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Rapid Responses: Rapid Responses published:
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Another Routine Study
- BM Hegde (2 May 2003)
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Might polyunsaturated fatty acid supplementation in infant formula be harmful?
- Richard G Fiddian-Green (2 May 2003)
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Perinatal supplementation of long-chain polyunsaturated fatty acids and adult diseases
- Undurti N Das (4 May 2003)
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Sex and response to fatty acid supplementation
- Claire E Parker (5 May 2003)
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Human milk is still best
- Yap-Seng Chong (6 May 2003)
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Harmful effects of polyunsaturated fats
- Jeffrey R Johnstone (6 May 2003)
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What was the nature of the informed consent?
- Frank J Leavitt (6 May 2003)
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What would David Horrobin Think?
- Paul S MacDougall (7 May 2003)
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Was the original trial ethical? Should we neglect the study's negative consequences for breastfeedin
- Luis Huicho, Rafael Gustin (9 May 2003)
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FFAs and blood pressure, is it only FFAs?
- Barbara J Boucher (11 May 2003)
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BM Hegde, Vice Chancellor Manipal-576 119. India
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Dear Sir, "Knowledge advances, not by repeating known facts but by refuting false dogmas". Another one of those fat studies to be added on to the plethora of studies in the past. I wish to point out the following weaknesses of this study.
yours ever,
Competing interests: None declared |
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Richard G Fiddian-Green, None None
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Supplementation with long chain polyunsaturated fatty acids in infancy results in a lower blood pressure later in childhood (1). So what? Long chain polyunsaturated fatty acids (PUFA) increase mitochondrial membrane permeability to protons and hence uncouple oxidative phosphorylation (2). The uncoupling, also caused by thyroxine, appears to be beneficial provided the metabolic rate can be increased to accommodate the decrease in efficiency of ATP resynthesis (3). The children in this study should have had no problems doing so. Might, therefore, the effect of PUFAs on blood pressure in childhood have been due to vasodilatation accompanying the increase in heat production induced by the uncoupling? All natural long chain FAs activate UCP2- and UCP3-mediated H(r)+ translocation, UCP2- and UCP3- being human uncoupling proteins (2). Activation kinetics reveal the highest apparent affinity to UCP2 for omega -6 polyunsaturated fatty acids, all-cis-8,11,14-eicosatrienoic and all-cis -6,9,12-octadecatrienoic acids. These are also the most potent agonists of the nuclear PPARbeta receptor in the activation of UCP2 transcription. It has been proposed, therefore, that some PUFAs have a dual role activating both UCPn expression and uncoupling activity. The efficiency of ATP resynthesis is sytematically compromised by the uncoupling of oxidative phosphhorylation. If it cannot be accommodated by an increase in metabolic rate it might cause the energy deficit that has been implicated in the pathogenesis of the metabolic syndrome which includes hypertension (4). Thus reversing the hypertension with medications in the metabolic syndrome might indeed be addressing an effect and not the cause. The data obtained in the present study (1) support this conclusion. The implication is that factors other than hypertension are responsible for the later development of the cardiovascular diseases associated with hypertension. The metabolic effects of administering PUFAs for extended periods are far from certain. UCP2- (UCP3)-dependent H(+) translocation activated by all the fatty acids tested in the above study was inhibited by purine nucleotides with apparent affinity to UCP2 decreasing in order: ADP > ATP ~ GTP > GDP >> AMP. This raises the possibility that ATP degradation products might exert a negative feedback control on heat production induced by PUFAs and upon the excessive demands for energy in patients who have an energy deficit. If, however, PUFAs also increase the fluidity of all cell membranes any adverse effect possibly induced by a decrease in the efficiency of ATP resynthsis might be offset by a decrease in the amount of energy required for active transmembrane transport processes. It would be unwise, therefore, to add long chain polyunsaturated fatty acid supplementation in infant formula for a extended period without monitoring the adequacy of mitochondrial oxidative phosphorylation. 