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Biomedical subjects

J B Mason

Publications and source records attributed to J B Mason.

At least 19 recordsLinked to original sources
PubMed2004

Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal.

Methylation events play a critical role in the ability of growth factors to promote normal development. Neurodevelopmental toxins, such as ethanol and heavy metals, interrupt growth factor signaling, raising the possibility that they might exert adverse effects on methylation. We found that insulin-like growth factor-1 (IGF-1)- and dopamine-stimulated methionine synthase (MS) activity and folate-dependent methylation of phospholipids in SH-SY5Y human neuroblastoma cells, via a PI3-kinase- and MAP-kinase-dependent mechanism. The stimulation of this pathway increased DNA methylation, while its inhibition increased methylation-sensitive gene expression. Ethanol potently interfered with IGF-1 activation of MS and blocked its effect on DNA methylation, whereas it did not inhibit the effects of dopamine. Metal ions potently affected IGF-1 and dopamine-stimulated MS activity, as well as folate-dependent phospholipid methylation: Cu(2+) promoted enzyme activity and methylation, while Cu(+), Pb(2+), Hg(2+) and Al(3+) were inhibitory. The ethylmercury-containing preservative thimerosal inhibited both IGF-1- and dopamine-stimulated methylation with an IC(50) of 1 nM and eliminated MS activity. Our findings outline a novel growth factor signaling pathway that regulates MS activity and thereby modulates methylation reactions, including DNA methylation. The potent inhibition of this pathway by ethanol, lead, mercury, aluminum and thimerosal suggests that it may be an important target of neurodevelopmental toxins.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2004

The national Vitamin A Supplementation Program and subclinical vitamin A deficiency among preschool children in the philippines.

The prevalence of vitamin A deficiency (serum retinol [SR] < 20 microg/dl) in children from one to five years of age in the Philippines rose from 35.8% to 38% between 1993 and 1998, despite a twice-yearly universal vitamin A capsule distribution program. The Philippines 1998 National Nutrition Survey, with one-time SR measurements from 11,620 children from one to four years of age, collected over an eight-month period from one month to more than six months after distribution of vitamin A capsules, was an opportunity to examine the impact of the program on the children's vitamin A status, using post hoc analysis. Overall, a detectable impact of vitamin A capsules on SR was limited to groups with the highest prevalence of vitamin A deficiency and lasted up to four months after dose administration. In highly urban cities in Visayas, where very high prevalences of deficient SR (SR < 10 microg/dl) were found, the prevalence of deficient SR was reduced from 27% to 9% one to two months after distribution of vitamin A capsules, and to 16% at three to four months. In Mindanao, a statistically significant reduction from 38% to 32% was seen in the prevalence of deficient to low SR (SR < 20 microg/dl) one to four months after distribution of vitamin A capsules. There was no overall reduction in the prevalence of vitamin A deficiency or deficient and low SR (SR < 20 microg/dl) in Luzon, but a significant interaction with stunting was observed in Luzon non-highly urbanized cities. Two aspects are of concern. First, the magnitude of the effect of high-dose vitamin A capsules on SR, and hence on the extent of reduction in deficiency, is limited. Second, the effect does not persist for six months, which is the interval between doses. Thus there is no decrease in the prevalence of deficiency over time. With more frequent dosing (especially to those most deficient in SR), a progressive reduction in vitamin A deficiency could, however, be expected; this hypothesis could be tested. The policy implication arising from these results is that a shift in resources is warranted. In areas of low prevalence of vitamin A deficiency, distribution of vitamin A capsules should be targeted to stunted children. In areas of high prevalence, vitamin A capsules should be distributed to children one to five years old at least three times a year.

Child, Preschool↗
PubMed2004

Evidence of increased substrate availability to in vitro-derived bovine foetuses and association with accelerated conceptus growth.

