Nutrition and Growth: Yearbook 2016

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ical as well as research issues related to child growth have selected and ... Diabetes, Schneider Children's Medical Center of Israel, Petach Tikva, Israel and ...
Nutrition and Growth: Yearbook 2016

World Review of Nutrition and Dietetics Vol. 114

Series Editor

Berthold Koletzko

Munich

Nutrition and Growth Yearbook 2016

Volume Editors

Berthold Koletzko Munich Raanan Shamir Petach Tikva/Tel Aviv Dominique Turck Lille Moshe Phillip Petach Tikva/Tel Aviv 2016

Basel Freiburg Paris London New York Chennai New Delhi Bangkok Beijing Shanghai Tokyo Kuala Lumpur Singapore Sydney •

























Berthold Koletzko

Raanan Shamir

Div. Metabolic and Nutritional Medicine Dr. von Hauner Children’s Hospital Univ. of Munich Medical Centre – Klinikum d. Univ. München Munich Germany

Institute of Gastroenterology Nutrition and Liver Diseases Schneider Children’s Medical Center of Israel Clalit Health Services Petach Tikva, Israel; and Sackler School of Medicine Tel Aviv University Tel Aviv Israel

Dominique Turck Division of Gastroenterology Hepatology and Nutrition Department of Pediatrics Jeanne de Flandre Children’s Hospital; and Lille University Faculty of Medicine INSERM U995 Lille France

Moshe Phillip Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes National Center for Childhood Diabetes Schneider Children’s Medical Center of Israel Petach Tikva, Israel; and Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel

Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents® and PubMed/MEDLINE. Disclaimer. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. © Copyright 2016 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) www.karger.com Printed in Germany on acid-free and non-aging paper (ISO 9706) by Kraft Druck, Ettlingen ISSN 0084–2230 e-ISSN 1662–3975 ISBN 978–3–318–05705–8 e-ISBN 978–3–318–05706–5

Contents

VII IX

1 21 50 66 84 103 120 128

138 146

List of Contributors Preface Koletzko, B. (Munich); Shamir, R. (Petach Tikva/Tel Aviv); Turck, D. (Lille); Phillip, M. (Petach Tikva/Tel Aviv) The Physiology and Mechanism of Growth Ahmed, S.F. (Glasgow); Phillip, M. (Petach Tikva/Tel Aviv); Grimberg, A. (Philadelphia, PA) Obesity, Metabolic Syndrome and Nutrition Shalitin, S. (Petach Tikva); Battelino, T. (Ljubljana); Moreno, L.A. (Zaragoza) Term and Preterm Infants van Goudoever, J.B. (Amsterdam); Turck, D. (Lille) Cognition Agostoni, C.; Bettocchi, S. (Milan) Nutrition and Growth in Chronic Disease Hartmann, C.; Shamir, R. (Petach Tikva/Tel Aviv) Early Nutrition and Its Effects on Growth, Body Composition and Later Obesity Michaelsen, K.F.; Larnkjær, A.; Larsson, M.W.; Mølgaard, C. (Copenhagen) Malnutrition and Catch-Up Growth during Childhood and Puberty Bhutta, Z. (Karachi/Toronto, ON); Yackobovitch-Gavan, M. (Petach Tikva) Pregnancy: Impact of Maternal Nutrition on Intrauterine Fetal Growth Hiersch, L. (Tel Aviv); Yogey, Y. (Tel Aviv) Author Index Subject Index

V

List of Contributors Carlo Agostoni

Adda Grimberg

Department of Clinical Sciences and Community Health Pediatric Clinic, University of Milan Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico IT–20122 Milan (Italy) E-Mail: [email protected]

Endocrinology/Diabetes The Children’s Hospital of Philadelphia 34th Street and Civic Center Blvd. Philadelphia, PA 19104-4399 (USA) E-Mail: [email protected]

Syed F. Ahmed Developmental Endocrinology Research Group Royal Hospital for Sick Children University of Glasgow Yokhill, Glasgow G3 8SJ (UK) E-Mail: [email protected]

Tadej Battelino Department of Pediatric Endocrinology, Diabetes and Metabolism UMC-University Children’s Hospital Bohoriceva 20 SI–1000 Ljubljana (Slovenia) E-Mail: [email protected]

Silvia Bettocchi Department of Clinical Sciences and Community Health Pediatric Clinic, University of Milan Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico IT–20122 Milan (Italy) E-Mail: [email protected]

Zulfiqar Bhutta The Hospital for Sick Children Research Centre for Global Child Health University of Toronto, Toronto, ON (Canada); and Department of Nutritional Sciences Division of Women and Child Health Aga Khan University, Karachi (Pakistan) E-Mail: [email protected]

Corina Hartman Institute of Gastroenterology, Nutrition and Liver Diseases Schneider Children’s Medical Center of Israel Clalit Health Services Petach Tikva (Israel); and Sackler Faculty of Medicine Tel Aviv University IL–39040 Tel Aviv (Israel) E-Mail: [email protected]

Liran Hiersch Department of Obstetrics and Gynecology, Lis Maternity Hospital, Tel Aviv Medical Center, Tel Aviv (Israel); and Sackler Faculty of Medicine Tel Aviv University IL–39040 Tel Aviv (Israel) E-Mail: [email protected]