1. Long chain polyunsaturated fatty acid supplementation in infant formula and blood pressure in later childhood: follow up of a randomised controlled trial J S Forsyth, P Willatts, C Agostoni, J Bissenden, P Casaer, and G Boehm BMJ 2003; 326: 953 2. Zackova M, Skobisova E, Urbankova E, Jezek P. Activating omega -6 polyunsaturated fatty acids and inhibitory purine nucleotides are high affinity ligands for novel mitochondrial uncoupling proteins UCP2 and UCP3. J Biol Chem. 2003 Apr 1 3. The pooped-out syndrome, ATP stores and hypothyroidism Richard G Fiddian-Green bmj.com/cgi/eletters/326/7384/295#30166, 4 Mar 2003 4. Hypertension: treating cause or effect? Richard G Fiddian-Green (14 April 2003) Rapid response to: Increase in blood glucose concentration during antihypertensive treatment as a predictor of myocardial infarction: population based cohort study Kristina Dunder, Lars Lind, Björn Zethelius, Lars Berglund, and Hans Lithell BMJ 2003; 326: 681 Competing interests: None declared |
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Undurti N Das, Research Director EFA Sciences LLC, 1420 Providence Highway, Suite # 266, Norwood, MA 02062, USA
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I read with interest the work of Forsyth et al which suggests that supplementation of long-chain polyunsaturated fatty acids (LCPUFAs) during infancy keeps the blood pressure lower in later childhood. There is ample evidence now to believe that supplementation of LCPUFAs during the first few months of life can prevent the development of other adult diseases such as obesity, diabetes mellitus, coronary heart disease and hyperlipidemias (1-5). It is possible when LCPUFAs are given during the critical stages of development, especially during the 2nd and 3rd trimesters of pregnancy and the first few years of life (preferably from birth till 5 years of age)they get incorporated into the cell membranes of varius organs in appropriate amounts so that various tissues are able to counteract the pathological mechanisms that tend to induce these adult diseases. But the exact mechanism(s) by which they bring about these beneficial actions is not clear. It is possible that LCPUFAs are able to suppress the production of various pro-inflammatory cytokines and thus, protect the tissues and prevent the development of metabolic syndrome X in the adult life. Since LCPUFAs are also essential for the growth and development of brain, it is possible that they may also prevent the development of certain neurological conditions such as schizophrenia, Alzheimer's disease, and other dementias. References: 1. Das UN. A Perinatal Strategy for Preventing Adult Diseases: The Role of Long-chain Polyunsaturated Fatty Acids. Kluwer Academic Publishers, Boston, MA, 2002. 2. Das UN. Is obesity an inflammatory condition? Nutrition 2001; 17: 953-966. 3. Das UN. Is metabolic syndrome X an inflammatory condition? Exp Biol Med 2002; 227: 989-997. 4. Das UN. Can perinatal supplementation of long-chain polyunsaturated fatty acids prevent hypertension in adult life? Hypertension 2001; 38: e6-e8. 5. Das UN. Can perinatal supplementation of long-chain polyunsaturated fatty acids prevent diabetes mellitus? Eur J Clin Nutr 2003; 57: 218-226. Competing interests: I run a comapny which does research on essential fatty acids. But does not have any products in the market related to essential fatty acids. |
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Claire E Parker, General Practitioner Jericho Health Centre, Walton St, OX2 6NW, Oxford
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Editor: Forsyth et al (BMJ vol.326, 3.5.2003) demonstrate an association between lower BP in childhood and supplementation of infant formula milk with long chain fatty acids. This is interesting and potentially very important. The authors say there are no demographic differences between the supplemented and non-supplemented groups. Eye-balling the data suggested a possible sex difference, with a preponderance of males in the supplemented group. However, the authors are correct and the difference in distribution of the sexes between the 2 groups gave a chi-square of 1.378, which is not significant for 1df at p = 0.05, let alone p = 0.005 to adjust for the number of different demographic factors considered. However I cannot help wondering if the study was adequately powered to detect a significant but small demographic difference between the groups. Given the importance of male sex as a risk factor for IHD, would this be worth exploring in a larger study? Two questions could perhaps be answered immediately. Firstly, what was the sex distribution within the breast-fed group, where BP outcome was similar to the supplemented group? Secondly, have animal studies been large enough to determine whether the degree of response is related to sex? If there is a small but significant (biological) difference between the sexes in their response to fatty acid supplementation as infants, this might translate to an important effect at the population level. Claire E. Parker, General Practitioner, Jericho Health Centre, Walton St, OX2 6NW, Oxford; Competing interests: None declared |
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Yap-Seng Chong, Assistant Professor & Consultant Dept of Obstetrics & Gynaecology, National University of Singapore, Lower Kent Ridge Rd, 119074.
