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Biomedical subjects

J McPartlin

Publications and source records attributed to J McPartlin.

32 records · Page 2Linked to original sources
PubMed1997

Plasma homocysteine, a risk factor for cardiovascular disease, is lowered by physiological doses of folic acid.

Elevated plasma homocysteine, an independent risk factor for cardiovascular disease (CVD) can be lowered by administration of pharmacological doses of folic acid. The effect of lower doses in apparently normal subjects is currently unknown but is highly relevant to the question of food fortification. Healthy male volunteers (n = 30) participated in a chronic intervention study (26 weeks). Folic acid supplements were administered daily at doses increasing from 100 micrograms (6 weeks), to 200 micrograms (6 weeks), to 400 micrograms (14 weeks). Fasting blood samples collected before, during and 10 weeks post intervention were analysed for plasma homocysteine, serum and red-cell folate levels. Results, expressed as tertiles of baseline plasma homocysteine concentration, showed significant (p < or = 0.001) homocysteine lowering in the top (10.90 +/- 0.83 mumol/l) and middle (9.11 +/- 0.49 mumol/l) tertiles only. In the low tertile, where the mean baseline homocysteine level was 7.07 +/- 0.84 mumol/l, no significant response was observed. Of the three folic acid doses, 200 micrograms appeared to be as effective as 400 micrograms, while 100 micrograms was clearly not optimal. There is thus a minimal level of plasma homocysteine below which folic acid has no further lowering effect, probably because an optimal folate status has been reached. A dose as low as 200 micrograms/day of folic acid is effective in lowering plasma homocysteine concentrations in apparently normal subjects. Any public health programme for lowering homocysteine levels, with the goal of diminishing CVD risk, should not be based on unnecessarily high doses of folic acid.

Adult↗
PubMed1996

A combined high-performance liquid chromatographic-microbiological assay for serum folic acid.

An assay of folic acid in human serum is described involving HPLC fractionation of deproteinized serum prior to Lactobacillus casei assay. High specific activity [3H]folic acid is added as internal standard to 1 ml serum prior to deproteinization with perchlorate and an aliquot is applied to a C18 reverse-phase HPLC column. The folic acid fraction was assayed by L. casei microtiter plate assay. Intra- and interassay variations (CV) were 5.5 and 7.5% respectively for sera (n = 10) spiked with folic acid. The percentage recovery for folic acid additions of 10 and 20 ng/liter were 105.2 and 103.7%, respectively. The lower limit of detection was 1 ng folic acid/ml serum. Folates other than folic acid and 5-methyltetrahydrofolate were not detected. The assay permitted serial measurements to be made of folates in serum following an oral dose.

Administration, Oral↗
PubMed1994

Folic acid metabolism and mechanisms of neural tube defects.

Folate acts as a cofactor for enzymes involved in DNA and RNA biosynthesis. Folate is also involved in the supply of methyl groups to the so-called methylation cycle, which uses methionine and makes homocysteine. The folate cofactor, N5-methyltetrahydrofolate, donates its methyl group to a vitamin B12-dependent enzyme, methionine synthase, which recycles homocysteine back to methionine. The cell's ability to methylate important compounds such as proteins, lipids and myelin will be compromised by deficiency of folate or vitamin B12, resulting in impaired cellular function. Methionine synthase plays another role: it converts circulating N5-methyltetrahydrofolate into tetrahydrofolate. The latter but not the former can act as a substrate for polyglutamate synthase, thereby becoming retained in the cell as polyglutamate. Interruption of DNA biosynthesis or methylation reactions could prevent the proper closure of the neural tube. Such inhibition could be caused by simple deficiency of either folic acid or vitamin B12. Studies comparing serum folate and vitamin B12 status in women who have had an affected pregnancy to those in control women indicate no difference between the two groups and show that most cases are not clinically deficient in either vitamin. A small number of studies using the level of folate in red blood cells, which is a better reflection of tissue stores, confirm this, suggesting instead a metabolic impairment in the biochemical functions of one of these vitamins. The trials using folic acid to prevent neural tube defects thus seem to be effectively overcoming a metabolic block rather than treating folate deficiency.

