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Newborns have unique confounding factors regarding the TfR-F ratio
Newborns have unique confounding factors regarding the TfR-F ratio - Authors' response
Translational regulation of TfR and ferritin
Translational regulation of TfR and ferritin - Authors' response
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Peter Reynolds, Research Fellow in Immunology Imperial College, Hammersmith Hospital, London, UK
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p.reynolds{at}ic.ac.uk Peter Reynolds
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Dear Editor, Sweet et al investigated the serum transferrin receptor (sTfR) and, for the first time in neonates, transferrin receptor-log ferritin (TfR-F) ratio in a prospective series of cord blood taken from term infants and their mothers. They are to be congratulated on completing another piece of the complex jigsaw that is fetal and neonatal iron metabolism. sTfR and TfR-F were increased in iron deficient mothers, but not in their infants. The authors discussed at some length the translational (not transcriptional as stated in the discussion) control of intracellular ferritin synthesis.[1] They measured serum ferritin (SF), which is a glycosylated form of L- ferritin, and has been shown to correlate with intracellular iron in the absence of confounding factors.[2] However, SF is secreted in response to a wide variety of other stimuli, including, for example, inflammation and shows gender differences in newborns.[3] Under these circumstances SF may not accurately represent tissue iron stores. It has already been reported that sTfR does not correlate with other measures of iron metabolism in the newborn,[4] mainly since it is highly expressed by reticulocytes and other immature erythroid cells, with or without iron deficiency. The high sensitivity and specificity of the TfR-F ratio in adults is based upon their relationship in iron deficiency in the absence of factors that might otherwise elevate sTfR levels.[5] With both variables subject to these confounding factors in the neonate, I don't agree with the author's assertion that the TfR-F index "gives a measure of iron requirements in relation to iron availability" in this unique population. References (2) Finch CA, Huebers HA. Perspectives in iron metabolism. N Engl J Med 1982;306:1520-8. (3) Tamura T, Hou J, Goldenberg RL, Johnston KE, Cliver SP. Gender difference in cord serum ferritin concentrations. Biol Neonate 1999;75:343-49. (4) Kuiper-Kramer EP, Baerts W, Bakker R, van Eyck J van Rann J, van Eijk HG. Evaluation of the iron status of the newborn by soluble transferrin receptors in serum. Clin Chem Lab Med 1998;36:17-21. (5) Punnonen K, Irjala K, Rajamaki A. Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency. Blood 1997;89:1052-7. |
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Henry L Halliday, Professor of Child Health Queen's University of Belfast, UK
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h.halliday{at}qub.ac.uk Henry L Halliday
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Dear Editor,
We thank Peter Reynolds for congratulating us for adding a piece to the jigsaw of fetal iron metabolism.[1] We would like to reply to some of his other comments. We feel that use of the term post-transcriptional to describe the regulation of intracellular iron metabolism was correct rather than post-translational as suggested by Reynolds. Iron regulatory elements (IREs) are stem cell loop structures of several key messenger RNA (mRNA)-encoding proteins of iron metabolism. IREs can be located in the 5' region (eg, ferritin) or 3' region (eg, transferrin receptor) of the untranslated region of the mRNA. In relative iron deficiency, through interaction of the IREs with iron responsive proteins, transferrin uptake increases because the transferrin receptor mRNA is stabilised, whereas ferritin storage of iron decreases because translation of ferritin mRNA is blocked. These are clearly post-transcriptional, not post-translational events. The reciprocal regulation of the transferrin receptor and ferritin have recently been expertly reviewed by Hentze and Kuhn.[2] We agree that serum ferritin is increased in response to inflammation but the infants that we studied were born at term following normal pregnancies. All the babies were well at birth and did not require neonatal care. We think that it is unlikely that inflammation or other stimuli affected our serum ferritin values. Furthermore, in this study[3] and in our previous study of preterm infants[4] we found no gender differences in contrast to the results published by Tamura et al.