Changes in placental development have been associated with foetal abnormalities after in vitro embryo manipulations. This study was designed to investigate bovine conceptus development and substrate levels in plasma and fluids in in vivo- and in vitro-produced (IVP) concepti and neonates. In vivo-produced and IVP embryos were derived by established embryo production procedures. Pregnant animals from both groups were slaughtered on days 90 or 180 of gestation, or allowed to go to term. Conceptus and neonatal physical traits were recorded; foetal, maternal and neonatal blood, and foetal fluids were collected for the determination of blood and fluid chemistry, and glucose, fructose and lactate concentrations. Placental transcripts for specific glucose transporters were determined by quantitative RT-PCR. No significant differences in uterine and conceptus traits were observed between groups on day 90. On day 180, larger uterine, placental and foetal weights, and an increase in placental gross surface area (SA) in IVP pregnancies were associated with increased glucose and fructose accumulation in foetal plasma and associated fluids, with no differences in the expression of components of the glucose transporter system. Therefore, the enlarged placental SA in IVP pregnancies suggests an increase in substrate uptake and transport capacity. Newborn IVP calves displayed higher birth weights and plasma fructose concentrations soon after birth, findings which appeared to be associated with clinical and metabolic distress. Our results indicated larger concepti and increased placental fructogenic capacity in mid- to late IVP pregnancies, features which appeared to be associated with an enhanced substrate supply, potentially glucose, to the conceptus.

Animals↗
PubMed2002

Iodine fortification is related to increased weight-for-age and birthweight in children in Asia.

Severe iodine deficiency causes stunting and mental retardation in utero, but the relation between mild deficiency and child growth is not well known. The use of iodated salt in relation to anthropometric data was examined from recent survey data. After potential confounding factors had been controlled for, significant associations were seen in Bangladesh, India, Nepal, and Sri Lanka. The use of iodated salt was related to increased weight-for-age and mid-upper-arm circumference, most strongly in the second year of life, mainly affecting soft tissue (thinness). The relation with weight-for-age was greater among children of mothers with lower body mass index. The use of iodated salt was related to birthweight in Sri Lanka and in the Philippines, where iodized oil capsules given during pregnancy had a negative effect when used with high levels of iodine in salt. The associations generally were concentrated in large geographic areas, possibly because of interactions with other environmental factors (e.g., selenium and arsenic). The apparent growth response to iodine may reflect functional effects of mild deficiency, which is widespread, possibly including effects on brain development.

Aging↗
PubMed2001

Folate status among patients with non-small cell lung cancer: a case-control study.

BACKGROUND AND OBJECTIVES: This case control study explored the purported inverse relationship between folate status and lung cancer development. METHODS: Folate status of 46 postoperative non-small cell lung cancer (NSCLC) patients was compared to that of 44 non-cancer patients. Cancer patients had completed treatment > 3 months prior and had no evidence of cancer. Ineligibility criteria for all patients included (1) > 2 alcoholic drinks/day (2) ongoing tobacco use, or (3) folate supplementation > 400 microg/day. RESULTS: No differences were found between groups in serum and RBC folate after adjustment for age and use of folate-interfering medications: geometric means (GM) x /geometric standard error (GSE): 7.9 ng/ml x /1.1 vs. 7.8 ng/ml x /1.1, respectively (P = 0.91) for serum folate; 264 ng/ml x /1.1 vs. 263 ng/ml x /1.1, respectively (P = 0.97) for RBC folate. Age- and creatinine-adjusted homocysteine was no different between groups: GM x /GSE: 9.4 micromol/L x /1.0 vs. 8.6 micromol/L x /1.0, respectively (P = 0.17). No difference were seen in folate intake. Frequencies of the homozygous genotype for the MTHFR polymorphism, an enzyme important in folate metabolism and associated with a reduced risk of other cancers, were no different. CONCLUSIONS: This case control study does not support the hypothesis that low folate is an independent risk factor for NSCLC.

Aged↗
PubMed2001

Acetabular labral tears in the athlete.

