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Biomedical subjects

J C Mathers

Publications and source records attributed to J C Mathers.

At least 19 recordsLinked to original sources
PubMed2006

Zinc transporters in the mouse placenta show a coordinated regulatory response to changes in dietary zinc intake.

The aim of the study was to determine if the expression of zinc transporters in the mouse placenta is regulated by dietary zinc, commensurate with regulating the supply of zinc to the fetus. Mice were fed diets differing only in the concentration of zinc (moderately zinc-restricted (ZnR)--15 mg Zn/kg; zinc-adequate (ZnA)--50 mg Zn/kg; zinc-supplemented (ZnS)--150 mg Zn/kg) from the onset of pregnancy until collection of tissue at day 17. Compared with mice fed the other diets, fetal weight was reduced in the ZnR group and total non-embryonic weight gain was reduced in mice fed the ZnS diet. Transcript levels of metallothionein and the zinc transporters ZnT1, ZnT4 and ZIP1 were reduced in the placenta of mice fed both the ZnR and ZnS diets compared with mice fed the ZnA diet. Placental ZnT7 and fetal liver metallothionein transcript levels did not differ significantly between mice fed the three diets and placental ZnT5 was reduced in mice fed the ZnS compared with the ZnA diet but did not differ significantly between the ZnA and ZnR diets. The pattern of mRNA expression in placenta was reflected at the protein level for ZnT1. Levels of ZnT5 protein were also highest in mice fed the ZnA diet. Both ZnT1 and ZnT5 were detected in the human villous syncytiotrophoblast by immunohistochemistry. The data indicate that the expression of zinc transporters in mouse placenta is responsive to dietary zinc supply but this modulation of expression is insufficient to maintain optimum fetal nutrition at even a modest level of dietary zinc restriction.

Animals↗
PubMed2005

Methylation of the ESR1 CpG island in the colorectal mucosa is an 'all or nothing' process in healthy human colon, and is accelerated by dietary folate supplementation in the mouse.

ESR1 is frequently silenced by CGI (CpG island) methylation, both in human colorectal tumours and, in an age-dependent manner, in healthy mucosa. It is not clear, however, whether methylation of individual cytosines occurs randomly within the epithelial genome, or preferentially within individual cells as an 'all-or-nothing' phenomenon. CGI methylation can be quantified in human DNA residues recovered from faecal samples. We used bisulphite genomic sequencing of human DNA from this source and from a colorectal cancer cell line (SW48) to show that the ESR1 CGI is methylated in an allele-specific manner. This provides support for the 'all or none' mechanism for methylation of this gene, and shows how age-dependent methylation of the ESR1 CGI leads rapidly to silencing of the gene within the cells, and hence the colonic crypt within which it occurs. Preliminary studies with a rodent model suggest the rate of age-dependent methylation of ESR1 is modifiable by dietary folate.

Aging↗
PubMed2005

DNA mismatch repair status may influence anti-neoplastic effects of butyrate.

HNPCC (hereditary non-polyposis colon cancer) is an autosomal-dominant disorder characterized by early-onset CRC (colorectal cancer). HNPCC is most often associated with mutations in the MMR (mismatch repair) genes hMLH1, hMSH2, hMSH6 or hPMS2. The mutator phenotype of a defective MMR system is MSI (microsatellite instability), which also occurs in approx. 15-25% of sporadic CRC cases, where it is associated with the hypermethylation of the promoter region of hMLH1. Dietary factors, including excessive alcohol consumption, ingestion of red meat and low folate intake, may increase the risk of MSI high tumour development. In contrast, aspirin may suppress MSI in MMR-deficient CRC cell lines. Butyrate, a short-chain-fatty-acid end product of carbohydrate fermentation in the colon, shares a number of anti-neoplastic properties with aspirin, including inhibiting proliferation and inducing apoptosis of CRC cells. Recent in vitro studies suggest that physiological concentrations of butyrate (0.5-2 mM) may have more potent anti-neoplastic effects in CRC cell lines deficient in MMR, but mechanisms for such a differential response remain to be established.

Anticarcinogenic Agents↗
PubMed2005

Homeostatic regulation of zinc transporters in the human small intestine by dietary zinc supplementation.

