Defectos del tubo neural y del ácido fólico: recorrido histórico de una intervención preventiva altamente efectiva / Neural tube defects and folic acid: a historical overview of a highly successful preventive intervention

Este artículo describe de forma comprehensiva parte del devenir histórico que han tenido, el conocimiento médico de los defectos del tubo neural (DTN) y el descubrimiento de la vitamina B9 o ácido fólico, así como algunos de los acontecimientos investigativos relevantes que a través de varios siglos definieron las relaciones entre la comprensión de la embriología del sistema nervioso central, el descubrimiento de la vitamina, la correlación del ácido fólico con la proliferación celular y finalmente el desarrollo de medidas preventivas de este tipo de defectos. Se pretende, a través de esta narrativa, exponer los conceptos históricamente relevantes que sustentan las acciones de índole clínico y de impacto poblacional que previenen los DTN a través del consumo preconcepcional de ácido fólico.

This article gives a broad overview of part of the historical evolution of medical knowledge about neural tube defects (NTD) and the discovery of vitamin B9 or folic acid, as well as some relevant research events that, over the course of several centuries, defined the relationships between the understanding of central nervous system embryology, the discovery of the vitamin, the correlation between folic acid and cell proliferation and lastly the development of preventive measures for this type of defects. This narrative allows us to examine historically relevant concepts underlying clinical actions with a populational impact that prevent NTDs via folic acid consumption prior to conception.

[Neural tube defects and folic acid: a historical overview of a highly successful preventive intervention]. / Defectos del tubo neural y del ácido fólico: recorrido histórico de una intervención preventiva altamente efectiva.

This article gives a broad overview of part of the historical evolution of medical knowledge about neural tube defects (NTD) and the discovery of vitamin B9 or folic acid, as well as some relevant research events that, over the course of several centuries, defined the relationships between the understanding of central nervous system embryology, the discovery of the vitamin, the correlation between folic acid and cell proliferation and lastly the development of preventive measures for this type of defects. This narrative allows us to examine historically relevant concepts underlying clinical actions with a populational impact that prevent NTDs via folic acid consumption prior to conception.

Making birth defects 'preventable': pre-conceptional vitamin supplements and the politics of risk reduction.

Since the mid-1990s, governments and health organizations around the world have adopted policies designed to increase women's intake of the B-vitamin 'folic acid' before and during the first weeks of pregnancy. Building on initial clinical research in the United Kingdom, folic acid supplementation has been shown to lower the incidence of neural tube defects (NTDs). Recent debate has focused principally on the need for mandatory fortification of grain products with this vitamin. This article takes a longer view, tracing the transformation of folic acid from a routine prenatal supplement to reduce the risk of anaemia to a routine 'pre-conceptional' supplement to 'prevent' birth defects. Understood in the 1950s in relation to social problems of poverty and malnutrition, NTDs were by the end of the century more likely to be attributed to individual failings. This transition was closely associated with a second. Folic acid supplements were initially prescribed to 'high-risk' women who had previously borne a child with a NTD. By the mid-1990s, they were recommended for all women of childbearing age. The acceptance of folic acid as a 'risk-reducing drug' both relied upon and helped to advance the development of preventive and clinical practices concerned with women's health before pregnancy.

[History of the therapy of pernicious anemia]. / Az anaemia perniciosa terápiájának története.

Increased blood cell regeneration in exsanguinated experimental animals treated either with liver or with aqueous liver extracts was reported by Whipple and by Jeney and Jobling, respectively. These findings stimulated Minot and Murphy to provide evidence for the efficacy of liver against anaemia in clinical studies. After oral administration of liver (45-50 g per day) for 45 patients with anaemia perniciosa improvement of the hematological status was demonstrated. Consequently, for proving the therapeutic value of liver therapy Whipple, Minot and Murphy received Nobel price in 1934. The isolation of the antianemic factor from the liver has been succeeded in 1948 and designated as vitamin B12. At the same time Lucy Wills applied yeast for the treatment of pregnant women with anemia related to undernourishment. The conclusions of this study inspired the discovery of folate. The detailed investigation of the mode of action of vitamin B12 and folate enriched our knowledge in the area of pathophysiology and extended the clinical application of these two drugs.