Berthold Koletzko Division of Metabolic and Nutritional Medicine Dr. von Hauner Children’s Hospital University of Munich Medical Centre Lindwurmstr. 4 DE–80337 Munich (Germany) E-Mail: [email protected]

Anni Larnkjær Department of Nutrition, Exercise and Sports University of Copenhagen Rolighedsvej 30 DK–1958 Frederiksberg C (Denmark) E-Mail: [email protected]

VII

Melanie W. Larsson

Raanan Shamir

Department of Nutrition, Exercise and Sports University of Copenhagen Rolighedsvej 30 DK–1958 Frederiksberg C (Denmark) E-Mail: [email protected]

Institute of Gastroenterology, Nutrition and Liver Diseases Schneider Children’s Medical Center of Israel Clalit Health Services 14 Kaplan Street Petach Tikva (Israel); and Sackler Faculty of Medicine Tel Aviv University IL–39040 Tel Aviv (Israel) E-Mail: [email protected]

Kim F. Michaelsen Department of Nutrition, Exercise and Sports University of Copenhagen Rolighedsvej 30 DK–1958 Frederiksberg C (Denmark) E-Mail: [email protected]

Christian Mølgaard Department of Nutrition, Exercise and Sports University of Copenhagen Rolighedsvej 30 DK–1958 Frederiksberg C (Denmark) E-Mail: [email protected]

Luis A. Moreno GENUD (Growth, Exercise, Nutrition and Development) Research University of Zaragoza c/Domingo Miral s/n ES–50009 Zaragoza (Spain) E-Mail: [email protected]

Moshe Phillip The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes National Center for Childhood Diabetes Schneider Children’s Medical Center of Israel 14 Kaplan Street Petach Tikva (Israel); and Sackler Faculty of Medicine Tel Aviv University, IL-39040 Tel Aviv (Israel) E-Mail: [email protected]

Dominique Turck Division of Gastroenterology, Hepatology and Nutrition Department of Pediatrics Jeanne de Flandre Children’s Hospital; and Lille University Faculty of Medicine INSERM U995 Avenue Eugène Avinée FR–59037 Lille cedex (France) E-Mail: [email protected]

Johannes B. van Goudoever Department of Pediatrics Emma Children’s Hospital-AMC and VU University Center Meibergdreef 9 NL–1105 AZ Amsterdam (The Netherlands) E-Mail: [email protected]

Michal Yackobovitch-Gavan The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes National Center for Childhood Diabetes Schneider Children’s Medical Center of Israel 14 Kaplan Street IL–4920235 Petach Tikva (Israel) E-Mail: [email protected]

Shlomit Shalitin

Yariv Yogev

The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes National Center for Childhood Diabetes Schneider Children’s Medical Center of Israel 14 Kaplan Street Petach Tikva (Israel); and Sackler Faculty of Medicine Tel Aviv University, IL–39040 Tel Aviv (Israel) E-Mail: [email protected]

Department of Obstetrics and Gynecology Lis Maternity Hospital Tel Aviv Medical Center Tel Aviv (Israel); and Sackler Faculty of Medicine Tel Aviv University IL–39040 Tel Aviv (Israel) E-Mail: [email protected]

VIII

List of Contributors

Preface

It is well known to the professional medical world that child growth depends on both an adequate amount and adequate quality of their nutrition. Pediatricians, including subspecialists in pediatric gastroenterology, metabolism and nutrition, and endocrinology, nutritionists and dieticians, obstetricians, and other health professionals involved in the care of children, use growth charts as diagnostic tools in their daily work with growing children and adolescents. Even though the mechanisms of fetal and child growth and their interactions with nutrition have not yet been fully elucidated and still pose challenges to our scientific understanding, knowledge of the role of genetic, epigenetic and growth factors, hormones, and intracellular changes have increased during the last 2 years since the first Nutrition and Growth yearbook was published in 2014. Thus, exchanging concepts and knowledge between professionals of all the different disciplines, as well as advancing research and interdisciplinary clinical collaborations, remain very important. The main purpose of the book is to provide an overview of peer-reviewed manuscripts published over the last 2 years (from July 1, 2013 to June 30, 2015) for practicing physicians and other health care professionals involved in the care of growing children. The topics and manuscripts reviewed were selected by our international editorial team of experts. We tried to select manuscripts that we believe are important and might shed some light on the mechanisms of the interaction between nutrition and growth, as well as add some insight for the readers. Each of the selected manuscripts is summarized briefly and is accompanied by editorial comments that evaluate the clinical importance of each article and discuss its application. We hope you will find the book helpful and useful. Berthold Koletzko, Munich Raanan Shamir, Petach Tikva/Tel Aviv Dominique Turck, Lille Moshe Phillip, Petach Tikva/Tel Aviv

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Koletzko B, Shamir R, Turck D, Phillip M (eds): Nutrition and Growth: Yearbook 2016. World Rev Nutr Diet. Basel, Karger, 2016, vol 114, pp 1–20 (DOI: 10.1159/000441808)

The Physiology and Mechanism of Growth Syed F. Ahmed 1  Moshe Phillip 2  Adda Grimberg 3 1

