correspondence
duce child mortality, which increases both when pregnancies are unwanted and when mothers die, leaving children with no one to care for them. Progress toward MDGs 4 and 5 requires the medical community to assert the necessity of family planning and safe abortion. Ana C. Gonzalez, M.D. Global Doctors for Choice–Colombia Bogota, Colombia [email protected]
J. Koku Awoonor-Williams, M.D., M.P.H. Global Doctors for Choice–Ghana Bolgatanga, Ghana No potential conflict of interest relevant to this letter was reported. 1. Singh S, Sedgh G, Hussain R. Unintended pregnancy: world-
wide levels, trends, and outcomes. Stud Fam Plann 2010;41:24150. 2. Sedgh G, Singh S, Shah IH, Ahman E, Henshaw SK, Bankole A. Induced abortion: incidence and trends worldwide from 1995 to 2008. Lancet 2012;379:625-32. 3. Cohen SA. Facts and consequences: legality, incidence and safety of abortion worldwide. Guttmacher Policy Rev 2009;12:26. 4. Austin J, Guy S, Lee-Jones L, McGinn T, Schlecht J. Reproductive health: a right for refugees and internally displaced persons. Reprod Health Matters 2008;16:10-21. DOI: 10.1056/NEJMc1316332
The Authors Reply: Meltzer-Brody and Stringer point out the importance of mental health issues and interventions for maternal and child health. These are indeed important areas, and evidence of the effectiveness of mental health interventions in child health and growth is emerging.1,2 However, since our focus was on survival and on addressing MDGs 4 and 5, we did not place these interventions on par with others, an approach that is consonant with the consensus on essential interventions for maternal and child health and survival.3 However, this consensus could well change in the future, and we recognize the range of outcomes, such as maternal–infant interaction, cognitive development, and growth, that have been shown to improve with the use of maternal mental health interventions.4 Although we would
dispute the stated centrality of mental health to maternal and child health, we acknowledge that mental health interventions are worth considering for their relevance to health and development. We disagree with Gonzalez and AwoonorWilliams that our article did not do justice to the issue of unintended pregnancies and safe abortion. Space constraints and editorial directives precluded a more thorough discussion of reproductive health issues, but we fully endorsed the critical importance of family planning to maternal and child health and underscored this in the article. Not only did we highlight unsafe abortions as an important contributor to maternal mortality (Fig. 2 of the article), but we also placed both family planning and postabortion care high on our list of essential interventions (Table S1 in the Supplementary Appendix of the article, available at NEJM.org). Zulfiqar A. Bhutta, M.B., B.S., Ph.D. SickKids Centre for Global Child Health Toronto, ON, Canada [email protected]
Robert E. Black, M.D., M.P.H. Johns Hopkins Bloomberg School of Public Health Baltimore, MD Since publication of their article, the authors report no further potential conflict of interest. 1. Rahman A, Malik A, Sikander S, Roberts C, Creed F. Cogni-
tive behaviour therapy-based intervention by community health workers for mothers with depression and their infants in rural Pakistan: a cluster-randomised controlled trial. Lancet 2008;372: 902-9. 2. Kieling C, Baker-Henningham H, Belfer M, et al. Child and adolescent mental health worldwide: evidence for action. Lancet 2011;378:1515-25. 3. Rahman A, Fisher J, Bower P, et al. Interventions for common perinatal mental disorders in women in low- and middleincome countries: a systematic review and meta-analysis. Bull World Health Organ 2013;91:593-601I. 4. The Partnership for Maternal Health, Newborn and Child Health, and Aga Khan University. Essential interventions, commodities and guidelines for reproductive, maternal, newborn and child health: a global review of the key interventions related to reproductive, maternal, newborn and child health (http://www.who.int/pmnch/topics/part_publications/essential _interventions_18_01_2012.pdf). DOI: 10.1056/NEJMc1316332
Mitochondrial Fission and Fusion in Human Diseases To the Editor: In his review of the diseases in which mitochondrial fission and fusion are implicated, Archer (Dec. 5 issue)1 does not comment on the implications of mitochondria in the age-
related loss of muscle mass (sarcopenia). Impaired mitochondrial biogenesis has been postulated as a key factor in sarcopenia. There is an association between the accumulation of mitochondrial
n engl j med 370;11 nejm.org march 13, 2014