A history of the isolation and identification of folic acid (folate).

In the 1930s, Lucy Wills identified a 'new hemopoietic factor' in yeast and liver which cured tropical macrocytic anemia in humans and experimental anemia in monkeys. Janet Watson and William B. Castle named the unknown substance, which would ultimately become a form of folate, 'Wills' factor'. Further studies with this unknown substance showed that it was active against nutritional pancytopenia in monkeys and experimental anemia in chicks, leading to various designations such as vitamin M (monkey) and vitamin B(c) (chick). Other factors with growth-promoting activity for microorganisms such as Lactobacillus casei were given the interim names including folic acid - in recognition of extracts from leafy greens. Competing pharmaceutical research groups headed by Robert Stokstad at Lederle Laboratories and Joseph John Pfiffner at Parke-Davis Research Laboratory independently isolated factors bearing the biological properties of Wills' factor and other unknown related factors including folic acid, Lederle Laboratories from a bacterial culture and Parke-Davis Laboratory from yeast and liver as a conjugate of folate. The new vitamin then was crystallized, chemically identified, and synthesized as pteroylglutamic acid and named folic acid between 1943 and 1945. Further studies of the monoglutamic folic acid and the yeast isolate polyglutamyl folate followed through the 1950s and to the present.

Folic acid food fortification-its history, effect, concerns, and future directions.

Periconceptional intake of folic acid is known to reduce a woman's risk of having an infant affected by a neural tube birth defect (NTD). National programs to mandate fortification of food with folic acid have reduced the prevalence of NTDs worldwide. Uncertainty surrounding possible unintended consequences has led to concerns about higher folic acid intake and food fortification programs. This uncertainty emphasizes the need to continually monitor fortification programs for accurate measures of their effect and the ability to address concerns as they arise. This review highlights the history, effect, concerns, and future directions of folic acid food fortification programs.

Lucy Wills (1888-1964): the life and research of an adventurous independent woman.

Lucy Wills was one of a pioneering generation of women in medicine and medical research in England. After a double first honours degree in botany and geology from Cambridge in 1911, she travelled to South Africa, where she worked as a nurse during the First World War. Wills then gained a medical degree in London in 1920. By the late 1920s she had developed an interest in haematology and began travelling to India to investigate pernicious anaemia in pregnancy. There she identified a substance often called 'the Wills' factor', which was later recognised as folic acid. Wills undertook a placebo trial of routine iron supplementation in pregnant women during the Second World War, hampered, but not stopped, by bombing. In retirement, she continued to study nutritional effects on health in South Africa and Fiji.

Oster rediscovered--mega-dose folate for symptomatic atherosclerosis.

Thirty years ago, Kurt Oster promulgated the avant-garde theory that bovine xanthine oxidase, absorbed intact from homogenized milk, promoted atherogenesis by oxidatively damaging membrane plasmalogens. Under the mistaken impression that folic acid is a xanthine oxidase inhibitor, he administered high-dose folate (80 mg daily) to hundreds of patients afflicted with symptomatic atherosclerosis, and reported marked improvements in angina, intermittent claudication, and wound healing; he also suspected that this regimen was decreasing heart attack risk. The xanthine oxidase theory has since fallen by the wayside, but there is now evidence that folic acid can lessen endothelial oxidative stress by improving the function of "uncoupled" nitric oxide synthase deficient in tetrahydrobiopterin. In light of these new findings, a properly controlled assessment of Oster's mega-dose folate therapy is warranted.