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Over ten years ago, the hypothesis of fetal programming was formed when David Barker and co-authors(1) showed that low birth weight babies had a higher mortality from ischaemic heart disease. Subsequently, it was found that fast postnatal catch-up growth was an additional risk factor for ischaemic heart disease(2), demonstrating that early childhood programming was as important as the in utero milieu. Clearly, the most significant form of early childhood programming and the form most amenable to beneficial intervention is nutrition, in particular, breastfeeding or the lack of it. While Forsyth and co-authors(3) should be congratulated on a finding that will no doubt greatly influence the strategies of infant formula companies for years to come, the key finding should be that breastfeeding does it all naturally, and for free. There is, by now, sufficient evidence that human milk, besides its role in preventing acute childhood infections, also protects against chronic diseases in childhood and beyond. It has been 136 years since a milk food for infants was first formulated, yet the search for an ideal formula still continues. Two years ago, an article(4), published in the BMJ, raised considerable consternation when it suggested that extending the duration of breastfeeding beyond three months decreased brachial arterial distensibility in young adults and, hence, increased their theoretical risk of developing hypertension later. To support their findings, the authors quoted another paper(5) from David Barker’s group, which found that men who were breastfed and not weaned at one year of age had a higher chance of death from ischaemic heart disease compared to those breastfed for less than a year. What was not emphasized was that the purely bottle- fed men also had a higher cardiac mortality than those breastfed for under one year. While the debate over the optimum duration of breastfeeding continues, one fact should remain clear- that human milk is the ultimate form of early nutrition for our children, and the search for the ideal substitution infant formula will never be concluded satisfactorily. 1. Barker DJP, Winter PD, Osmond C, Migetts B, Simmonds SJ. Weight in infancy and death from ischaemic heart disease. Lancet 1989; 2: 577-580. 2. Eriksson JG, Forsén T, Tuomilehto J, Winter PD, Osmond C, Barker DJP. Catch up growth in childhood and death from coronary heart disease: longitudinal study. BMJ 1999; 318: 427-431. 3. Forsyth JS, Willatts P, Agostoni C, Bissenden J, Casaer P, Boehm G. Long chain polyunsaturated fatty acid supplementation in infant formula and blood pressure in later childhood: follow up of a randomized controlled trial. BMJ 2003; 326: 953. 4. Leeson CPM, Katternhorn M, Deanfield JE, Lucas A. Duration of breast feeding and arterial distensibility in early adult life: population based study. BMJ 2001; 322: 643-647. 5. Fall CH, Barker DJP, Osmond C, Winter PD, Clark PM, Hales CN. Relation of infant feeding to adult serum cholesterol concentration and death from ischaemic heart disease. BMJ 1992; 304: 801-805. Competing interests: None declared |
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Jeffrey R Johnstone, Self-employed 7 Bruce St, Nedlands 6009, Western Australia
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The paper by Forsyth et al is disturbing not for what it says but for what it fails to say. There are two studies on the effects of a diet high in polyunsaturated fats, both of which produced alarming results. In the New York Anti-Coronary Club Program (Christakis et al, 1966) 814 men were placed on such a diet and compared with a control group of 463 men. After 4 years, obesity, hypertension and serum cholesterol had all improved in the test group as compared with the control. But there were 27 deaths (3.3%) in the test group compared with 6 (1.3%) in the control group. There were 9 deaths from coronary heart disease, all in the test group. In the Sydney Diet-Heart Study (Woodhill et al, 1977) 458 men with clinical coronary disease took part in a similar trial. The test group of 221 men were encouraged to change to a diet high in polyunsaturated fat and compared with a control group of 237 men. After 5 years, serum