Biomedical subjects
M A Eastwood
Publications and source records attributed to M A Eastwood.
A molecular biological basis for the nutritional and pharmacological benefits of dietary plants.
Individuals who regularly eat fruit and vegetables gain protection against a number of diseases. These advantages are usually ascribed to the rich vitamin, antioxidant and dietary fibre content of fruit and vegetables. However, clinical trials testing whether these nutrients are protective against specific diseases have been less consistent. The secondary metabolites of plant metabolism, particularly those from the terpenoid and phenolic families, could provide some of this health protection, through regulatory effects on the functional domains of ancient conserved proteins and DNA regions common to both plants and mammals. Small-molecular-mass molecules can regulate gene expression in a variety of ways, e.g. targeting DNA sequences, inducing gene expression and binding to protein-regulating sites. Secondary plant metabolites may also modulate the function of transmembrane channel receptors and enzymes.
Dietary calcium supplementation increases apoptosis in the distal murine colonic epithelium.
BACKGROUND: Increased dietary calcium might reduce colorectal cancer risk, possibly by reduction of colonic epithelial hyperproliferation, but not all studies have demonstrated this. Little is known about the effects of calcium on colonic apoptosis. AIM: To quantify the effects of increasing calcium on apoptosis and cell proliferation in normal murine colonic crypt epithelium. METHODS: Twenty one day old male C57B1/6 mice were fed either control AIN-76 diet (0.5% calcium wt/wt; n = 10) or the same supplemented with calcium carbonate (1.0% calcium; n = 10) for 12 weeks. Apoptotic cells in proximal and distal segments were counted and expressed as an apoptotic index (AI: frequency of apoptosis/100 longitudinal crypts). The bromodeoxyuridine (BrdU) labelling index was also determined. Differences were analysed by the student's t test. RESULTS: In control animals, the AI was significantly higher in the caecum/proximal colon (mean, 28.6; SEM, 2.0) compared with the distal colon (mean, 19.9; SEM, 1.8; p = 0.004). In the calcium treated group, the AI in the caecum/proximal colon (mean, 30.6; SEM, 1.7) was similar to controls (p = 0.71) but the AI in the distal colon was significantly greater (mean, 32.6; SEM, 1.8; p = 0.001) than in control mice and was raised to values similar to those in the proximal colon. Calcium was also associated with reduced crypt cellularity and, in the proximal colon, a downward shift in the crypt position at which apoptosis occurred. There were no significant differences in the BrdU labelling index between groups or between proximal and distal colonic segments in each group. CONCLUSIONS: Increased dietary calcium is associated with the induction of apoptosis in normal mouse distal colonic epithelium without affecting cell proliferation. This might contribute to its putative chemopreventive role in colorectal carcinogenesis. Whether this effect is direct or indirect requires further study.
Interaction of dietary antioxidants in vivo: how fruit and vegetables prevent disease?
Epidemiological studies indicate that fruit and vegetables are health-promoting and protective against disease, particularly cardiovascular disease and cancer. Possible plant nutrients providing this protection include antioxidants and dietary fibre. Clinical trials with antioxidant supplements give inconsistent results for protection against lung cancer in smokers, invasive cervical cancer, oesophageal and gastric cancers, colorectal polyps and coronary heart disease. The antioxidants used in trials may be contributing to a more complex system. Antioxidants have differing solubilities which partition across the phases of tissues, cells and macromolecular structures: water-soluble ascorbate, glutathione and urate; lipid-soluble tocopherols and carotenoids, and intermediatory-soluble flavonoids and hydroxycinnamic acids. The health protection provided by fruit and vegetables could arise through an integrated reductive environment delivered by plant antioxidants of differing solubility in each of the tissue, cellular and macromolecular phases.
The use of 14C-labelled substrates to study plant cell wall breakdown in the gastrointestinal tract.
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Serum 7 alpha-hydroxy-4-cholesten-3-one and selenohomocholyltaurine (SeHCAT) whole body retention in the assessment of bile acid induced diarrhoea.