BACKGROUND: The role of intestinal transporter regulation in optimising nutrient absorption has been studied extensively in rodent and cell line models but not in human subjects. AIMS: The aim of the present study was to investigate the response in vivo of zinc transporters in the human enterocyte to dietary zinc supplementation. SUBJECTS: Eighteen patients who had previously undergone ileostomy, all free of any symptoms of inflammatory bowel disease. METHODS: Subjects took a daily zinc supplement of 25 mg for 14 days in a double blind, placebo controlled, crossover trial. The effect of the supplement on expression in ileal biopsies of the zinc transporters SLC30A1, SLC30A4, SLC30A5, SLC39A1, SLC39A4, and metallothionein was measured by reverse transcription-polymerase chain reaction RT-PCR. Expression of SLC30A1, SLC30A5, and SLC39A4 was also examined by immunoblotting. RESULTS: The zinc supplement reduced SLC30A1 mRNA (1.4-fold) together with SLC30A1, SLC30A5, and SLC39A4 protein (1.8-fold, 3.7-fold, and to undetectable levels, respectively) in ileal mucosa and increased metallothionein mRNA (1.7-fold). The supplement had no effect on expression of SLC30A4 or SLC39A1 mRNA. Localisation of SLC30A5 at the apical human enterocyte/colonocyte membrane and also at the apical membrane of Caco-2 cells was demonstrated by immunohistochemistry. Commensurate with these observations in zinc supplemented human subjects, SLC30A1, SLC30A5, and SLC39A4 mRNA and protein were reduced in Caco-2 cells cultured at 200 muM compared with 100 muM zinc. CONCLUSIONS: These observations indicate that, in response to variations in dietary zinc intakes, regulated expression of plasma membrane zinc transporters in the human intestine contributes to maintenance of zinc status.

Adult↗
PubMed2005

Bioavailability of fluoride in drinking water: a human experimental study.

It has been suggested that systemic fluoride absorption from drinking water may be influenced by the type of fluoride compound in the water and by water hardness. Using a human double-blind cross-over trial, we conducted this study to measure c(max), T(max), and Area Under the Curve (AUC) for plasma F concentration against time, following the ingestion of naturally fluoridated hard and soft waters, artificially fluoridated hard and soft waters, and a reference water. Mean AUC over 0 to 8 hours was 1330, 1440, 1679, 1566, and 1328 ng F.min.mL(-1) for naturally fluoridated soft, naturally fluoridated hard, artificially fluoridated soft, artificially fluoridated hard, and reference waters, respectively, with no statistically significant differences among waters for AUC, c(max), or T(max). Any differences in fluoride bioavailability between drinking waters in which fluoride is present naturally or added artificially, or the waters are hard or soft, were small compared with large within- and between-subject variations in F absorption. Abbreviations used: F, fluoride; AUC, Area under the Curve for plasma F concentration against time; AUC(0-3), Area under the Curve for plasma F concentration against time for 0 to 3 hours following water ingestion; AUC(0-8), Area under the Curve for plasma F concentration against time for 0 to 8 hours following water ingestion; c(max), maximum plasma F concentration corrected for baseline plasma F and dose (i.e., F concentration of individual waters); T(max), time of c(max).

Adult↗
PubMed2004

Changes in water intake of Northumbrian adolescents 1980 to 2000.

OBJECTIVES: To determine: total water intake in young English adolescents; the relative importance of sources of water intake; and changes in water intake and sources of water between 1980 and 2000. DESIGN: A cross-sectional observational study of the diets of 11-12-year-old children attending seven schools in south Northumberland, UK. The information obtained was compared with results from a similar survey carried out 20 years previously. METHODS: All children attending these schools were invited to participate. They completed a three-day diet diary with an interview on the fourth day, on two occasions during the school year. Standard UK food composition tables were used and water intake from various sources calculated. Anthropometric and social class information was obtained. RESULTS: Four hundred and twenty-four children completed all aspects of the study (64% of those eligible). The mean total water intake was 1,130 g d(-1), approximately the same as that recorded 20 years before. Water intake in relation to energy intake: water intake was 139 g MJ(-1) in boys and 143 g MJ(-1) in girls. Sixty-five per cent of water came from drinks and 35% from foods; very similar to proportions 20 years before. The sources of water in drinks had changed considerably, with a marked increase in consumption of soft drinks (especially carbonated drinks) and a decrease in consumption of hot drinks and milk. There were a few differences between sexes but little difference between social groups. CONCLUSIONS: Total water intake was similar to that recorded 20 years previously and lower than intakes reported in other countries. Changes in the sources of water meant that less water consumed was likely to come from the tap in the house and more from drinks made elsewhere, than 20 years previously. These changes have implications for estimating fluoride intake in fluoridated areas.