The New England Journal of Medicine Downloaded from nejm.org at NEW YORK UNIVERSITY on February 7, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1073
The
n e w e ng l a n d j o u r na l
DNA mutations and deficiencies in mitochondrial oxidative phosphorylation in aging skeletal muscle.2 The expression of the peroxisome-proliferator–activated receptor γ coactivator 1α (PGC-1α), nuclear respiratory factor 1, and cytochrome c is substantially lower in the heart and skeletal muscle of old persons.3 An age-associated lack of PGC-1α induction has also been reported in the skeletal muscle of old animals.4 The transgenic overexpression of PGC-1α efficiently prevents sarcopenia in old mice by limiting the degradation of muscle proteasome and apoptosis.5 All these facts highlight the role of most mitochondrial proteins, and probably those involved in mitochondrial fission and fusion, in the loss of muscle mass associated with aging and emphasize the importance of mitochondria as targets for pharmacologic interventions intended to prevent sarcopenia. Fabian Sanchis-Gomar, M.D., Ph.D. University of Valencia Valencia, Spain [email protected]
Frederic Derbré, Ph.D. University Rennes 2 Rennes, France No potential conflict of interest relevant to this letter was reported. 1. Archer SL. Mitochondrial dynamics — mitochondrial fis-
sion and fusion in human diseases. N Engl J Med 2013;369:223651. 2. Viña J, Gomez-Cabrera MC, Borras C, et al. Mitochondrial biogenesis in exercise and in ageing. Adv Drug Deliv Rev 2009;61:1369-74. 3. Dillon LM, Rebelo AP, Moraes CT. The role of PGC-1 coactivators in aging skeletal muscle and heart. IUBMB Life 2012;64:231-41. 4. Derbré F, Gomez-Cabrera MC, Nascimento AL, et al. Age associated low mitochondrial biogenesis may be explained by lack of response of PGC-1α to exercise training. Age (Dordr) 2012;34:669-79. 5. Wenz T, Rossi SG, Rotundo RL, Spiegelman BM, Moraes CT. Increased muscle PGC-1alpha expression protects from sarcope-
of
m e dic i n e
nia and metabolic disease during aging. Proc Natl Acad Sci U S A 2009;106:20405-10. DOI: 10.1056/NEJMc1316254
The Author Replies: Sanchis-Gomar and Derbré correctly note that I failed to discuss the role of mitochondrial dynamics in the atrophy of skeletal muscle (sarcopenia) in my recent article. This omission (and several others) reflects the limitation on the length of the article. Fission and fusion serve a quality-control function, eliminating dysfunctional mitochondria and protecting the aging cell or organism from the accumulation of mitochondria that have mutated DNA and oxidized proteins. Impairment of mitochondrial dynamics contributes to the decline in mitochondrial function with age in muscle, neurons, and other tissues.1 The expression of mitofusin-2 and dynaminrelated protein 1 (DRP1) is reduced in skeletal muscle as we age.2 The resulting fusion–fission imbalance may impair mitochondrial DNA repair and mitochondrial metabolism, promoting muscle atrophy. Both mitofusin-2 and PGC-1α (a transcriptional regulator of mitochondrial biogenesis and a transcriptional coactivator of mitofusin-2) preserve muscle mass; conversely, DRP1 may promote atrophy.1 Stephen L. Archer, M.D. Queen’s University Kingston, ON, Canada [email protected] Since publication of his article, the author reports no further potential conflict of interest. 1. Seo AY, Joseph AM, Dutta D, Hwang JC, Aris JP, Leeuwen-
burgh C. New insights into the role of mitochondria in aging: mitochondrial dynamics and more. J Cell Sci 2010;123:2533-42. 2. Crane JD, Devries MC, Safdar A, Hamadeh MJ, Tarnopolsky MA. The effect of aging on human skeletal muscle mitochondrial and intramyocellular lipid ultrastructure. J Gerontol A Biol Sci Med Sci 2010;65:119-28. DOI: 10.1056/NEJMc1316254
Early Specialty Palliative Care To the Editor: We concur with the Sounding Board article by Parikh et al. (Dec. 12 issue)1 and believe that additional barriers to access to palliative care deserve mention and may or may not be amenable to change in the short term.2 Oncologists may not refer patients because of personal biases. In addition, the palliative care team 1074
itself can sometimes be an obstacle — referrals will continue only if recommendations are thought to be valuable. Furthermore, screening to identify patients who will benefit from palliative care is an issue: oncologists may be aware of the benefits of palliative care and open to referral but lack the ability to identify patients in need of
n engl j med 370;11 nejm.org march 13, 2014
The New England Journal of Medicine Downloaded from nejm.org at NEW YORK UNIVERSITY on February 7, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