OBJECTIVE: To assess the reliability of serum 7 alpha-hydroxy-4-cholesten-3-one (7 alpha-3ox-C) in the differential diagnosis of bile acid induced diarrhoea by comparison with 75selenohomocholyltaurine whole body retention (SeHCAT WBR). DESIGN: One hundred and sixty-four patients with chronic diarrhoea were investigated prospectively in two centres (Edinburgh and Sweden) by two different tests which measure bile acid loss or synthesis: the SeHCAT test which measures the 7-day SeHCAT WBR and serum 7 alpha-3ox-C which reflects the rate of bile acid synthesis. RESULTS: Forty-six patients had SeHCAT WBR of less than 10% (19 with ileal disease or resection, nine with idiopathic bile acid induced diarrhoea and 18 with miscellaneous causes for bile acid induced diarrhoea). All patients with ileal or idiopathic disease showed a favorable response to treatment as did 13 of the miscellaneous group. Serum 7 alpha-3ox-C was raised in all subjects with ileal disease/resection, seven patients with idiopathic disease and all subjects in the miscellaneous group who responded to treatment. Sixteen out of 118 patients with SeHCAT WBR greater than or equal to 10% had raised serum 7 alpha-3ox-C. CONCLUSION: The positive predictive value of serum 7 alpha-3ox-C was 74%. The high negative predictive value (98%) of serum 7 alpha-3ox-C indicates the possible use of this test for excluding bile acid malabsorption in this population. All but two subjects who responded to treatment had raised serum 7 alpha-3ox-C concentrations. The possibility that the sensitivity of the test can be improved by repeat testing needs to be further investigated. There was a significant correlation between fractional catabolic rate (FCR) SeHCAT and serum 7 alpha-3ox-C (r = 0.63, P < 0.0001). Further data are required to validate the reference range in women over 70 years of age.
Collagen alteration in an animal model of colonic diverticulosis.
BACKGROUND: Changes in the structure and integrity of the colon dependent on collagen content and crosslinkage occur with age. AIMS: This study using an animal model examines colonic collagen content and crosslinkage over the lifetime of rats on fibre deficient and higher fibre diets. METHODS: Two groups of 20 rats were fed either a fibre deficient diet (1.7 g NSP (non-starch polysaccharide)/100 g) or a higher fibre diet (13.3 g NSP/100 g) for 18 months. Diverticula were identified by postmortem examination. Caecal and colonic contents were weighed and assayed for short chain fatty acids. Collagen solubility in weak acid was measured to give an indication of the nature and amount of crosslinks in the collagen of the bowel wall. RESULTS: The incidence of colonic diverticula was greater (42.1% fibre deficient rats; 0% higher fibre rats). Colonic collagen solubility index in fibre deficient rats was significantly lower than higher fibre diet fed rats (p < 0.001 in all four sections of the large bowel). Rats with diverticula had the lowest solubility index (p < 0.001 in all four sections of the large bowel). Higher fibre diet rats had increased caecal and colonic contents, caecal and colonic tissue wet weights, and greater caecal short chain fatty acids. Fibre deficient diet fed rats had more pathological abnormalities. CONCLUSIONS: This animal model permits a study of the relation between collagen crosslinkage and the development of colonic diverticulosis. A higher fibre diet protects against collagen crosslinking and this is related to a decreased incidence of diverticula.
Long-term results of subtotal colectomy and evidence of noncolonic involvement in patients with idiopathic slow-transit constipation.
BACKGROUND: Patients with chronic idiopathic constipation can be difficult to manage either medically or surgically. We report our experience of long-term follow-up of 21 patients who had undergone colectomy with ileorectal anastomosis for difficult chronic idiopathic constipation. METHODS: The patients (19 female, 2 male) were aged 26-68 (median = 46) years and had undergone subtotal colectomy 5-12 (median = 8) years before their assessment. They answered a questionnaire about severity of abdominal pain, bloating, urgency, and straining. They also completed the hospital anxiety and depression questionnaire. Fifteen ulcerative colitis patients with panproctocolectomy and 13 colon cancer patients with colonic resection who had a similar follow-up period served as control groups. The following assessments were performed in chronic idiopathic constipation patients with subtotal colectomy: a) oesophageal manometry; b) scintigraphic gastric emptying test; c) review of barium follow-through; d) glucose H2 breath test; e) urodynamic studies; and f) autonomic function tests. RESULTS: Twenty-four per cent of patients with chronic idiopathic constipation had a family history of difficult constipation requiring hospital investigations and treatment. At the time of assessment abdominal pain, bloating, urgency, and straining at defecation were all significantly more frequent in patients with chronic idiopathic constipation with colectomy than in the control groups with colectomy. Seventy-one per cent of chronic idiopathic constipation patients had at least one episode of intestinal obstruction after subtotal colectomy, which is significantly higher (P < 0.01) than in the control groups (ulcerative colitis, 13%; colonic carcinoma, 8%). In patients with chronic idiopathic constipation, among those studied, 68% had some oesophageal motor dysfunction: 19% delayed gastric emptying; 10%, prolonged small-bowel transit on barium follow-through; 54%, abnormal urodynamic variables; and 14%, abnormal autonomic function tests. CONCLUSIONS: This study shows considerable morbidity in a selected cohort of patients with chronic idiopathic constipation who were sufficiently disabled by their symptoms to undergo subtotal colectomy. They had more abdominal and rectal symptoms and more frequent intestinal obstructive episodes than control groups with colonic resection. Evidence of generalized smooth-muscle dysfunction and familial occurrence of constipation suggests a primary chronic intestinal pseudo-obstruction-like disorder in some of these patients.