Developmental Endocrinology Research Group, Royal Hospital for Sick Children, University of Glasgow, Glasgow, UK; 2 Jesse Z. and Sara Lea Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3 Division of Endocrinology/Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

Children’s growth is a unique field of interest to obstetricians and other care givers among the professional community (subspecialists in pediatric nutrition, endocrinology and gastroenterology, pediatric nutritionist and dieticians, and other health professionals involved in the care of children). With the development of new investigational tools in genetic, epigenetic proteomic and microbiomics, our understanding of the mystery associated with child growth has somewhat increased. However, so many issues related to the mechanisms controlling growth are still awaiting discovery, especially those related to the interaction between nutrition and growth. We still do not fully understand the mechanisms that control stunted growth associated with mal- and undernutrition or chronic diseases, or those that determine the timing and magnitude of catch-up growth, and what is the ideal nutritional rehabilitation. In this chapter, three pediatric endocrinologists who have focused their work on clinical as well as research issues related to child growth have selected and commented on some recently published articles in the field. In the process of choosing important manuscripts for discussion, we probably missed some other important studies which are also of value to the reader. We hope that the summary of the published manuscripts and our comments will stimulate the readers to look for more manuscripts in the field and that our comments will serve as ‘food for thought’.

Elevated FGF21 leads to attenuated postnatal linear growth in preterm infants through GH resistance in chondrocytes Guasti L1, Silvennoinen S2, Bulstrode NW3, Ferretti P4, Sankilampi U2, Dunkel L1 1Centre for Endocrinology, William Harvey Research Institute, Barts and the London, Queen Mary University of London, London, UK; 2Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland; 3Department of Plastic Surgery, Great Ormond Street Hospital for Children National Health Service Trust, London, UK; 4Developmental Biology Unit, University College London Institute of Child Health, London, UK

J Clin Endocrinol Metab 2014;99:E2198–E2206

Background: Murine models of the endocrine and paracrine factor, fibroblast growth factor 21 (FGF21), have indicated a role in mediating growth inhibition from food restriction; transgenic mice overexpressing FGF21 have stunted somatic and bone growth, while FGF21 knockout mice are protected from the decreased bone growth (and induction of FGF21 expression in liver and growth plate) seen in wild-type mice exposed to the same degree of food restriction. This study used postnatal growth failure of very preterm infants as a clinical model of FGF21 growth effects, and explored supporting in vitro mechanistic studies of FGF21 action in human primary chondrocytes. Methods: Thirty-two very preterm infants (19 boys) were recruited in the neonatal intensive care unit during the first week of life as part of the Finnish PreBaby Study. Median gestational age at birth was 28.2 weeks (range: 23.4–31.9), and median postmenstrual age at hospital discharge was 38.6 weeks (range: 35.4–51.0). All babies survived, though a subset had morbidities commonly associated with prematurity (including late-onset sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, grade III or IV intraventricular hemorrhage, and retinopathy of prematurity). Only two had birth weight or length below –2 SD (i.e. were also small for gestational age). Full enteral nutrition was achieved, following dependence on intravenous nutrition, at a median age of 10 days (range: 3–101). Mixed umbilical blood samples were collected immediately after birth, as well as blood samples in weeks 1, 3 and 5, for measurement of FGF21 and IGF-I levels. Cultures were established from primary chondrocytes obtained from the rib cartilage of 3 consenting boys undergoing autologous costal cartilage to ear graft as part of facial reconstruction; all 3 boys were aged 9–11 years and had normal growth. Cells were tested for effects of FGF21 (recombinant and from patients’ serum), GH and IGF-I responsiveness, and proliferation rates. Results: FGF21 levels were below the assay sensitivity in 85% of very preterm infants in umbilical blood, 31% of infants at week 1, 25% at week 3 and 18% at week 5. Median blood levels of FGF21 increased significantly from week 1 to 3, and from week 3 to 5. In a linear regression model, the average FGF21 level during the first 5 weeks of life associated negatively (β –0.415, p < 0.005) with the change in length SD score, but was not associated significantly with change in weight SD score. The primary chondrocytes were found to express the FGF21 receptor complex (FGFR1/β-KLOTHO), yet their FGF21 expression levels were lower than that of liver. FGF21 (recombinant and from patient serum) upregulated basal and GH-induced expression of suppressor of cytokine signaling 2 (SOCS2) and inhibited both GH-induced phosphorylation of signal transducer and activator of transcription 5 (STAT5) and GH-induced expression of COLII and ALP, two markers of chondrocyte maturation. FGF21 also inhibited GH-induced expression of IGF-1 and cell proliferation, but did not affect IGF-1-induced cell proliferation. Conclusions: In very preterm infants, elevated FGF21 serum levels during the first 5 weeks of life are associated specifically with linear growth failure, but not weight gain. Furthermore, the in vitro data provide mechanistic support that FGF21 causes GH resistance in primary chondrocytes, which may contribute to the growth failure seen in prematurity and possibly chronic conditions of childhood.