Adolescent↗
PubMed2004

Folate and DNA methylation during in utero development and aging.

DNA methylation is one of several epigenetic mechanisms that play a regulatory role in genome programming and imprinting during embryogenesis. Aberrant DNA methylation has been implicated in the pathogenesis of a number of diseases associated with aging, including cancer and cardiovascular and neurological diseases. Evidence is accumulating that dietary factors in utero modulate disease risk in later life. Although folic acid is a key component of DNA methylation, the impact of folic acid availability in utero on DNA methylation patterns and disease risk in adulthood is at present poorly characterized. This review describes the relationship between folic acid and DNA methylation, and the association between DNA methylation during in utero development and aging.

Aging↗
PubMed2004

Changes over 20 years in macronutrient intake and body mass index in 11- to 12-year-old adolescents living in Northumberland.

Monitoring adolescent diets over time enables the assessment of the effectiveness of public health messages which are particularly important in vulnerable groups such as adolescents. In 2000, 424 children aged 11-12 years old completed two 3 d estimated dietary records. On the fourth day one nutritionist interviewed each child to clarify the information in the diary and foods were quantified with the aid of food models. Nutrient intake was calculated using computerised food tables. These children attended the same seven schools in the same Northumberland area as the 11- to 12-year-old children who recorded their diet using the same method in 1980 (n 405) and 1990 (n 379), respectively. Height and weight, and parental occupation were recorded in all three surveys for each child. Height and weight were used to calculate BMI, weight was used to estimate BMR and parental occupation was used to determine social class. Comparing the macronutrient intakes in 2000 with 1980 and 1990, energy intakes (EI) fell in boys (to 8.45 MJ) and girls (to 7.60 MJ). This fall may, at least in part, be due to an increase in low energy reporting. For 1980, 1990 and 2000 the percentage of boys with EI:BMR below 1.1 was 6, 15 and 23 %, respectively; for girls, 3, 14 and 18 %, respectively. Percentage energy from fat was unchanged between 1980 and 1990 but fell to 35 % (about 76 g/d) in 2000, alongside a 3 % increase in percentage energy from starch (30 %). Percentage energy from non-milk extrinsic sugars remained above recommendations (16 %; about 82 g/d). The number of overweight and obese children increased from 11 % to 30 % between 1980 and 2000. Positive changes have occurred in the Northumbrian adolescent diet but social inequalities, reported in previous surveys, remain.

Body Mass Index↗
PubMed2003

A lifecourse study of risk for hyperinsulinaemia, dyslipidaemia and obesity (the central metabolic syndrome) at age 49-51 years.

AIMS: Suboptimal maternal nutrition and catch-up growth in early childhood predispose to insulin resistance and other components of metabolic syndrome in later life. A central metabolic syndrome (CMS) has been identified comprising obesity, dyslipidaemia and insulin resistance. This study was designed to investigate determinants of risk for CMS. METHODS: Persons born in Newcastle in May and June 1947 (n = 358) were followed to 1996-1998. A lifecourse approach was used to estimate the proportion of variance in a summary measure of CMS at age 49-51 years accounted for by factors operating at different stages of life. RESULTS: After adjustment for other early life variables, childhood catch-up growth in men accounted for significant variation in the CMS score independent of adult lifestyle. In adulthood, exercise level in men and smoking in both genders were independently associated with CMS. Over two-thirds of explained variation in the CMS score in women, and almost half in men, was accounted for exclusively by factors measured in adulthood. CONCLUSIONS: While risk for CMS in men is compounded by early life disadvantage, promotion of a healthier adult lifestyle and a reduction in the number of people taking up smoking would appear to be the public health interventions most likely to reduce the prevalence of CMS in middle age.