Pathologic involvement of the acetabular labrum is an increasingly recognized phenomenon. Athletes involved in sports that require repetitive twisting or who suffer trauma to the hip are at risk of injury to the acetabular labrum. Injury mechanisms that include hyperextension, hyperflexion, or extremes of abduction place the labrum at particular risk. Symptoms may be acute in onset or, more commonly, insidious onset with persistence or escalation of symptoms. The orthopaedic surgeon evaluating patients with sports-related hip injuries needs to remain cognizant of intraarticular injuries within the hip and, in particular, injuries to the acetabular labrum. Further investigation is needed to fully define the functional importance of the acetabular labrum. Arthroscopic management has been successful in evaluation and management of acetabular labral tears.

Acetabulum↗
PubMed2001

Early failures in total knee arthroplasty.

Total knee arthroplasty is a predictable operation. Unfortunately, there is a subset of patients who do not do well and require revision surgery within the first 5 years. The purpose of the current study was to analyze the mechanisms of failure in patients who had revision surgery within 5 years of their index arthroplasty. Between 1986 and 1999, 440 patients with total knee arthroplasties were referred for revision surgery. An analysis of patients in whom the arthroplasties failed within 5 years of the index arthroplasty and the reasons for early failure were documented. Of the 440 patients who had revision surgery, 279 (63%) had revision surgery within 5 years of their index arthroplasty: 105 of the 279 patients with early failures (38%) had revision surgery because of infection; 74 (27%) had revision surgery because of instability; 37 (13%) had revision surgery because of failure of ingrowth of a porous-coated implant; 22 (8%) had revision surgery because of patellofemoral problems; and 21 (7%) had revision surgery because of wear or osteolysis. Only eight of the 279 patients with early failures (3%) had revision surgery because of aseptic loosening of a cemented implant. The remaining 12 patients had revision surgery because of miscellaneous problems. Host factors may prevent infection from ever being eradicated totally. The two other major patterns of failure in this series were failure of cementless fixation and instability. If all of the arthroplasties in the patients in this early failure group would have been cemented routinely and balanced carefully, the total number of early revisions would have decreased by approximately 40%, and the overall failures would have been reduced by 25%.

Arthroplasty, Replacement, Knee↗
PubMed2001

Effects of folate supplementation on two provisional molecular markers of colon cancer: a prospective, randomized trial.

OBJECTIVES: Dietary folate intake is inversely associated with the risk of colorectal cancer. This study investigated the effect of folate supplementation on genomic DNA methylation and DNA strand breaks in exons 5-8 of the p53 gene of the colonic mucosa, two provisional biomarkers of colon cancer. METHODS: Twenty subjects with adenomas were randomized to receive either folate (5 mg/day) or placebo for 1 yr after polypectomy. At baseline, 6 months and 1 yr, systemic and colonic measures of folate status were determined, as were the biomarkers mentioned earlier. RESULTS: Folate supplementation increased serum, red blood cell and colonic mucosal folate concentrations (p < 0.02). Folate supplementation also increased the extent of genomic DNA methylation at 6 months and 1 yr (p = 0.001), whereas placebo administration was associated with an increase in the extent of genomic DNA methylation only at 1 yr. Similarly, folate supplementation decreased the extent of p53 strand breaks in exons 5-8 at 6 months and 1 yr (p < 0.02), whereas placebo administration was associated with a decrease in the extent of p53 strand breaks only at 1 yr. CONCLUSIONS: Both of these provisional biomarkers of colon cancer underwent accelerated improvement at 6 months with folate supplementation. However, these markers also improved with placebo at 1 yr. Therefore, potential confounding factors that seem to modulate these biomarkers need to be identified and corrected in order for these markers to serve as suitable surrogate endpoints in folate chemoprevention trials.

Adenoma↗
PubMed2001

Colonic mucosal concentrations of folate are accurately predicted by blood measurements of folate status among individuals ingesting physiologic quantities of folate.