2

Ahmed  Phillip  Grimberg

Serum fibroblast growth factor 21 levels are inversely associated with growth rates in infancy Mericq V1, De Luca F4, Hernandez MI4, Peña V2, Rossel K2, Garcia M2, Avila A1, Cavada G3, Iñiguez G1 1Institute

of Maternal and Child Research, Faculty of Medicine, University of Chile, Santiago, Chile; Unit, San Borja Arriaran Hospital, Santiago, Chile; 3Public Health Department, University of Chile and University of Los Andes, Santiago, Chile; 4Section of Endocrinology and Diabetes, St. Christopher’s Hospital for Children, Drexel University College of Medicine, Philadelphia, PA, USA 2Neonatology

Horm Res Paediatr 2014;82:324–331

Background: Human circulating concentrations of fibroblast growth factor 21 (FGF21) are elevated in (1) adults or adolescents who are overweight, or have type 2 diabetes or impaired glucose tolerance, (2) people on very low calorie diets, and (3) girls with anorexia nervosa. When adjusted for insulin sensitivity and body fat, the increased serum FGF21 levels in anorectic patients are associated positively with integrated GH concentration. This study aimed to investigate the role of FGF21 during growth in infancy. Methods: Newborns were recruited consecutively at the neonatal unit in a hospital in Santiago, Chile that serves an ethnically and socioeconomically homogeneous stratum of the city. The crosssectional group consisted of 55 term and 40 preterm babies (26–35 weeks’ gestation) whose cord blood was used to measure FGF21, glucose, insulin and leptin levels. The longitudinal group consisted of 40 term and 40 preterm (2 for girls and genital stage >3 for boys), and blood samples were collected to determine insulin, glucose, leptin, adiponectin and PAI-1 concentrations. Results: The undernourished group had the lowest mean leptin level (0.92 ng/ml, 95% CI: 0.67, 1.25 vs. 2.03 ng/ml, 95% CI: 1.46, 2.82 in the control and 1.66 ng/ml, 95% CI: 1.15, 2.44 in the recovered groups; p < 0.005); the two latter groups did not differ significantly. Girls had significantly higher leptin concentrations than boys. Adiponectin and PAI-1 concentrations did not differ among the three nutritional groups. Conclusion: Nutritional repletion that normalizes weight and height in previously undernourished and impoverished children also leads to normal leptin concentrations. Comments

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Kudos to the team at CREN at the Federal University of São Paulo for tackling the challenging and important public health problem of undernutrition among impoverished children in such a well-designed, carefully monitored and researched, and successful way! When reading through the paper, three clues to what underlies their success readily jump out: 1 CREN offers an integrated, multidisciplinary treatment program. Pediatricians, nutritionists, social workers and psychologists all participate in complementary roles. Undernutrition, like many chronic diseases, cannot be managed successfully without also addressing the social context of the patient. 2 CREN’s interventions fit in the natural milieu of the patients’ lives. Children with mild undernutrition receive outpatient assistance and those with moderate/severe undernutrition receive day hospital care. Thus, the children remain with their families of origin and their lives are not massively disrupted by relocations or placement with other caregivers. Further, the dietary interventions are based on Brazilian staple diets of natural foods, rather than formulas [children also receive iron and vitamins (A, B, C and D) supplementation], and thus are more likely to be acceptable to the patients. 3 CREN’s program focuses on normalizing linear growth as well as weight gain. Previous studies of short-term nutritional repletion for undernourished children that fo-

Ahmed  Phillip  Grimberg

cused on weight gain as their primary outcome resulted in high leptin concentrations. Accelerated weight gain during short-term nutritional recovery in children has been associated with increased risk of metabolic and cardiovascular diseases in the future. Thus, this paper serves as another clinical example of the power of utilizing linear growth as a marker of child health. By tailoring the recovery program to also normalize linear growth, CREN’s interventions normalize body composition, leptin levels and other biochemical parameters linked with long-term health outcomes.

The local CNP/GC-B system in growth plate is responsible for physiological endochondral bone growth Nakao K1, Osawa K1, Yasoda A2, Yamanaka S1, Fujii T2, Kondo E2, Koyama N1, Kanamoto N2, Miura M2, Kuwahara K3, Akiyama H4, Bessho K1, Nakao K5 1Department of Oral and Maxillofacial Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan; 2Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan; 3Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan; 4Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu, Japan; 5Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan

Sci Rep 2015;5:10554

Background: C-type natriuretic peptide (CNP) and its receptor, guanylyl cyclase-B (GC-B) are potent stimulators of endochondral bone growth. Methods: The role of the local CNP/GC-B in the growth plate on bone growth was investigated using cartilage-specific knockout mice. Results: Bones were as short in cartilage-specific CNP or GC-B knockout mice and the extent as previously described in the respective systemic knockout mice. Cartilage-specific GC-B knockout mice were shorter than cartilage-specific CNP knockout mice, and all stages of chondrogenesis were affected. The survival rate of cartilage-specific CNP knockout mice was comparable to that of systemic CNP knockout mice. Conclusion: The local CNP/GC-B system in growth plate is responsible for bone growth and its links to survival needs further investigation. Comments

