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Homocysteine as a risk factor for cardiovascular and related disease: nutritional implications
- Donald G. Weir, John M. Scott
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- Journal:
- Nutrition Research Reviews / Volume 11 / Issue 2 / December 1998
- Published online by Cambridge University Press:
- 14 December 2007, pp. 311-338
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The objectives were firstly to assess the evidence that homocysteine is a significant and independent risk factor for vascular disease with special reference to cardiovascular disease, and secondly to evaluate the evidence that a food staple fortified with folic acid will reduce this problem on a population basis.
The structure of plasma homocysteine (tHcy) is described. Homocysteine, a highly reactive compound, is synthesized from the amino acid, methionine, and is metabolized by two pathways, the catabolic transsulphuration route via cystathionine β-synthase (EC 4.2.1.22) and the remethylation path using 5-methyltetrahy-drofolate polyglutamate, the product of 5,10-methylenetetrahydrofolate reductase (MTHFR; EC 1.1.1.171), via the cobalamin dependent enzyme, methionine synthase (MS; EC 2.1.1.13).
The mechanisms whereby hyper-tHcy is produced include both increased rates of synthesis and decreased metabolism. The latter may occur owing to nutritional deficiency of the vitamin cofactors which are necessary for the normal function of the metabolic enzymes. In particular, folate is required for methylene reductase, pyridoxal phosphate for cystathionine synthase and cobalamin for methionine synthase. When these vitamins are deficient hyper-tHcy is induced and this occurs especially in the elderly. Alternatively, a variant form of methylene reductase has recently been described which occurs in nearly 10% of the normal population. This variant is associated with hyper-tHcy, especially in situations associated with a low folate nutritional status.
Meta-analysis of both retrospective case-control studies, nested prospective case-control surveys and a secondary trial of mortality in postmyocardial infarct patients have shown that the association of hyper-tHcy with vascular disease is beyond doubt. This has been further supported by direct assessments of the degree of vascular disease in the carotid brachial and aortic arteries in relation to tHcy levels. Furthermore, treatment with a cocktail of the vitamin cofactors has produced lowering of tHcy levels and regression of the vascular disease in the carotid arteries of affected individuals.
Suggested pathogenic mechanisms in vascular disease induced by hyper-tHcy include vascular endothelial cell dysfunction, smooth muscle proliferation and derangements of normal intravascular regulation mechanisms. A variety of clinical conditions are known to be associated with a high incidence of thromboembolic complications. Some of these are associated with hyper-tHcy.
Low physiological doses of folic acid, as well as pharmocological doses, lower tHcy. However, because of the poor bioavailability of food folate (50%) and the considerable chemical instability of the naturally occurring reduced forms of folate, in most people it would require unacceptably high consumption of green vegetables to accomplish the necessary increase in intracellular folate and reduction in tHcy. Accordingly, folic acid, the nonreduced synthetic form of the vitamin, which is 100% bioavailable and chemically extremely stable, should be added to a food staple such as flour to ensure maximum protection for most of the population.
Postprandial serum folic acid response to multiple doses of folic acid in fortified bread
- Mary R. Sweeney, Joseph McPartlin, Donald G. Weir, Leslie Daly, John M. Scott
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- Journal:
- British Journal of Nutrition / Volume 95 / Issue 1 / January 2006
- Published online by Cambridge University Press:
- 08 March 2007, pp. 145-151
- Print publication:
- January 2006
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The benefit of the introduction of mandatory folic acid fortification of all flour products in the USA in 1998 has been amply demonstrated in a reduction of neural tube defect births. Doubt has been cast on the actual level of fortification and recent calculations have shown that the level of folic acid fortification is likely to have been over twice the amount mandated. The implication of this is that a greater proportion of the population are likely to have consumed folic acid at >1mg/d, the Food and Drug Administration safe upper level of intake. Using the criteria of appearance of synthetic folic acid in serum, the objective of this pilot study was to investigate the consequences of consumption of baked bread preparations containing 1mg folic acid. Four healthy adult volunteers undertook each dosing schedule 2 weeks apart. This consisted of a single dose of 1000μg, two doses of 500μg, three doses of 333μg, five doses of 200μg and, finally, ten doses of 100μg. Serum was collected pre- and postprandially and analysed for synthetic folic acid by a combined HPLC–microbiological assay for folic acid. Folic acid appeared in all subjects at all test doses, with the effect more pronounced as the standard dose was administered in smaller amounts over the test period. Approaches to optimise folic acid intake in target populations as part of a universal fortification strategy should take into consideration the potential hazard of over-exposure in groups consuming high amounts of flour-based products.