Bleeding duodenal diverticulum.
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Caecal and faecal short-chain fatty acids and stool output in rats fed on diets containing non-starch polysaccharides.
The exact mechanisms by which non-starch polysaccharides increase stool output are unknown. In the present study the hypothesis that the site of fermentation and short-chain fatty acid (SCFA) accumulation is related to the action of non-starch polysaccharides (NSP) on stool output was tested. The basal diet (45 g NSP/kg) of forty-three male Wistar rats was supplemented with 50 g/kg of either guar, karaya, tragacanth, gellan, xanthan or ispaghula for 28 d. A further twenty-three rats were maintained on the basal diet for the same time period. Faeces were then collected over 2 d and caecal contents obtained post-mortem. Caecal and faecal wet and dry weights and SCFA were measured. Each supplement had a different effect on the caecal and faecal contents but they appeared to fall into three groups when compared with the basal diet. In group 1, guar gum affected only caecal SCFA. It had no effect on stool output or faecal SCFA. In group 2, karaya increased caecal SCFA and tragacanth, karaya and xanthan increased faecal SCFA and faecal water. In group 3, ispaghula and gellan had no consistent effect on caecal or faecal SCFA concentrations but increased total faecal SCFA output and increased faecal wet and dry weight. Although the knowledge that SCFA are rapidly absorbed in the large intestine has led us to believe that they play no role in determining faecal output, these results suggest that in some cases where NSP are slowly fermented, and increase faecal SCFA, the role of the SCFA may need to be reassessed.
Taurocholic acid adsorption during non-starch polysaccharide fermentation: an in vitro study.
The association of radiolabelled taurocholic acid with the solid fraction of a faecal fermentation mixture was measured. A human faecal inoculum was incubated with [24-14C]taurocholic acid and several non-starch polysaccharide sources (pectin, wheat bran, ispaghula (Plantago ovata) husk and seed), glucose or a substrate-free control. Portions of fermentation mixture were taken at 0, 3, 6, 21 and 24 h and centrifuged to acquire a supernatant fraction and a pellet containing the fermentation residue. 14C was measured in supernatant fractions and pellets at all time points. Volatile fatty acids (VFA) were measured at 0 and 24 h to confirm bacterial growth. Radioactivity in the pellet increased over time for all substrates. Glucose resulted in the greatest incorporation of taurocholic acid into the pellet, followed by pectin. At 24 h the proportion of the total radioactivity found in the pellet was 92% for glucose, 79% for pectin, 60% for wheat bran, 59% for ispaghula seed, 53% for ispaghula husk and 26% for the control (mean of duplicates). Glucose and pectin produced the greatest quantity of VFA at 24 h. VFA production was highly correlated with radioactivity in the pellet (r0.976, P < 0.005). These results suggest that the bile acid binding capacity of a faecal culture mixture may be strongly influenced by the fermentability of the available substrate and hence related to bacterial metabolic activity.
Successful Helicobacter pylori eradication incorporating a one-week antibiotic regimen.
BACKGROUND: The optimum regimen for the eradication of Helicobacter pylori remains unclear. The aim of this study was to determine the efficacy and tolerability of omeprazole 40 mg daily given for 2 weeks, plus amoxycillin 500 mg t.d.s. and metronidazole 400 mg t.d.s. given for the first 7 days, in the treatment of H. pylori associated peptic ulcer disease. RESULTS: One hundred and thirty-two consecutive patients with peptic ulcer disease were entered into the study (89 male, 41 female; median age 47 years; inter-quartile range: 36-58 years). H. pylori was eradicated successfully in 109 of 130 patients (intention-to-treat: 83%; 95% confidence limits: 76-89%); per protocol: 85% (95% CI: 78-91%)). Ninety per cent of patients completed the full course of therapy. Only four patients (3%) stopped treatment as a result of side effects although these occurred in 41% of patients. One patient developed pseudomembranous colitis requiring hospital admission. CONCLUSION: Omeprazole combined with one week of treatment of amoxycillin and metronidazole is an effective and well tolerated Helicobacter eradication regimen. Occasional severe side effects remain a risk, even when the duration of antibiotic exposure is reduced.
Cross linking of collagen is increased in colonic diverticulosis.
Development of colonic diverticulosis is a function of age and declining colonic wall mechanical strength. The latter is partly a consequence of changes in the collagen structure. Collagen from unaffected human colons (n = 20, age range 20-80 years) and those with colonic diverticulosis (n = 5, age range 67-80 years) were obtained at necropsy. The total collagen content was measured as the hydroxyproline content and cross linkage by collagen solubility in weak acid was studied. The colonic total collagen content was constant with age (mean (SD) 15.8 (0.3) mg/100 mg wet weight of tissue). The acid solubility of the collagen, however, increased after the age of 40 years: at over 60 years, colonic diverticulosis was associated with an increased acid solubility ratio compared with values in unaffected colons (15.3 (0.2); compared with 9.2 (0.2), p < 0.001). The cross linking of colonic collagen increases with age. These changes seem to be a factor in the aetiology of colonic diverticulosis.