cholesterol was significantly lower in the test group, as was survival: 17.6% of the test group died compared with 11.8% of the control group. I am not aware of any controlled trials which have produced results which differ from these two. On the contrary, interventions to “improve” dietary fat intake have produced at best no effect and at worst a reduction in life expectancy (Johnstone,1989,1991). Bottle-fed infants are not healthy men or men with coronary disease but the results produced by Christakis et al and Woodhill et al are sufficiently alarming to question the harmlessness of the Forsyth trial. But most alarming is the fact that both Forsyth et al and your referees should be unaware of these results or saw no need to refer to them. Christakis, G., S.H. Rinzler, M. Archer and A. Kraus (1966): 'Effect of the anti-coronary club program on coronary heart disease risk-factor status', Journal of the American Medical Association, 198, pages 597-604. Johnstone, J.R (1989): Controlled trials, cholesterol, coronary heart disease and health. In: "Coronaries and cholesterol," eds. W.J. Cliff and G.I. Schoeff, Chapman and Hall, London, pp 115-35. Johnstone, J.R (1991): "Health Scare. The Misuse of Science in Public Health Policy." Australian Institute for Public Policy, Perth. Woodhill, J.M., A.J. Palmer, B. Leelarthaepin, C. McGilchrist and R.B. Blacket (1977): 'Low fat, low cholesterol diet in secondary prevention of coronary heart disease', in “Drugs, lipoproteins and atherosclerosis”, New York: Plenum Press, pages 317-330. Competing interests: None declared |
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Frank J Leavitt, Chairman, Centre for Asian and International Bioethics, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
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Bravo to Dr Yap-Seng Chong, for the data on the benefits of breast feeding. I wonder if the parents' consent can be considered to have been "informed" is the parents in the test group did not receive a full and clear expanation of what is already known about the benefits of breast feeding. Competing interests: None declared |
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Paul S MacDougall, Microbiology Technologist/Instructor University College of Cape Breton
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Dear Mr. Smith I find it ironic in the week following your "wildy intemperate" chronicling of the life of David Horrobin, one of a handful of people who could arguably be called a true expert in fatty acid metabolism, you see fit to grace the cover of your esteemed ejournal with of all things, a fatty acid research paper. Is this your way of saying sorry, we forgot to mention how influential Dr Horrobin's work was, but here's a cover article to prove we at least think there's some merit to some of his life's work. Did Ms. Richmond approve of this article or is she waiting for the authors to die before she'll comment on it. As an aside I suggest you read David's obituary of Linus Pauling (In Med Hypo) and forward it to Ms.Richmond. Maybe she can read it and see how a real obit is written. He's even better at that than she is. All the best Paul MacDougall Competing interests: None declared |
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Luis Huicho, Professor of Paediatrics, Department of Paediatrics, San Marcos University Department of Paediatrcis, San Marcos University, Av. Brasil 600, Lima 05, Peru, Rafael Gustin
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How was the informed consent obtained for the randomized study previously reported by the authors?.1,2 It is said that the parents were informed of the study after they had stated to midwifery staff that they wished to formula feed. But were the parents informed by the investigators on the advantages of breastfeeding and on the risks of formulae?. Although these questions should have been posed and answered before the study, they are of paramount importance for determining whether the study was ethical or not. And the authors should make clear how this issue of informed consent was conducted at the time of the study reported in 1999. The results seem to suggest that supplemented children have lower blood pressure values six years after. The