Body Mass Index↗
PubMed2001

Randomised controlled trial evaluating the effectiveness of behavioural interventions to modify cardiovascular risk factors in men and women with impaired glucose tolerance: outcomes at 6 months.

AIMS: To evaluate the efficacy of interventions to promote a healthy diet and physical activity in people with impaired glucose tolerance (IGT). METHODS: A randomised controlled trial in Newcastle upon Tyne, UK, 1995-98. Participants included 67 adults (38 men; 29 women) aged 24-75 years with IGT. The intervention consisted of regular diet and physical activity counselling based on the stages of change model. Main outcome measures were changes between baseline and 6 months in nutrient intake; physical activity; anthropometric and physiological measurements including serum lipids; glucose tolerance; insulin sensitivity. RESULTS: The difference in change in total fat consumption was significant between intervention and control groups (difference -21.8 (95% confidence interval (CI) -37.8 to -5.8) g/day, P=0.008). A significantly larger proportion of intervention participants reported taking up vigorous activity than controls (difference 30.1, (95% CI 4.3--52.7)%, P=0.021). The change in body mass index was significantly different between groups (difference -0.95 (95% CI -1.5 to -0.4) kg/m(2), P=0.001). There was no significant difference in change in mean 2-h plasma glucose between groups (difference -0.19 (95% CI -1.1 to 0.71) mmol/l, NS) or in serum cholesterol (difference 0.02 (95% CI -0.26 to 0.31) mmol/l, NS). The difference in change in fasting serum insulin between groups was significant (difference -3.4 (95% CI -5.8 to -1.1) mU/l, P=0.005). CONCLUSIONS: After 6 months of intensive lifestyle intervention in participants with IGT, there were changes in diet and physical activity, some cardiovascular risk factors and insulin sensitivity, but not glucose tolerance. Further follow-up is in progress to investigate whether these changes are sustained or augmented over 2 years.

Adult↗
PubMed2001

Comparative gastrointestinal and plasma cholesterol responses of rats fed on cholesterol-free diets supplemented with guar gum and sodium alginate.

The present study investigated the digestion and cholesterol-lowering effects of the water-soluble NSP guar gum (GG) and sodium alginate (SA) in laboratory animals. Groups of five male Wistar strain rats were fed semi-purified cholesterol-free diets containing 0, 50 or 100 g NSP source/kg for 21 d which comprised a 14-d adaptation period followed by a 7-d balance period. Weight gain over the balance period and food conversion ratio decreased linearly with increasing NSP intake ( and respectively). DM digestibility decreased with increasing NSP intake and this effect was greater for SA-containing diets compared with GG-containing diets At the lower inclusion rate, 0.9-1.0 of the additional NSP was digested, but this value fell to 0.8 for both NSP sources at the 100 g/kg inclusion rate, implying that the capacity for near complete digestion of the test NSP had been exceeded. Intestinal tissue mass was increased in response to inclusion of both NSP sources. Caecal digesta pH decreased linearly with additional GG, but increased slightly with consumption of SA. Total caecal short-chain fatty acid concentrations (micromol/g caecal contents) increased markedly with 50 g GG/kg but did not increase further with 100 g GG/kg, and were slightly lower than control values in rats consuming SA. Plasma cholesterol concentration fell linearly with increasing NSP in the diet and the effect was similar for both GG and SA. Total output of faecal bile acids rose in rats fed 50 g GG/kg and 50 g SA/kg (59 micromol/7 d v. 24 micromol/7 d for control rats) with no further increase at the higher inclusion rate. These results show that SA has a strong hypocholesterolaemic effect in rats which is similar to that of GG, and that this effect is most likely to be mediated through an interruption in the entero-hepatic circulation of bile acids and not through increased hepatic supply of propionate from fermentation of the NSP in the large bowel.

Alginates↗
PubMed2001

Curcumin modifies Apc(min) apoptosis resistance and inhibits 2-amino 1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induced tumour formation in Apc(min) mice.