duce child mortality, which increases both when pregnancies are unwanted and when mothers die, leaving children with no one to care for them. Progress toward MDGs 4 and 5 requires the medical community to assert the necessity of family planning and safe abortion. Ana C. Gonzalez, M.D. Global Doctors for Choice–Colombia Bogota, Colombia [email protected]
J. Koku Awoonor-Williams, M.D., M.P.H. Global Doctors for Choice–Ghana Bolgatanga, Ghana No potential conflict of interest relevant to this letter was reported. 1. Singh S, Sedgh G, Hussain R. Unintended pregnancy: world-
wide levels, trends, and outcomes. Stud Fam Plann 2010;41:24150. 2. Sedgh G, Singh S, Shah IH, Ahman E, Henshaw SK, Bankole A. Induced abortion: incidence and trends worldwide from 1995 to 2008. Lancet 2012;379:625-32. 3. Cohen SA. Facts and consequences: legality, incidence and safety of abortion worldwide. Guttmacher Policy Rev 2009;12:26. 4. Austin J, Guy S, Lee-Jones L, McGinn T, Schlecht J. Reproductive health: a right for refugees and internally displaced persons. Reprod Health Matters 2008;16:10-21. DOI: 10.1056/NEJMc1316332
The Authors Reply: Meltzer-Brody and Stringer point out the importance of mental health issues and interventions for maternal and child health. These are indeed important areas, and evidence of the effectiveness of mental health interventions in child health and growth is emerging.1,2 However, since our focus was on survival and on addressing MDGs 4 and 5, we did not place these interventions on par with others, an approach that is consonant with the consensus on essential interventions for maternal and child health and survival.3 However, this consensus could well change in the future, and we recognize the range of outcomes, such as maternal–infant interaction, cognitive development, and growth, that have been shown to improve with the use of maternal mental health interventions.4 Although we would
dispute the stated centrality of mental health to maternal and child health, we acknowledge that mental health interventions are worth considering for their relevance to health and development. We disagree with Gonzalez and AwoonorWilliams that our article did not do justice to the issue of unintended pregnancies and safe abortion. Space constraints and editorial directives precluded a more thorough discussion of reproductive health issues, but we fully endorsed the critical importance of family planning to maternal and child health and underscored this in the article. Not only did we highlight unsafe abortions as an important contributor to maternal mortality (Fig. 2 of the article), but we also placed both family planning and postabortion care high on our list of essential interventions (Table S1 in the Supplementary Appendix of the article, available at NEJM.org). Zulfiqar A. Bhutta, M.B., B.S., Ph.D. SickKids Centre for Global Child Health Toronto, ON, Canada [email protected]
Robert E. Black, M.D., M.P.H. Johns Hopkins Bloomberg School of Public Health Baltimore, MD Since publication of their article, the authors report no further potential conflict of interest. 1. Rahman A, Malik A, Sikander S, Roberts C, Creed F. Cogni-
tive behaviour therapy-based intervention by community health workers for mothers with depression and their infants in rural Pakistan: a cluster-randomised controlled trial. Lancet 2008;372: 902-9. 2. Kieling C, Baker-Henningham H, Belfer M, et al. Child and adolescent mental health worldwide: evidence for action. Lancet 2011;378:1515-25. 3. Rahman A, Fisher J, Bower P, et al. Interventions for common perinatal mental disorders in women in low- and middleincome countries: a systematic review and meta-analysis. Bull World Health Organ 2013;91:593-601I. 4. The Partnership for Maternal Health, Newborn and Child Health, and Aga Khan University. Essential interventions, commodities and guidelines for reproductive, maternal, newborn and child health: a global review of the key interventions related to reproductive, maternal, newborn and child health (http://www.who.int/pmnch/topics/part_publications/essential _interventions_18_01_2012.pdf). DOI: 10.1056/NEJMc1316332
Mitochondrial Fission and Fusion in Human Diseases To the Editor: In his review of the diseases in which mitochondrial fission and fusion are implicated, Archer (Dec. 5 issue)1 does not comment on the implications of mitochondria in the age-
related loss of muscle mass (sarcopenia). Impaired mitochondrial biogenesis has been postulated as a key factor in sarcopenia. There is an association between the accumulation of mitochondrial
n engl j med 370;11 nejm.org march 13, 2014