Folate status is inversely related to the risk of colorectal cancer. Whether conventional blood measurements of folate status accurately reflect folate concentrations in the colorectal mucosa has been a controversial topic. This is an important issue because accurate measures of folate status in the colorectal mucosa are important for ascertaining the risk of colorectal cancer in epidemiological studies and for determining the effects of folate supplementation in clinical trials. We examined whether conventional blood measurements of folate and a more sensitive, inverse indicator of systemic folate status, serum homocysteine, accurately reflect folate concentrations in human colonic mucosa obtained by endoscopic biopsy. Study subjects (n = 20) were participants in a randomized trial that investigated the effect of folate supplementation (5 mg daily for 1 year) on provisional molecular markers of colon cancer. Blood samples and biopsies of normal rectosigmoid mucosa were obtained at baseline, at 6 months, and at 1 year. Serum, RBC, and colonic mucosal folate and serum homocysteine concentrations were determined. Colonic mucosal folate concentrations correlated directly with serum folate concentrators at each time point (r = 0.572-0.845; P < 0.015) and with RBC folate concentrations at 6 months and 1 year (r = 0.747-0.771; P < 0.001). Colonic mucosal folate concentrations correlated inversely with serum homocysteine concentrations at each time point (r = -0.622-0.666; P < 0.008). Systemic measures of folate status did not correlate with colonic mucosal folate concentrations among individuals receiving supplemental folate. Our observations indicate that colonic mucosal concentrations of folate may be predicted accurately by blood measurements of folate status only among individuals not ingesting supraphysiological quantities of folate.

Adenoma↗
PubMed2000

Effects of dietary folate on intestinal tumorigenesis in the apcMin mouse.

Dietary folate appears to be inversely related to colorectal cancer risk. This study investigated the effects of dietary intervention with folate or the development of intestinal polyps in Min (Apc +/-) mice. Weanling Mil mice were fed diets containing 0, 2 (basal requirement), 8, or 20 mg folate/kg diet. At 3 and 6 months of dietary intervention, 50% of the mice from each group were sacrificed, and the small intestine and colon were analyzed for polyps and aberrant crypt foci (ACF). Serum folate concentrations accurately reflected dietary folate levels (P < 0.001). At 3 months no significant difference in the average number of total small intestinal polyps was observed among the four groups. However, increasing dietary folate levels significantly reduced the number of ileal, but not duodenal or jejunal, polyps in a dose-dependent manner (P-trend = 0.001); folate supplementation at 20 mg/kg diet was associated with a 68-78% reduction in the number of ileal polyps compared with the other three diets (P < 0.007). The number of ileal polyps was inversely correlated with serum folate concentrations (P = 0.03). At 3 months, increasing dietary folate levels significantly decreased the number of colonic ACF in a dose-dependent manner (P = 0.05); the control and two folate supplemented diets significantly reduced the number of colonic ACF by 75 100% compared with the folate-deficient diet (P < 0.04). The number of colonic ACF was inversely correlated with serum folate concentration (P = 0.05). No significant difference in the number of colonic adenoma was observed among the four groups at 3 months. At 6 months, no significant differences in the average number of total small intestinal, duodenal, and jejunal polyps, colonic adenomas, and colonic ACF wer observed among the four groups. However, the folate-deficient diet had 62-76% lower number of ileal polyps compared with the control and two folate-supplemented diets (P < 0.003). Serum folate concentrations, but not dietary folate levels, were directly correlated with the number of ilea polyps (P = 0.006). These data suggest that dietary folate supplementation suppresses the development of ileal polyps and colonic ACF in this model However, at later time points, folate supplementation appears to have an opposite effect on ileal polyps. These data generally support the role of folate in intestinal tumorigenesis suggested in epidemiological studies and chemical carcinogen animal models. Notwithstanding the limitations associated with this model, these data suggest that the optimal timing and dose of folate intervention need to be determined for safe and effective folate chemoprevention.

Adenoma↗
PubMed2000

Effects of dietary folate on DNA strand breaks within mutation-prone exons of the p53 gene in rat colon.