Fortification of industrialized foods with vitamins

Vitaminas são nutrientes essenciais à vida. Hábitos alimentares inadequados, alto consumo energético e falhas no metabolismo levam a deficiências de micronutrientes, que afetam mais de dois bilhões de pessoas mundialmente. O consumo, cada vez maior, de alimentos industrializados, somado à baixa estabilidade das vitaminas, têm induzido à prática de adição de nutrientes aos alimentos processados. Esta revisão discute terminologia, disponibilidade, ingestão e risco de hipervitaminose devida ao consumo desses produtos, e a importância nutricional dos de alimentos fortificados com vitaminas. A adição de nutrientes deve ocorrer em alimentos que, efetivamente, participem da dieta da população alvo e deve obedecer às necessidades reais de segmentos significativos da população. No Brasil, se encontra, disponível em supermercados, um total de 166 produtos enriquecidos com vitaminas. Um estudo de coorte de 10 anos, desenvolvido na Alemanha, com crianças e adolescentes, comprovou que 90% dos pesquisados utilizaram, pelo menos, um alimento fortificado. Ao longo do período estudado, observou-se o consumo de 472 diferentes produtos fortificados. O enriquecimento de alimentos, entretanto, deveria basear-se nas necessidade de cada país, e, se possível, nas necessidades regionais, que variam de região a região. Na Dinamarca, por exemplo, durante o inverno, e principalmente nos idosos, a vitamina D necessita ser adicionada aos alimentos, para que aumente o seu consumo. No Brasil, diferentemente, não há evidências de necessidade de fortificação de alimentos com essa vitamina. Apesar disso, uma investigação mostrou que, de 76 produtos lácteos enriquecidos, 37 continham vitamina D. A fortificação de alimentos é uma estratégia importante para resolver problemas de deficiência nutricional, porém também pode ocasionar muitos danos à saúde.

The significance of folic acid for epilepsy patients.

The following is a comprehensive review of the current understanding of the many important roles of folic acid in the health of patients with epilepsy. A review of past and current literature reveals that folic acid plays important roles in the areas of hematology, neurology, development, and reproduction. Also highlighted are new areas for exploration.

Jewels in the crown: The Medical Journal of Australia's 10 most-cited articles.

According to data from the Institute for Scientific Information (ISI), the most-cited MJA article is Cade's ground-breaking report on the effect of lithium in mania (1949; 888 citations), followed by Marshall et al's reports on the role of Helicobacter pylori in gastroduodenal disease (1985; 766 and 523 citations, respectively). Others in the "top 10" span decades and disciplines; all have a common grounding in Australian data of global relevance.

Ácido fólico (I) / Folic acid

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Homocysteine and human reproduction.

Homocysteine is an amino acid that is capable of disturbing the proper growth of cells. Hyperhomocysteinemia can lead to a non-closure of the neural tube. The underlying basis is a derangement of homocysteine metabolism due to a missense mutation of the MTHFR enzyme that has to catalyze the folate metabolic cycle furnishing sufficient methyl groups for DNA and tRNA synthesis. Folate can overcome the dysfunction of the mutation and the decreased activity of the thermolabile MTHFR. Homocysteine is also recognized as an independent risk factor for obstetrical vascular disease that can manifest itself in maternal veins (thrombosis), arteries (preeclampsia) or spiral arteries supplying the placenta (placental abruption). Low vitamin status (folic acid, vitamin B6 and B12), hyperhomocysteinemia, the MTHFR gene mutation C677T, and thrombotic factors like Protein C, Protein S. antithrombin III, factor V Leiden and Activated Protein C, are alone or in combination high risk factors for obstetrical vascular disease. Their values can be modulated by B-vitamin status and could be able to prevent disease from occurring or recurring. Placebo-randomized trials have been done in neural tube defects but are urgently needed in the vascular area. The common denominator of the effect of homocysteine on the embryo and the blood vessels (endothelium) could be sited in the process of proliferation of cells that need proper methyl groups for proper function.

The history of the development and clinical use of CB 3717 and ICI D1694.

The antifolate thymidylate synthase inhibitors represent an exciting area in new drug development and show that with an understanding of the structural basis for toxicity, new drugs can be synthesised which have a more manageable spectrum of side effects whilst retaining activity. ICI D1694 does not show the nephrotoxicity which affected the development of CB 3717. Myelosuppression and gut toxicity are seen and are more typical of the toxicities one associates with this class of agent. Changes in hepatic enzymes have been seen with both drugs, and are also seen with other anti-folates including MTX, but these changes settle with repeat dosing and with cessation of treatment. We await the results of the planned phase II trials of ICI D1694 with great interest.