The New England Journal of Medicine Downloaded from nejm.org at NEW YORK UNIVERSITY on February 7, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1073
The
n e w e ng l a n d j o u r na l
DNA mutations and deficiencies in mitochondrial oxidative phosphorylation in aging skeletal muscle.2 The expression of the peroxisome-proliferator–activated receptor γ coactivator 1α (PGC-1α), nuclear respiratory factor 1, and cytochrome c is substantially lower in the heart and skeletal muscle of old persons.3 An age-associated lack of PGC-1α induction has also been reported in the skeletal muscle of old animals.4 The transgenic overexpression of PGC-1α efficiently prevents sarcopenia in old mice by limiting the degradation of muscle proteasome and apoptosis.5 All these facts highlight the role of most mitochondrial proteins, and probably those involved in mitochondrial fission and fusion, in the loss of muscle mass associated with aging and emphasize the importance of mitochondria as targets for pharmacologic interventions intended to prevent sarcopenia. Fabian Sanchis-Gomar, M.D., Ph.D. University of Valencia Valencia, Spain [email protected]
Frederic Derbré, Ph.D. University Rennes 2 Rennes, France No potential conflict of interest relevant to this letter was reported. 1. Archer SL. Mitochondrial dynamics — mitochondrial fis-
sion and fusion in human diseases. N Engl J Med 2013;369:223651. 2. Viña J, Gomez-Cabrera MC, Borras C, et al. Mitochondrial biogenesis in exercise and in ageing. Adv Drug Deliv Rev 2009;61:1369-74. 3. Dillon LM, Rebelo AP, Moraes CT. The role of PGC-1 coactivators in aging skeletal muscle and heart. IUBMB Life 2012;64:231-41. 4. Derbré F, Gomez-Cabrera MC, Nascimento AL, et al. Age associated low mitochondrial biogenesis may be explained by lack of response of PGC-1α to exercise training. Age (Dordr) 2012;34:669-79. 5. Wenz T, Rossi SG, Rotundo RL, Spiegelman BM, Moraes CT. Increased muscle PGC-1alpha expression protects from sarcope-
of
m e dic i n e
nia and metabolic disease during aging. Proc Natl Acad Sci U S A 2009;106:20405-10. DOI: 10.1056/NEJMc1316254
The Author Replies: Sanchis-Gomar and Derbré correctly note that I failed to discuss the role of mitochondrial dynamics in the atrophy of skeletal muscle (sarcopenia) in my recent article. This omission (and several others) reflects the limitation on the length of the article. Fission and fusion serve a quality-control function, eliminating dysfunctional mitochondria and protecting the aging cell or organism from the accumulation of mitochondria that have mutated DNA and oxidized proteins. Impairment of mitochondrial dynamics contributes to the decline in mitochondrial function with age in muscle, neurons, and other tissues.1 The expression of mitofusin-2 and dynaminrelated protein 1 (DRP1) is reduced in skeletal muscle as we age.2 The resulting fusion–fission imbalance may impair mitochondrial DNA repair and mitochondrial metabolism, promoting muscle atrophy. Both mitofusin-2 and PGC-1α (a transcriptional regulator of mitochondrial biogenesis and a transcriptional coactivator of mitofusin-2) preserve muscle mass; conversely, DRP1 may promote atrophy.1 Stephen L. Archer, M.D. Queen’s University Kingston, ON, Canada [email protected] Since publication of his article, the author reports no further potential conflict of interest. 1. Seo AY, Joseph AM, Dutta D, Hwang JC, Aris JP, Leeuwen-
burgh C. New insights into the role of mitochondria in aging: mitochondrial dynamics and more. J Cell Sci 2010;123:2533-42. 2. Crane JD, Devries MC, Safdar A, Hamadeh MJ, Tarnopolsky MA. The effect of aging on human skeletal muscle mitochondrial and intramyocellular lipid ultrastructure. J Gerontol A Biol Sci Med Sci 2010;65:119-28. DOI: 10.1056/NEJMc1316254
Early Specialty Palliative Care To the Editor: We concur with the Sounding Board article by Parikh et al. (Dec. 12 issue)1 and believe that additional barriers to access to palliative care deserve mention and may or may not be amenable to change in the short term.2 Oncologists may not refer patients because of personal biases. In addition, the palliative care team 1074
itself can sometimes be an obstacle — referrals will continue only if recommendations are thought to be valuable. Furthermore, screening to identify patients who will benefit from palliative care is an issue: oncologists may be aware of the benefits of palliative care and open to referral but lack the ability to identify patients in need of
n engl j med 370;11 nejm.org march 13, 2014
The New England Journal of Medicine Downloaded from nejm.org at NEW YORK UNIVERSITY on February 7, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
