympathetic activity under basal conditions in patients with (responders) and without (non-responders) increases in aspartate aminotransferase after challenge with morphine. When compared to non-responders, morphine responders had higher plasma concentrations of noradrenaline (p = 0.0001) and dopamine (p = 0.02) and higher urinary excretion of noradrenaline over 24 h (p = 0.03). Plasma and urinary levels of adrenaline were similar in the two groups. These observations indicate higher basal levels of sympathetic activity in the subgroup of patients showing increases in aspartate aminotransferase after challenge with morphine.

Aspartate Aminotransferases↗