BACKGROUND & AIMS: Diminished folate status has been observed to increase colorectal cancer risk. Folate plays an important role in DNA synthesis and repair. This study investigated the effects of dietary folate on DNA strand breaks in the p53 and Apc genes, and how these changes are related to steady-state levels of the corresponding transcripts. METHODS: Three groups of rats were fed diets containing 0, 2 (basal requirement), or 8 mg folate/kg for 5 weeks. At each weekly time point, plasma and colonic mucosal folate concentrations were determined. Site-specific DNA strand breaks were assessed by semiquantitative PCR. Steady-state levels of messenger RNA were measured by semiquantitative RT-PCR. RESULTS: Dietary folate deficiency produced progressive DNA strand breaks within exons 5-8 of the p53 gene in rat colon (P<0.02). Accumulation of strand breaks was not observed in other exons of the p53 gene, in the Apc and beta-actin genes, or at the genomic level. Folate supplementation at 4 times the basal requirement significantly increased p53 integrity compared with the basal and deficient diets (P<0.05). p53 integrity in exons 5-8 was significantly correlated with folate status (P<0.03). Dietary folate deprivation progressively decreased, whereas supplementation increased, steady-state levels of p53 transcript over 5 weeks (P<0.05). No such changes were observed for the Apc gene. Steady-state levels of p53 transcript were significantly correlated with folate status and p53 integrity in exons 5-8 (P<0.002). CONCLUSIONS: These data provide a plausible mechanism by which folate deficiency promotes, and folate supplementation suppresses, colorectal carcinogenesis.

Adenomatous Polyposis Coli↗
PubMed2000

Folate and carcinogenesis: an integrated scheme.

Collectively, the evidence from epidemiologic, animal and human studies strongly suggests that folate status modulates the risk of developing cancers in selected tissues, the most notable of which is the colorectum. Folate depletion appears to enhance carcinogenesis whereas folate supplementation above what is presently considered to be the basal requirement appears to convey a protective effect. The means by which this modulation of cancer risk is mediated is not known with certainty, but there are several plausible mechanisms which have been described. Folate plays a major role in the formation of S-adenosylmethionine, the universal methyl donor, as well as in the formation of purine and thymidine synthesis for DNA and RNA. Therefore, most mechanistic studies performed to date have focused on alterations in DNA methylation, disruption of DNA integrity and disruption of DNA repair, all of which have been observed with folate depletion. These aberrations in DNA are believed to enhance carcinogenesis by altering the expression of critical tumor suppressor genes and proto-oncogenes. Recently, the role of a common polymorphism of the methylenetetrahydrofolate reductase gene has been highlighted as well. This review presents those mechanisms which are the most likely candidates to explain folate's effects and it proposes an integrated scheme to explain how these mechanisms might interact.

Animals↗
PubMed2000

Articulating versus static spacers in revision total knee arthroplasty for sepsis. The Ranawat Award.

Antibiotic laden spacer blocks frequently are used to treat an infected total knee arthroplasty. Static spacer blocks make exposure at reimplantation difficult secondary to quadriceps shortening. Unexpected bone loss attributable to migration of the spacer block also has been reported. To avoid these problems, a temporary articulating molded implant made of antibiotic cement was used in a consecutive series. The authors sought to determine whether its use would affect the reinfection rate, improve functional results, or prevent bone loss compared with static spacers. Twenty-five patients were treated with static nonarticulating spacers. Since 1996, 30 patients have been treated with tobramycin-laden articulating spacers. The knee arthroplasties in three patients treated with a static spacer became reinfected (12%). The knee arthroplasty in one patient with an articulating spacer became reinfected (7%). Fifteen of the 25 patients with static spacers had unexpected bone loss between stages. No appreciable bone loss could be measured in the patients who received articulating spacers. The average Hospital for Special Surgery score was 83 points in the patients with static spacers and 84 points for the patients with articulating spacers. Range of motion at final followup averaged 98 degrees in the patients who received static spacers and 105 degrees in the patients who received articulating spacers. Articulating spacers seem to facilitate reimplantation of infected total knee arthroplasty without additional risk of infection. Unexpected bone loss is no longer a concern with this two-stage technique. Articulating spacers offered no functional advantage over static spacers in this study group.

Anti-Bacterial Agents↗
PubMed2000

Effect of chronic alcohol consumption on total plasma homocysteine level in rats.