Denis Parsons Burkitt - 28 February 1911--23 March 1993.
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Beeturia and colonic oxalic acid.
Beeturia is the excretion of red beetroot pigment (betalaine) in urine and faeces. It occurs in about 14% of humans. Betalaine is a redox indicator whose colour is protected by reducing agents. We investigated pigment-decolourizing systems in the intestinal tracts of beeturic and non-beeturic subjects. Betalaine was decolourized by hydrochloric acid, ferric ions and colonic bacteria preparations, but not by pancreatic or mucosal enzymes. In animals, oral betalaine did not produce beeturia, but injection of betalaine into the peritoneum did. Oral betalaine and 1 g oxalic acid produced beeturia in non-beeturic normal humans, but passed into ileostomies without beeturia. Thus, beeturia results from colonic absorption of betalaine. Oxalic acid preserves the red colour to the colon, otherwise it is decolourized in non-beeturic individuals by non-enzymic processes in the stomach and colon.
The effect of olestra on breath gas production and faecal microbial counts.
OBJECTIVE: To assess the effect of olestra consumption on breath hydrogen (H2) and methane (CH4) production and faecal microbial counts in humans consuming moderate or high fibre diets. A secondary objective was to assess the effect of olestra consumption on health status. DESIGN: Thirty-six-day parallel, placebo-controlled, double-blind study with baseline low fibre period (3 g/meal, 8 days) and treatment period (28 days). Four treatment groups: moderate (7 g/meal) or high fibre (24 g/meal), with olestra (24 g) or placebo. SETTING: Queen Margaret College, Edinburgh, Scotland. SUBJECTS: Ninety-seven adult subjects (30 males and 67 females) from the hospital staff and student population participated in the study. Ninety-four subjects successfully completed the study. INTERVENTION: Breath H2 and CH4 production were measured and faecal specimens were obtained for faecal microbial viable counts and direct microscopic cell counts at the end of the baseline period and the end of the treatment period. Standard clinical blood and urine assays were performed. Subjects were questioned regarding adverse events. RESULTS: Olestra demonstrated no significant effect on breath H2 or CH4 production following either moderate or high fibre intake. A trend for lower breath H2 production in the high fibre olestra group was seen. No effect of olestra consumption on faecal microbial counts or health status was observed. CONCLUSION: In normal subjects 24 g/d of olestra for 36 days does not interfere with normal intestinal fermentation of dietary fibre and does not significantly alter gut microflora populations.
Satisfactory outcome of percutaneous endoscopic gastrostomy in two patients with cirrhosis and portal hypertension.
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Idiopathic bile acid malabsorption: long-term outcome.
OBJECTIVE: Idiopathic bile acid malabsorption (IBAM) is a rare cause of diarrhoea. The natural history of this disorder has not previously been reported. The aim of our study was to determine the long-term outcome in a cohort of patients with severe IBAM using a subjective assessment and by measuring the proportion of 75Se-homocholic acid taurine (75SeHCAT) retained 7 days after its ingestion. PATIENTS AND METHODS: Twenty-three patients with IBAM were identified in 1989. All had responded well to treatment with a bile acid chelator (cholestyramine or aluminium hydroxide). Questionnaires relating to current clinical symptoms and prescriptions were sent to these patients and their general practitioners. 75SeHCAT tests were performed for objective assessment. RESULTS: Three patients were lost to follow-up, three had died owing to malignancy and three had been diagnosed as suffering from inflammatory bowel disease. The mean period of follow-up for the remaining fourteen patients was 99.2 (range 48-140) months. Seven of the patients showed an improvement in symptoms and no longer required treatment with cholestyramine. In the remaining seven symptomatic patients, diarrhoea was well controlled by continued treatment with cholestyramine (five patients) or standard anti-diarrhoeal treatment (two patients). All seven symptomatic patients and three asymptomatic patients underwent repeat 7 day 75SeHCAT tests. The test results in the asymptomatic group had all improved so that the retention of the tracer after 7 days was above 5%; all but two patients in the symptomatic group still had values under 5%. However, the small number of patients in both groups precluded statistical analysis. CONCLUSIONS: IBAM is a rare cause of diarrhoea and should be diagnosed only after malignancy and inflammatory bowel disease have been excluded by rigorous investigations. Patients should be followed up as some develop other serious gastrointestinal diseases. Fifty per cent of the patients in our survey have remitted spontaneously and no longer require medication with bile acid chelators or anti-diarrhoeal agents.