The natriuretic peptide family consists of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), which signal through membrane-bound proteins, two of which are biologically active guanylyl cyclase (GC)-coupled receptors (GC-A and GC-B), and one of which is a biologically silent metabolic clearance receptor (C-receptor). ANP and BNP, which exert their biological activities through GC-A, are cardiac hormones produced predominantly in the heart, and play a critical role in circulatory support. CNP exerts its biological activities through GC-B and is present in several tissues including brain, pituitary, blood vessels, ovary, testis and cartilage. Total knockout mouse models of CNP or GC-B show severely impaired skeletal growth, and transgenic mice with elevated circulating CNP exhibit skeletal overgrowth. In addition, the knockout models have increased mortality due to restricted feeding which can be reversed by 75% by feeding them a pulverized diet. By generating cartilage-specific CNP as well as a separate GC-B knockout mice, this study investigated the physiological effects of CNP and its signaling system on endochondral bone growth

The Physiology and Mechanism of Growth

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in the growth plate. The investigators reported that the phenotype was the same for these cartilage-specific knockouts as the global knockout. However, the growth restriction was greater for the GC-B cartilage-specific knockout compared to the CNP model. This was most likely due to the fact that CNP is also secreted from tissues other than cartilage. On detailed examination of the growth plate, the investigators revealed that although the CNP/GC-B system may have an effect on all stages of growth plate chondrogenesis, promotion of the transitional differentiation from prehypertrophic chondrocytes to hypertrophic chondrocytes seemed to be its major focus. In addition, the investigators also showed that the cartilage-specific knockout mice had a similar mortality phenotype to the global knockout model, indicating that the early death was related to the physical restrictions imposed by the impaired skeletal growth.

Increased linear bone growth by GH in the absence of SOCS2 is independent of IGF-1 Dobie R1, Ahmed SF2, Staines KA1, Pass C1, Jasim S1, MacRae VE1, Farquharson C1 1

The Roslin Institute and R(D)SVS, University of Edinburgh, Midlothian, UK; 2Developmental Endocrinology Research Group, School of Medicine, University of Glasgow, Glasgow, UK J Cell Physiol 2015;230:2796–2806

Introduction: The relative importance of GH actions on the liver and/or growth plate cartilage in comparison to IGF-1 remains unclear. Methods: Investigation of the linear growth of the suppressor of cytokine signaling-2 (SOCS2) knockout mice was compared to wild-type mice. Results: Wild-type embryonic ex vivo metatarsals did not grow in response to GH, but displayed increased Socs2 transcript levels (p < 0.01). In the absence of SOCS2, GH increased metatarsal linear growth. However, this increased growth was not associated with raised IGF-1 transcript and protein. In addition, IGF-1 levels were unchanged in the medium of the GH challenged postnatal Socs2−/−. GH did elevate IGF-binding protein 3 levels in the conditioned medium, and this was more apparent in Socs2−/− metatarsals. GH did not enhance the growth of Socs2−/− metatarsals when the IGF receptor was inhibited, suggesting that IGF receptor-mediated mechanisms are still required. In addition to IGFBP3, Igf2 expression was also elevated in Socs2 metatarsals in response to GH. Discussion: SOCS2 is important for regulating the action of GH in promoting bone growth. Also, GH may act via a mechanism that is independent of IGF-1. Comments

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Although the anabolic role of GH in long bones is well accepted, the relative contributions of GH acting on the liver (to produce secondary growth-promoting circulating factors) or directly on growth plate cartilage (to produce local growth-promoting factors) remains unclear. It is likely that both these modes of GH action function in a highly coordinated manner to regulate growth plate function and linear bone growth. GH increases IGF-1 production in a number of tissues, including the liver, the main source of circulating IGF-1. GH also induces IGF-1 production within the growth plate cartilage and it is also possible that GH acts on the growth plate via IGF-1-independent mechanisms. A number of mouse models exist to study the relative roles, and in this study the investigators study the Socs2−/− model. The SOCS family of proteins is vital as a negative feedback mechanism for cytokine signaling in general, and previous studies by these investigators have shown that the SOCS2 protein may be the critical member of

Ahmed  Phillip  Grimberg

this family in the growth plate for regulating GH action. Other mouse models that have been studied for dissecting the relative roles of GH and IGF-1 in growth have been associated with abnormal circulating levels of GH and or IGF-1. However, this model has normal circulating levels of GH and IGF-1. Through a series of studies in juvenile mice as well as embryonic metatarsal cultures, the investigators show that a substantial component of the growth that is observed in this model of increased GH signaling does not depend on raised local or systemic IGF-1. The investigators observed a rise in other GH-responsive proteins, including IGF-2 and IGF-binding proteins, and their respective role in promoting growth at the level of the growth plate needs further study.

Effects of long time exposure to simulated micro- and hypergravity on skeletal architecture Canciani B1, Ruggiu A1, Giuliani A2, Panetta D3, Marozzi K2, Tripodi M3, Salvadori PA3, Cilli M4, Ohira Y1, Cancedda R1, Tavella S1 1 Dipartimento di Medicina Sperimentale, Universita’ di Genova & IRCCS AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy; 2Dipartimento di Scienze Cliniche Specialistiche e Odontostomatologiche, Sezione di Biochimica, Biologia e Fisica, Università Politecnica delle Marche, Ancona, Italy; 3Istituto di Fisiologia Clinica, CNR, Pisa, Italy; 4Animal Facility, IRCCS AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy; 5 Graduate School of Health and Sports Science, Doshisha University, Kyoto, Japan

J Mech Behav Biomed Mater 2015;51:1–12.