Female↗
PubMed1993

Reversed-phase high-performance liquid chromatographic method for the quantitation of endogenous folate catabolites in rat urine.

We describe a reversed-phase high-performance liquid chromatographic procedure for the analysis of rat urine for p-aminobenzoylglutamate (pABGlu) and its acetamido derivative (p-acetamidobenzoylglutamate, apABGlu). These two catabolites arise following the in vivo cleavage of the folate molecule at the C-9-N-10 bond. Known quantities of high-specific-activity tritiated forms of the catabolites are added as internal standards to aliquots of rat urine. Following preliminary sample clean-up on C18 Sep-Pak cartridges, including derivatisation in the case of pABGlu, the urinary extracts are quantitated by HPLC. The present assay makes possible for the first time the determination of endogenous folate breakdown in the rat.

4-Aminobenzoic Acid↗
PubMed1993

Accelerated folate breakdown in pregnancy.

During pregnancy there is an increased requirement for folate. We studied pregnant women to determine whether the increased requirement might be due to enhanced catabolism of the vitamin. Six normal pregnant women provided 24 h urine samples during each trimester and postpartum while taking a defined diet. The urines were assayed for the folate breakdown products p-amino-benzoylglutamate (pABGlu) and its acetylated derivative p-acetamidobenzoylglutamate (apBGlu) by high-pressure liquid chromatography. Mean concentration of excreted apABGlu rose significantly in the second trimester but returned to baseline postpartum. This increased rate of folate catabolism produces an extra demand for dietary folate of about 200-300 micrograms per day in pregnant women, a considerably greater value than recent recommendations.

4-Aminobenzoic Acid↗
PubMed1992

The quantitative analysis of endogenous folate catabolites in human urine.

In man folates are catabolized and excreted as inactive cleaved degradation products, a mixture of pteridines and p-aminobenzoylglutamate (pABGlu) or its acetamido derivative (apABGlu). The daily rate of excretion represents the inescapable use of the vitamin in metabolic activity and thus has implications for determining the recommended dietary allowance for the vitamin. Furthermore, the rate of catabolism has been suggested to rise during pregnancy and in certain disease states. A method is described for the quantitative extraction and assay of the folate catabolites pABGlu and apABGlu in human urine. Aliquots of 24-h urine collections are acidified and applied to columns of Dowex 50W cation-exchange resin. The catabolites are selectively batch-eluted with increasing concentrations of HCl. The fraction containing pABGlu is diazotized and then applied to a C18 Sep Pak column for further purification and concentration. The fraction containing apABGlu was deacetylated and reapplied to the Dowex column and then treated identically to the pABGlu fraction. The methanolic concentrates of both extracts were evaporated to dryness and reconstituted with water and pABGlu was regenerated by reductive cleavage of the diazotized material with Zn/HCl. The extracts of the two catabolites were separated by reverse-phase HPLC using a Radial Pak C18 column. Recovery of isolated material was monitored by the addition of high specific activity tritiated labels of both compounds added as internal standards to all urine aliquots prior to purification and analysis.

4-Aminobenzoic Acid↗
PubMed1988

Methylation deficiency causes vitamin B12-associated neuropathy in the pig.

Pigs were treated with N2O which is known to impair vitamin B12 function in vivo. Such pigs demonstrated an inability to gain weight, progressive ataxia, and spinal neuropathy. The ataxia was totally and the neuropathy partially preventable by dietary methionine supplementation. Methionine synthase activity was inhibited in both the liver and brain. There was a marked elevation of S-adenosylhomocysteine in the neural tissues and a concomitant failure of S-adenosylmethionine to rise and thus maintain the methylation ratio, except when supplementary dietary methionine was added. In contrast, the methylation ratio in the rat was affected to a lesser extent. The neuropathy, it is suggested, is caused by raised S-adenosylhomocysteine levels in neural tissue; as a result, the methylation ratio is inverted and S-adenosylmethionine-dependent methylation reactions are inhibited.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1982

Hypercalcitoninaemia in medullary carcinoma of the thyroid and other malignancies: value of calcitonin as tumour marker.