[5] Our figure for cord ferritin levels at term (listed first as mean + SD) in female infants is almost identical to that of Tamura et al (164 + 106 microg/l vs 166 + 110 microg/l), but our value for male infants is higher (160 + 97 microg/l vs 123 + 71 microg/l). We doubt if there are real gender differences in fetal ferritin levels. Therefore we are still of the opinion that TfR-F index is a measure of iron requirements in relation to iron availability in the fetus and newborn as in adults and children. Professor H L Halliday Professor TRJ Lappin References (2) Hentze MW, Kuhn LC. Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide and oxidative stress. Pro Natl Acad Sci USA 1996;93:8175-82. (3) Sweet DG, Savage G, Tubman TRJ, Lappin TRJ, Halliday HL. Study of maternal influences on fetal iron status at term using cord blood transferrin receptors. Arch Dis Child Fetal Neonatal Ed 2001;84:F40-F3. (4) Halliday HL, Lappin TRJ, McClure BG. Iron status of the preterm infant during the first year of life. Biol Neonate 1984;45: 228-35. (5) Tamura T, Hou J, Goldenberg RL, Johnston KE, Cliver SP. Gender difference in cord serum ferritin concentrations. Biol Neonate 1999;75:342-9. |
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Peter Reynolds, Research Training Fellow
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p.reynolds{at}ic.ac.uk Peter Reynolds
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Dear Editor,
I thank Professors Halliday and Lappin for their riposte.[1] They suggest that I wish to describe the control of intracellular iron as "post-translational". That is an incorrect reading of my earlier response, where I described the control as "translational".[2] In their original article (and I quote) "Simultaneously, in a highly coordinated process IRPs bind to the 5' end of the ferritin gene and prevent its transcription when iron is scarce." This is not what occurs, and it is important to understand that the control exists with the translation of the mRNA. Translational dysregulation is gaining prominence as the unifying molecular mechanism in a varied and important group of disorders. These are the so-called translational pathophysiologies, which include hereditary thrombocythaemia, familial susceptibility to melanoma and hereditary hyperferritinaemia with cataract. Translational disorders may also be implicated in Alzheimers disease, and in familial predisposition to other malignancies, and I would refer interested readers to an excellent review article by Cazzola and Skoda.[3] I am still therefore of the belief that translational control is the best description. Post-transcriptional control is not incorrect, but does not help to identify at what level the regulation is occurring. Dr PR Reynolds References (2) Reynolds P. Newborns have unique confounding factors regarding the TfR-F ratio [Rapid Response]. Arch Dis Child 12 January 2001. http://adc.bmjjournals.com/cgi/eletters/fetalneonatal;84/1/F40#EL2 (3) Cazzola M, Skoda RC. Translational pathophysiology: a novel molecular mechanism of human disease. Blood 2000;95:3280-8. |
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Henry L Halliday, Neonatologist Regional Neonatal Unit, The Queen's University of Belfast, UK, Terry RJ Lappin
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h.halliday{at}qub.ac.uk Henry L Halliday, et al.
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Dear Editor
We thank Peter Reynolds for his continuing interest in our recent article.[1] In his first letter[2] he made a number of interesting points to which we responded.[3] He has now clarified[4] a point raised in his first letter. This turns out to be our inadvertent use of the word "transcription" when we meant "translation" in the discussion section of our original paper.[1] We apologise for this oversight. Whether one uses the term "post-transcriptional control" or "translational control" is a matter of personal choice, but we do agree wholeheartedly with Peter Reynolds that the concept of "translational dysregulation" is gaining prominence as the unifying mechanism in a varied and important group of disorders. Professor Henry L Halliday Professor Terry RJ Lappin References (2) Reynolds P. Newborns have unique confounding factors regarding TfR-F ratio [Rapid Response]. Arch Dis Child 12 January 2001. http://adc.bmjjournals.com/cgi/eletters/fetalneonatal;84/1/F40#EL2 (3) Halliday HL, Lappin TRJ. Newborns have unique confounding factors regarding the TfR-F ratio - Authors' response [Rapid Response]. Arch Dis Child 24 January 2001. http://adc.bmjjournals.com/cgi/eletters/fetalneonatal;84/1/F40#EL3 (4) Reynolds P. Translational regulation of TfR and ferritin. [Rapid Response]. Arch Dis Child 14 February 2001. http://adc.bmjjournals.com/cgi/eletters/fetalneonatal;84/1/F40#EL4 |
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