Evidence of unmetabolised folic acid in cord blood of newborn and serum of 4-day-old infants
- Mary R. Sweeney, Joseph McPartlin, Donald G. Weir, Sean Daly, Kristina Pentieva, Leslie Daly, John M. Scott
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- Journal:
- British Journal of Nutrition / Volume 94 / Issue 5 / November 2005
- Published online by Cambridge University Press:
- 08 March 2007, pp. 727-730
- Print publication:
- November 2005
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Oral folic acid above certain threshold doses results in unmetabolised folic acid in serum. This raises a number of public health safety issues, principally the potential to mask pernicious anaemia; more recently the theoretical potential for high-dose folic acid to promote cancer has been highlighted. In this paper we set out to examine the appearance of unmetabolised folic acid both in cord blood from newborn full-term and premature infants and serum from 4-d-old infants post-formula feeding. Blood was collected from the umbilical cord of eleven infants in the delivery room immediately after birth. A follow-up serum sample (n 9) was collected 4d later from infants post-formula feeding. We detected unmetabolised folic acid in cord blood from all infants at birth. In addition, unmetabolised folic acid was present in serum of seven infants post-formula feeding, six of which had increased from birth. Our results imply that infants in Ireland, which does not yet have mandatory fortification, could potentially have circulatory unmetabolised folic acid at the time of birth. We do not know if the presence of folic acid in cord blood will have any adverse consequences. However, if theoretical safety concerns are borne out by future research, the likelihood is that the longer the exposure the more likely the potential for harm. This would also be the case in infants exposed to unmetabolised folic acid as a result of formula feeding.
11 - Blood group phenotypes and infectious diseases
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- By C. Caroline Blackwell, Discipline of Immunology and Microbiology and Hunter Immunology Unit, University of Newcastle, Newcastle, Australia; Institute for Scientific Evaluation of Naturopathy, University of Cologne, Cologne, Germany, Donald M. Weir, Department of Medical Microbiology, The Medical School, University of Edinburgh, Abdulhamid M. Alkout, Department of Medical Microbiology, The Medical School, University of Edinburgh, Omar R. Elahmer, Department of Medical Microbiology, The Medical School, University of Edinburgh, Doris A. C. MacKenzie, Department of Medical Microbiology, The Medical School, University of Edinburgh, Valerie S. James, Department of Medical Microbiology, The Medical School, University of Edinburgh, J. Matthias Braun, Department of Medical Microbiology, The Medical School, University of Edinburgh; Institute for Scientific Evaluation of Naturopathy, University of Cologne, Cologne, Germany, Osama M. Almadani, Department of Medical Microbiology, The Medical School University of Edinburgh; Forensic Medicine Unit, Edinburgh, Scotland, United Kingdom, Anthony Busuttil, Forensic Medicine Unit, The Medical School University of Edinburgh, Edinburgh, Scotland, United Kingdom
- Edited by Richard Bellamy, Kintampo Health Research Centre, Ghana
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- Book:
- Susceptibility to Infectious Diseases
- Published online:
- 14 August 2009
- Print publication:
- 22 December 2003, pp 309-336
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Summary
INTRODUCTION
The first observations on associations between blood groups and infectious diseases were made in the 1950s, but the underlying mechanisms were not elucidated for many years. This could have been due to limited explanations for the epidemiological findings or to conflicting reports of associations between different blood groups with the same disease. An example of the latter is the large numbers of papers on Helicobacter pylori and ABO or Lewis blood groups/secretor status during the past few years which have reported inconsistent or conflicting results. Because determination of blood groups is a relatively simple and inexpensive procedure, many investigators have used it for quick “simple” studies without consideration of possible confounding factors. For all studies on blood groups and infection, the following points (gained with the experience of hindsight) need to be considered in planning or assessment of surveys:
The disease or organism under investigation needs to be clearly defined. Severity of the symptoms should be also be considered, e.g., differentiation of cases of Escherichia coli O157 infection between patients with uncomplicated diarrhoeal disease and those that develop haemolytic uraemic syndrome (HUS) (Blackwell et al., 2002).
It should be made clear that the investigation examined an outbreak or defined epidemic due to a particular strain in contrast to sporadic cases which could be due to strains with different antigenic characteristics or virulence factors.
Different populations express different quantities of antigens such as H, Lewisa, or Lewisb.
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