Elevated plasma calcitonin was detected by radioimmunoassay in 19 of 99 unselected cancer patients (19%). The frequency of hypercalcitoninaemia in patients with tumours of lung, uterus, gastrointestinal tract, and urinary bladder was about 40%, in carcinoma of the breast 18%, and in carcinoma of the skin 4%. In 8 patients with bone metastases, 4 were hypercalcitoninaemic. None of 19 patients with non-malignant disorders had elevated plasma calcitonin. The highest plasma calcitonin level in cancer patients was 8200 ng/l. Urinary cyclic AMP was elevated in patients with hypercalcitoninaemia as compared with patients with normal plasma calcitonin. All 6 patients with medullary carcinoma of the thyroid had very high plasma calcitonin levels: more than 50000 ng/l in five and 30000 ng/l in one patient. Of the family members of these patients, raised plasma calcitonin was detected after stimulation with oral alcohol in 6 of 12. It is concluded that plasma calcitonin levels in excess of 10000 ng/l suggest the presence of medullary carcinoma of the thyroid, while levels below 10000 ng/l have a poor diagnostic value but should alert the clinician to look for a possible malignancy.

Calcitonin↗
PubMed1980

Tumor hypercalcemia and "ectopic hyperparathyroidism".

1. All available evidence for and against the concept of ectopic hyperparathyroidism, including 307 case reports of tumor hypercalcemia, was collated. 2. Of 104 combined cases of tumors of the kidney, lung, liver, head, neck and esophagus, 91 (88%) were in men. 3. The parathyroid glands were examined in 170 of 307 cases and parathyroid hyperplasia or adenoma were described in 34 cases. This high frequency may reflect higher likelihood of reporting such association. 4. Analysis of the histological pattern of tumors associated with humoral hypercalcemia revealed a marked association with certain histological types in different organs, such as clear-cell carcinoma of the kidney and ovary, hepatocarcinoma and cholangiocarcinoma, pheochromocytoma, and squamous-cell carcinoma of the lung, head, neck, esophagus, and urogenital tract. This histological correlation is not compatible with the "random derepression" hypothesis. 5. The existence of tumor humoral hypercalcemia is well documented, as 61 of 74 operated patients sustained remission of hypercalcemia following tumor removal. 6. The evidence for ectopic PTH being produced by tumor is not well documented and is based on conflicting radioimmunoassay results. We have found no case in the literature which fulfilled unequivocally criteria of ectopic production of biologically active PTH. There has been a lack of studies of tumors for the presence of biologically active hypercalcemic factors because only relatively insensitive bioassays are available at present. More information is also required on microscopic bone changes in tumor hypercalcemia as x-ray studies alone are inadequate. 7. On the basis of the present evidence, causes and mechanisms of tumor hypercalcemia are likely to be multiple.

Adrenal Gland Neoplasms↗
PubMed1978

Humoral hypercalcaemia in a patient with renal-cell carcinoma.

In a patient with hypercalcaemia secondary to a renal-cell carcinoma, a concentration gradient of bioactivity was detected between the tumour effluent vein and the peripheral venous blood that was capable of stimulating adenylate cyclase in bone cells. Immuno-reactive PTH was undetectable in the tumour effluent and in the peripheral blood. It is concluded that a non-parathyroid humoral factor whose action involved cyclic AMP stimulation was responsible for the hypercalcaemia.

Adenocarcinoma↗
PubMed1978

Early effects of parathyroid hormone on rat calvarian bone alkaline phosphatase.

Using a quantitative cytochemical method, explanted calvaria of 1- to 6-day-old male rats were used for the measurement of the in situ effect of parathyroid hormone (PTH) on the activity of alkaline phosphatase (AP) in the calcifying bone. The earliest effect of PTH was observed at 4--7 min. The direction and magnitude of the response of AP was dependent on the age of the animal and on the dose of PTH (50 fg-500 pg/ml). The calvaria of younger animals (2-days old) showed a decrease in AP activity, whereas in 5-day-old rats, AP activity was stimulated by PTH. In 5-day-old animals, the linear dependence of ATP stimulation on the PTH dose in the concentration range 50 fg-50 pg/ml could serve as the basis for a bioassay of a high sensitivity. The age-dependent response of AP to PTH may reflect the difference between the early and late stages of the calcification process. Our observations may reconcile conflicting reports on the effect of PTH on bone AP.

Aging↗