Introduction: There is a need to understand the effects of reduced as well as increased gravity on bone health. Methods: The structural alterations occurring in the mouse skeleton as a consequence of 90 days of simulated microgravity by hindlimb unloading and hypergravity (2 g) were investigated by conebeam X-ray micro-CT, synchrotron radiation micro-CT and histology. Results: Morphometric analysis confirmed bone architectural deficits in the microgravity model. In the femurs from hypergravity-exposed mice, the cortical thickness was noticed to be increased. In addition, the number of trabeculae that were larger was significantly increased. Mineralization of cartilage and bone deposition was increased in the 2-g mice, whereas an enlargement of the growth plate cartilage was observed in the hindlimb-unloaded group. Discussion: Not only do these data confirm previous findings of microgravity, but they also pave the way for improving the understanding of the effects of hypergravity on bone development and maintenance. Comments

Understanding the effects of gravity on physiological functions in human and animal organisms is a field of great interest. A deep understanding of the effect of gravity on bone has been limited because of a lack of technical capability and because there is a need for simulating true microgravity for periods that are long enough to be relevant as a suitable model for human conditions. The investigators describe a novel model that allows them to study mice in altered gravity (increased and decreased) for a longer period of 90 days. The hindlimb-unloading model that they describe is comparable to previous models of microgravity as far as the effects on bone go with the greatest decremental effects being observed in trabecular bone rather than cortical bone. In the hypergravity model, exposed to a force of 2 g for 23 h a day for 90 days, the mice

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had increased cortical thickness as well as an increase in the number of large trabeculae. The investigators also showed some abnormalities of the growth plate, but these were difficult to interpret given that the mice were already 8 weeks old at baseline. In summary, although the detrimental effects of reduced gravity were greater on the skeleton than the incremental effects of hypergravity, the experiments would be of interest to those considering hypergravity as a therapeutic measure. There is a need to study these effects in growing mammals.

The growth plate’s response to load is partially mediated by mechano-sensing via the chondrocytic primary cilium Rais Y1, Reich A1,2, Simsa-Maziel S1, Moshe M1, Idelevich A1, Kfir T1, Miosge N3, Monsonego-Ornan E1 1 Institute of Biochemistry and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University, Rehovot, Israel; 2Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Development, Bethesda, MD, USA; 3Department of Prosthodontics, Oral Biology and Tissue Regeneration Work Group, Medical Faculty, Georg August University, Goettingen, Germany

Cell Mol Life Sci 2015;72:597–615

Introduction: The mechanisms of how bone and growth plate respond to mechanical stimulation is unclear. The primary cilium has been identified as a mechanosensor in several cell types. Methods: In this work, the authors show that mechanical load enhances ciliogenesis in the growth plate and this leads to alterations in the Ihh-PTHrP pathway and altered chondrogenesis. To further understand the underlying mechanisms, the authors use the ATDC5 cell line to show that KIF3A plays a vital role. Conclusion: The cilium is critical for chondrocyte mechanosensing. Comments

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Recent findings in genetic research have highlighted the critical role of cilia in several multisystem diseases, several of which are also associated with a disorder of growth and skeletal development. The organelle functions as a mechanosensor in several cell types, including renal epithelial cells and endothelium. In the skeletal system, the primary cilium has also been shown as an important mechanosensor: in osteoblasts and osteocytes, the primary cilium is required for bone cell response to dynamic fluid flow, for formation of new bone in response to mechanical loading and in mediating the osteogenic differentiation of human mesenchymal stem cells to osteoblasts in response to fluid flow. Primary cilium has also been shown to be involved in several signaling pathways essential for regulation of the growth plate, such as the noncanonical Wnt and Ihh pathways. Chondrocytes express a single cilium, which projects from the cell surface into the extracellular matrix and interacts with molecules such as collagen and glycoprotein. It is found in all zones of the growth plate, oriented parallel to the longitudinal axis of the bone. In this study the investigators aimed to study the role of cilium in mediating the effects of mechanical loading on the growth plate. The investigators use the chicken as well as the ATDC5 cell line to investigate this link and show for the first time that mechanical load alters IHH signaling, inhibits chondrocyte proliferation and upregulates the number of primary cilia in the chicken growth plate concomitant with altered chondrogenesis. In the ATDC5 cell line, the investigators show that KIF3A, which is a subunit of the heterotrimeric motor protein, kinesin-2, is essential for ciliary function in the growth plate.