authors explicitly state that these results are “…relevant to public health strategies aimed at improving the long term health of the population” and that “…these benefits can be achieved by simple dietary measures early in life”. The message seems clear to me: “parents of the world, let’s feed our infants with LCPUFA supplemented formulae”. I can not understand why the authors did not add that “however, breastfeeding is at least as effective, and it is infinitely cheaper, besides having countless additional advantages not addressed by this study”. I am particularly concerned on the potentially devastating consequences that the dissemination and publicity of this study may have on the parents feeding behaviour and on the health workers advice behaviour regarding breast feeding. These consequences can be more dramatic in poor countries, where breast feeding is a critical protective factor against infant morbidity and mortality. 1. Willatts P, Forsyth JS, DiModugno MK, Varma S, Colvin M. Effect of long-chain polyunsaturated fatty acids in infant formula on problem solving at 10 months. Lancet 1998; 352: 688-691 2. Forsyth JS, Varma S, Colvin M. A randomised controlled study of the effect of long chain polyunsaturated fatty acid supplementation on stool hardness during formula feeding. Arch Dis Child 1999; 81: 253-256 Competing interests: None declared |
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Barbara J Boucher, Hon Sen Lect. Diabetes & Metabolic Medicine Royal London Hospital, London E11BB
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Forsyth et al (1) report supplementation of formula milk in early infancy to be associated with reduction in blood pressure in later years. The attribution of this effect to long chain poly unsaturated fatty acids [PUFAs] is an assumption, however, that requires some thought since the egg yolk used for supplementation also contains saturated and monstaurated fats, all the essential amino acids, and others; the fat soluble vitamins D and A and many minerals [Mn, Zn, Cu as well as Fe]. To consider vitamin D as an example, it has been shown to be necessary for normal brain development (2), to reduce blood pressure in adults whether given orally or induced by UVb irradiation (3,4) and the supplementation used can be calculated to add ~ 48IU of vitamin D to each 100 ml milk feed. [Egg yolk from hen’s eggs contains ~390mg arachidonic acid [AA] per 100 G fat. Each egg yolk contains ~5G fat. To raise milk formula AA by ~350mg/100G fat when the formula contains 40G fat/100 ml of feed requires ~ 8 yolks per litre of milk feed and each yolk contains ~ 60 IU of vitamin D, adding a total of ~ 480 IU of vitamin D to 1 litre of milk feed]. Since the study findings have important implications for the reduction of chronic disease in the future, and since other workers in the field have also used ‘foods’ such as cod-liver oil [well known as a source of vitamins A & D] for supplementing formula feeds rather than purified FFAs in their studies, it would be helpful if authors could provide the detailed composition of supplemented and control feeds in their studies so that the effective factor or factors can be identified with reasonable certainty; hopefully this data can be provided from available data. References 1. Forsyth J, Willatts P, Agostini C, Bissenden J, Casaer P, Boehm G. 2003 Long chain polyunsaturated fatty acid supplementation in infant formula and blood pressure in later childhood: follow up of a randomised control trial. 326: n953-5 2. Eyles D, Brown J, Mackay-Sim A, McGrath J, Feron F. 2003 Vitamin D(3) and brain development. Neuroscience 118(3):641-53 3. Lind L, Wengle B, Wide L Ljunghall S. 1989. Reduction of blood pressure during long-term treatment with active vitamin D [alphacalcidol] is dependent on plasma rennin activity and calcium status. Am J Hypertension 2:20-5 4. Krause R, Buhring M, Hopfenmuller W, Holick MF, Sharma A. 1998 Ultraviolet B and blood pressure. Lancet 709-110 5. Helland IB, Smith L, Saarem K, Saugstad OD, Drevon CA. 2003 Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy and lactation augments children’s IQ at 4 years of age. Pediatrics 111:e39-44 Competing interests: None declared |
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