Curcumin, the active ingredient of the rhizome of Curcuma longa, promotes apoptosis and may have chemopreventive properties. This study investigates the effects of curcumin on apoptosis and tumorigenesis in male Apc(min) mice treated with the human dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Intestinal epithelial apoptotic index in response to PhIP treatment was approximately twice as great in the wild-type C57BL/6 APC(+/+) strain than in Apc(min) mice (3.7% Apc(+/+) versus 1.9% Apc(min); P < 0.001). PhIP promoted tumour formation in Apc(min) proximal small intestine (4.6 tumours per mouse, PhIP treated versus 2.1 tumours per mouse, control untreated; P < 0.05). Curcumin enhanced PhIP-induced apoptosis (4.0% curcumin + PhIP versus 2.1% PhIP alone; P < 0.01) and inhibited PhIP-induced tumorigenesis in the proximal small intestine of Apc(min) mice (2.2 tumours per mouse, curcumin + PhIP versus 4.6 tumours per mouse PhIP alone; P < 0.05). This study shows that the Apc(min) genotype is associated with resistance to PhIP-induced apoptosis in intestinal epithelium. Curcumin attenuates Apc(min) resistance to PhIP-induced apoptosis and inhibits PhIP-induced tumorigenesis in proximal Apc(min) mouse small intestine.

Animals↗
PubMed2001

Colonic crypt cell proliferation state assessed by whole crypt microdissection in sporadic neoplasia and familial adenomatous polyposis.

BACKGROUND: It has yet to be established whether proliferative activity in the macroscopically normal colonic mucosa is causally correlated with neoplastic risk. Measurement of proliferative activity in human subjects is of necessity usually undertaken using indirect methods with inherent limitations, and relatively little has been published on the effect of normal biological variables on such indices. AIMS: To establish the validity of mitosis counts following whole crypt microdissection as an index of the crypt cell proliferative state (CCPS) and to examine the effect of normal biological variables (age, sex, and colonic site) and colonic neoplasia on the mitotic index in macroscopically normal human colon. SUBJECTS: Mucosal samples were obtained at colectomy or colonoscopy from 107 individuals (24 controls, 23 sporadic adenoma patients, 31 sporadic carcinoma patients, and 29 patients with familial adenomatous polyposis (FAP)). METHODS: Mucosal specimens were hydrated, hydrolysed, and small groups of crypts separated from the main specimen under a dissecting microscope. The total number of mitoses/crypt were counted by one observer for each of 10 complete crypts. RESULTS: Validation work established that whole crypt mitoses counts were reliable and reproducible. There was no relation between age and mean mitoses/crypt (Pearson correlation coefficient -0.1). The CCPS count was higher for males than for females (difference in means 2.8 (95% confidence interval 0.80-4.66)) among controls but there was no gender difference in the three disease groups. For all disease groups and controls, the crypt mitotic count showed a significant linear increase (p=0.004) from the rectum to the caecum. Biopsies from within 5 cm of the macroscopic margin of a carcinoma (near) gave a mean mitosis count of 12.6 while those from more than 10 cm (far) were lower but not significantly so (p=0.12) with a count of 9.0. The mean mitoses/crypt were similar for the controls and adenomas (5.6 and 4.7, respectively) but greater for the cancers and especially for FAP (8.3 and 14.2, respectively). Statistical analysis confirmed that there were significant differences (p<0.05) between controls and all disease groups together, between sporadic disease and FAP, and between adenoma and carcinoma subjects at each of the four colonic sites. Post hoc comparison by t test showed significantly greater CCPS for FAP compared with controls (p<0.001) and for sporadic cancer versus controls (p=0.04). CONCLUSIONS: Whole crypt microdissection and mitosis counting is a reliable, reproducible, and robust technique for assessing CCPS in the human colon. CCPS is unaffected by age but increases from the distal to the proximal colon. CCPS is increased if a sporadic cancer is present and markedly increased in FAP. However, the precise relation of an increased CCPS to the neoplastic process remains uncertain.

Adenoma↗
PubMed2001

Susceptibility markers in colorectal cancer.

Many susceptibility factors contribute to an individual's risk of developing colorectal cancer. Family history of colorectal cancer (particularly with early age of onset), maleness and increasing age are all factors associated with increasing risk. About three quarters of colorectal cancers are thought to be due to somatic mutations, and both high- and low-penetrance predisposing genes contribute to the remaining quarter of cases. Many of the highly penetrant dominant genes are known, but others remain to be identified. Describing the contribution of individual genes is likely to be very complex, as some modify the impact of other genes and other environmental factors rather than incurring a direct, easily attributable effect. The two dominant predisposing syndromes are familial adenomatous polyposis and Lynch syndrome, the first due to a mutant tumour-suppressor gene APC, and the second due to mutations in a number of genes responsible for mismatch repair in DNA at cell division. Establishing genetic susceptibility for colorectal cancer will soon be possible, and could save lives by allowing targetting of screening and the encouragement of preventive behaviours. However, there will always be a risk of making healthy people "sick" through the identification of predisposing genes, and there are many potential ways by which a gene carrier may be stigmatized by society, insurance companies and employers.