Ahmed  Phillip  Grimberg

Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation Yang L1,2, Tsang KY1, Tang HC1, Chan D1,3, Cheah KSE1,3 1Department

of Biochemistry, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong, China; 2Institute of Orthopaedics, Xi-Jing Hospital, Fourth Military Medical University, Xi’an, China; 3Centre for Reproduction, Development and Growth, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China Proc Natl Acad Sci USA 2014;111:12097–12102

Introduction: Generally, chondrocytes and osteoblasts are considered to be independent lineages derived from a common osteochondroprogenitor. Methods: The investigators used a cell-specific tamoxifen-inducible genetic recombination approach to track the fate of murine hypertrophic chondrocytes. Results: These chondrocytes can become osteogenic cells in fetal and postnatal endochondral bones. Conclusion: The discovery of a continuum between chondrocytes and osteoblasts revises concepts of the ontogeny of osteoblasts. Comments

This study is interesting as it challenges the view that chondrocytes and osteoblasts are completely separate lineages in development, being derived from common mesenchymal progenitors that express the transcription factors sex-determining region Y (SRY)-box 9 (Sox9) and runt-related transcription factor 2 (Runx2). Lineage determination toward the chondrocyte or osteoblast fate is controlled by the relative expression of Sox9 and Runx2. Sox9 controls chondrocyte proliferation and their progression into hypertrophy. By contrast, Runx2 is essential for specifying the osteoblast lineage and directly regulates other downstream signals. Maintenance of bone and bone regeneration, as well as a better understanding of bone and growth plate defects in skeletal dysplasias are clinical fields where it is important to understand the overlap between these two differentiation processes. By tracking the fate of murine hypertrophic chondrocytes in a cell-specific tamoxifen-inducible genetic recombination model, the investigators show that these cells can survive the cartilage-to-bone transition and become osteogenic cells in fetal and postnatal endochondral bones, and persist into adulthood. In fact, their results suggest that most hypertrophic chondrocytes become osteoblasts rather than undergo apoptosis. Their studies also suggest that events such as bone repair may accelerate the conversion of hypertrophic chondrocytes into osteoblasts. This discovery provides the basis for a conceptual change of a chondrocyte-to-osteoblast lineage continuum, with new insights into the process of endochondral bone formation, the ontogeny of bone cells and bone homeostasis. Furthermore, the findings have implications for current concepts on mechanisms of skeletal disorders and bone repair and regeneration.

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Growth plate abnormalities in pediatric cancer patients undergoing phase 1 anti-angiogenic therapy: a report from the Children’s Oncology Group Phase I Consortium Voss SD1, Glade-Bender J2, Spunt SL3, DuBois SG4, Widemann BC5, Park JR6, Leary SES6, Nelson MD7, Adamson PC8, Blaney SM9, Weigel B10 1Department of Radiology, Boston Children’s Hospital Dana-Farber Cancer Institute, Boston, MA; USA; 2Department of Pediatric Oncology, Columbia University Medical Center, New York, NY, USA; 3Department of Pediatric Hematology/Oncology, Lucile Packard Children’s Hospital Stanford University, Palo Alto, CA, USA; 4Department of Pediatric Hematology/Oncology, UCSF Medical Center-Parnassus, San Francisco, CA, USA; 5Department of Pharmacology and Experimental Therapeutics, Pediatric Oncology Branch, NCI, CCR, Mark O Hatfield-Warren Grant Magnuson Clinical Center, Bethesda, MD, USA; 6Department of Hematology/Oncology, Seattle Children’s Hospital, Seattle, WA, USA; 7Department of Radiology, Children’s Hospital of Los Angeles, Los Angeles, CA, USA; 8Children’s Hospital of Philadelphia, Abramson Research Center, Philadelphia, PA, USA; 9Texas Children’s Cancer Center/Baylor College of Medicine, Houston, TX, USA; 10Division of Hematology and Oncology, University of Minnesota, Amplatz Children’s Hospital, Minneapolis, MN, USA

Pediatr Blood Cancer 2015;62:45–51

Background: Angiogenesis is a critical component of chondrogenesis and antiangiogenic agents may be toxic to the developing growth plate. Methods: Radiological studies from 53 subjects enrolled in six separate Children’s Oncology Group Phase 1 and Pilot Consortium clinical trials evaluating new anticancer agents interfering with angiogenesis were reviewed. Results: Five patients out of 48 (9.4%), all of whom received a specific VEGF/VEGFR inhibitor, had growth plate abnormalities. Four patients had growth plate widening that was apparent on at least two successive radiographs, but was not confirmed by MRI. The fifth patient had progressive growth plate widening and evidence of physeal cartilage hypertrophy on MRI. Subsequent offtreatment radiographs showed that the growth plate changes were reversible. Conclusions: Growth plate abnormalities occur in a small number of patients undergoing antiangiogenic therapy and may be reversible but need further monitoring. Comments

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In the developing skeleton, the growth plates are active sites of new blood vessel growth and proliferation as cartilage and new bone are deposited along the zone of provisional calcification in the growing bone. Blood vessels arising in the juxtaphyseal metaphysis deliver essential growth factors, vitamins and minerals, such as Ca+2 and PO4−3, and are crucial to the coordinated program of chondrocyte proliferation, maturation, apoptosis and matrix mineralization central to the process of endochondral ossification. This process of angiogenesis and neovascularization is highly dependent on factors such as VEGF, a cytokine that acts as a powerful mitogen on endothelial cells, promoting the formation of new vessels. VEGF receptors are also expressed on the vascular endothelium of most tumor types, and blocking VEGF-mediated angiogenesis may be beneficial in controlling the growth and metastatic spread of many types of tumors. To date there are limited clinical data that drugs which block VEGF action have a detrimental effect on growth. In this study, the investigators aimed to evaluate the incidence of growth plate abnormalities in children who were receiving antiangiogenic therapy in the phase 1 setting for the treatment of refractory or recurrent cancer. On radiological examination, it seemed that approximately 10% of children may have an abnormality of the growth plate and these changes seemed to be

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reversible. It is possible that X-ray-based examination may not be sufficiently sensitive for detecting more subtle abnormalities of the growth plate. Given that other drugs such as glucocorticoids and methotrexate may also have an effect on skeletal development, it is unclear from the study whether the children were exposed to other cytotoxic drugs. Monitoring the growth of these children over the longer term will provide helpful insight.