BACKGROUND: Chronic alcoholism in humans is associated with the development of hyperhomocysteinemia, the mechanism of which remains unclear. Among the causes of hyperhomocysteinemia is depletion of folate, vitamin B12, or vitamin B6. Population-based studies indicate that folate is the strongest vitamin determinant of hyperhomocysteinemia and, in most settings, folate supplementation effectively lowers elevated homocysteine levels. However, it is not clear whether folate deficiency is the cause of alcohol-related hyperhomocysteinemia. METHODS: In the present study, 10 male Sprague Dawley rats were fed ethanol-containing Lieber-DeCarli diets with 13 mg of folic acid per kilogram of diet. This represents a folate intake more than 20 times the basal requirement. Ethanol represented 36% of total energy, which yielded a concentration of 6.2% (vol/vol). The same number of rats were pair-fed with isocaloric control diets that contained an identical level of folate in which ethanol was entirely replaced by maltodextrin. RESULTS: At the end of 4 weeks, alcohol-fed rats did not show any significant reduction in plasma or hepatic folate concentrations, plasma pyridoxal-5'-phosphate concentration, or plasma vitamin B12 concentration. On the other hand, alcohol-fed rats were significantly hyperhomocysteinemic (17.24 +/- 4.63 micromol/liter,p < 0.01) compared to the nonalcohol group (10.73 +/- 2.76 micromol/liter). Alcohol-fed rats also had a significantly lower hepatic S-adenosylmethionine and higher hepatic S-adenosylhomocysteine levels. CONCLUSIONS: Chronic alcohol consumption produces hyperhomocysteinemia by a mechanism that is related to interference with one-carbon metabolism, and not through vitamin depletion.

Alcohol Drinking↗
PubMed2000

Genomic DNA hypomethylation, a characteristic of most cancers, is present in peripheral leukocytes of individuals who are homozygous for the C677T polymorphism in the methylenetetrahydrofolate reductase gene.

DNA methylation is an epigenetic feature of DNA that influences cellular development and function, and aberrations of DNA methylation are a candidate mechanism for the development of cancer. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, the methyl donor for methionine synthesis and the precursor of S-adenosylmethionine. S-adenosylmethionine is the universal methyl donor for methylation reactions, including that of DNA methylation. In the present study, we investigated whether a common C677T mutation in the MTHFR gene, which results in reduced enzyme activity in vitro, affects genomic DNA methylation. We selected 9 subjects homozygous for the wild-type MTHFR and 10 subjects homozygous for the mutation (T/T). Genomic DNA methylation was determined by an established enzymatic assay that measures the capacity of DNA to accept methyl groups in vitro, which is inversely related to endogenous methylation. DNA from subjects with the T/T MTHFR genotype had a significantly higher methyl group acceptance capacity (12,615 +/- 1836 dpm/2 microg of DNA) compared with wild-type MTHFR (7843 +/- 1043 dpm/2 microg of DNA; P < 0.05), indicating DNA hypomethylation in the T/T genotype. Furthermore, DNA methylation was directly and significantly related to RBC folate concentrations in persons with the T/T genotype, but not in those with wild-type MTHFR. These data are consistent with prior observations, which suggest that the T/T genotype is associated with impaired MTHFR activity in vivo and that the cellular impact of this impairment is determined, in part, by folate status. The relationship of genomic DNA hypomethylation in persons with the T/T MTHFR genotype to the development of cancer remains to be defined.

Adult↗
PubMed1999

Nutritional strategies in the prevention of colorectal cancer.

A variety of dietary factors have been implicated as agents that can modulate the development of malignancies of the gastrointestinal tract, particularly colorectal cancer. The effects of fat, red meat, fruits, vegetables, and alcohol on colorectal carcinogenesis have been examined extensively and appear to play substantial roles. Although fiber may play a protective role, recent studies raise the question of whether the protection is conveyed by other components in fiber-laden foods. Folate, selenium, calcium, and omega-3 fatty acids have emerged as factors more recently but may be equally important agents in nutritional chemoprevention, whereas the role of antioxidant vitamins is less certain. Until more firm data are available, the dietary recommendations provided by the American Cancer Society and the National Cancer Institute are appropriate for use in counseling patients on this issue.

Antioxidants↗