Aged↗
PubMed2000

Changes to the quantity and processing of starchy foods in a western diet can increase polysaccharides escaping digestion and improve in vitro fermentation variables.

This study investigated how readily achievable changes to the quantity and processing of starchy foods in a typical Western diet: (1) were reflected in levels of resistant starch (RS) and NSP excreted from the small intestine; and (2) more favourable profiles of butyrate, NH3 and phenol production. Two diets, a low-starch diet (LSD) and a high-starch, low-fat diet (HSLFD) were compared. The LSD with 20% total energy (%E) from starch was based on a 'typical' Australian diet, while the HSLFD (40%E as starch) was the same Australian diet modified by an increased content of legumes, starchy foods and coarsely-ground cereals and by a reduced fat content. Four subjects with iliostomies consumed each diet for 2 d, with ileal effluent collection on the second day. On the HSLFD compared with the LSD, RS in ileal effluent increased from from 0.49 to 1.7 g/MJ per d (P < 0.005) while ileal NSP excretion increased from 2.0 to 3.3 g/MJ per d (P < 0.05). Ileal effluents obtained after each diet were incubated for 24 h in vitro with a human faecal innoculum. After fermentation, ileal effluent from the HSLFD produced more butyrate relative to other short-chain fatty acids (17.5 v. 15.8 molar %, P < 0.005) and less phenol (2.3 v. 5.7 mg/l, P < 0.05) and NH3 (20.3 v. 23.1 mmol/l, P < 0.005) than the LSD diet. The HSLFD also generated a lower pH (6.15 v. 6.27, P < 0.05). On a wt/wt basis, RS was 2.3-fold higher in the HSLFD effluent while NSP did not increase, suggesting that the change in RS largely contributed to the fermentation effects. Changes in in vitro variables when the HSLFD ileal effluent was ground before fermentation indicated the importance of physical structure in determining ileal excretion of RS. We conclude that: (1) readily achievable modifications to the amount and processing of starchy foods in an Australian diet would produce potential benefits for in vitro fermentation variables; and (2) the physical structure of grains and cereals is important in determining access by colonic bacteria to a carbohydrate substrate.

Adolescent↗
PubMed2000

Kill and cure: dietary augmentation of immune defences against colon cancer.

At its most fundamental, cancer is a genetic disease resulting from inherited or acquired mutations in tumour suppressor genes and proto-oncogenes. Environmental factors, including ingested food components, interact with genetic inheritance to determine individual cancer risk. There is growing evidence that the immune system exerts selective pressure during neoplastic development. Tumour cells that evade this immunosurveillance because they are non-antigenic or because they defend themselves successfully against immune attack have a survival advantage. Effective chemopreventative agents will include dietary components that enhance the immune system's ability to identify transformed cells and to target them for apoptosis.

Animals↗
PubMed2000

Gastric emptying rate of solids is reduced in a group of ileostomy patients.

Feedback inhibition from the colon acts as a potent inhibitor of gastrointestinal motility via an array of gut peptides and neural pathways. The effect of total colonectomy on gastric emptying was assessed in five healthy ileostomy patients (<5 cm ileal resection) and five matched controls. Each subject consumed two isoenergetic test meals of contrasting fat-carbohydrate ratio in random order. Emptying of solids was measured using the [13C]octanoic acid breath test, and liquid emptying was assessed after oral dosing with paracetamol. Ileostomist subjects exhibited an increased half-emptying time for solids (P = 0.047), which included components of an increased gastric lag time (P = 0.004) and a reduction in the linear emptying rate (P = 0.003). There was no difference in the pattern of liquid emptying between subject groups. In conclusion, the gastric emptying rate of solids was reduced in ileostomy patients compared with controls.

Adult↗