Insulin-like growth factor-independent effects of growth hormone on growth plate chondrogenesis and longitudinal bone growth Wu S1,2, Yang W2, De Luca F1 1Section

of Endocrinology and Diabetes, St. Christopher’s Hospital for Children, Drexel University College of Medicine, Philadelphia, PA; 2Center for Translational Medicine, The First Affiliated Hospital of Xi’an Jiaotong University School of Medicine, Xi’an, PR China Endocrinology 2015;156:2541–2551

Background: GH and IGF-1 are the most important hormones controlling longitudinal bone growth. GH has a direct effect of on longitudinal bone growth, probably by inducing the expression and the action of IGF-1 locally in the growth plate. However, it is not clear yet whether these effects are entirely mediated by the local expression and action of IGF-1 and IGF-2, and if GH may also have IGF-1-independent effects on bone growth. The aim of the study was to determine whether GH can affect growth plate chondrogenesis and longitudinal bone growth without the mediation of IGF-1 or IGF-2. Methods: Transgenic mice were used in which the type 1 IGF receptor (Igf1r) gene was conditionally ablated postnatally by Cre-lox recombination only in chondrocytes. A tamoxifen (Tam)-inducible TamCartIgf1r−/− mouse was created that enabled the ablation of the Igf1r gene in chondrocytes during postnatal life after systemically injecting Tam. In addition, to study the direct and specific effects of GH on growth plate chondrocyte function, cultured chondrocytes transfected with small interfering RNAs (siRNAs) specific for Igf1r and/or GH receptor were used. TamCartIgf1rflox/flox tamoxifen-treated mice [knockout (KO) mice] and their Igf1rflox/flox control littermates (C mice) were injected for 4 weeks with GH. Results: The tibial growth and growth plate height of GH-treated KO mice were greater than those of untreated C or untreated KO mice at the end of the 4-week period. The postnatal ablation of Igf1r in the mouse growth plate resulted in diminished body and tibial growth. Despite the lack of Igf1r expression in the growth plate, postnatal systemic administration of GH induced body and tibial growth as well as cartilage formation in the growth plate. Conclusion: GH can modulate growth plate chondrogenesis and longitudinal bone growth through IGF-1R-independent mechanisms in the growth plate. Comments

This is an important article. In the present study, Wu et al. in a beautifully designed study selectively knocked out the IGF-1 receptor in the chondrocytes of the growth plate and demonstrated that GH can stimulate an animal’s tibia length independently of the IGF-1-R. Is the pendulum of the somatomedin theory moving all the way to the other side of the physiological spectrum? At first we were made to believe that the entire effect that GH has on linear growth in extrauterine life is mediated by IGF-1. Over the years it has been recognized that GH might have some local synergistic effect on IGF-1 within the growth plate, but now these authors have shown that the lo-

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cal activation of IGF-1-R is not needed to influence longitudinal growth. They have shown that GH has an IGF-1-independent effect on all layers of the growth plate. Did we get to the final conclusion concerning the way in which GH stimulates linear growth in the growth plate? Several lines of evidence have documented the importance of local IGF-1 in the growth plate and quite a few children are treated with IGF1 alone because of their extreme short stature and suspected GH resistance. Despite the fact that the present study is a very important contribution to our understanding of the physiology of growth, more studies are needed to shed light on the mechanism of action of GH and IGF-1 alone as well as in combination.

High protein intake from meat as complementary food increases growth but not adiposity in breastfed infants: a randomized trial Tang M, Krebs NF Section of Nutrition, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA Am J Clin Nutr 2014;100:1322–1328

Background: Infant dietary intakes have a significant impact on infant growth and weight gain. Some observational studies have shown greater weight gain in formula-fed infants in comparison to breastfed infants. High intake of cow-milk protein in formula-fed infants is associated with higher weight gain and increased adiposity, which have led to recommendations to limit protein intake in later infancy. For infants who are breastfed only, meat is a good source of high-quality protein and provides highly bioavailable iron and zinc. The evidence available to evaluate the effect of protein quantity specifically from complementary foods on the growth of breastfed infants is very limited. Thus, the purpose of this study was to examine the effect of a lower- compared with higherprotein complementary feeding regimen, with meat being the primary protein source, on infant growth and metabolic profile in older breastfed-only infants. Methods: This was a secondary analysis from a trial in which exclusively breastfed infants were included. Forty-two infants (18 boys) between the ages of 5 and 6 months from the Denver metropolitan area were enrolled and completed the study between January 2008 and September 2010. They were randomly assigned to receive commercially available pureed meats (meat group; n = 14) or infant cereal (cereal group; n = 28) as their primary complementary feedings for approximately 5 months. Anthropometric measures and diet records were collected monthly from 5 to 9 months of age. Results: The meat group had significantly higher protein intake, whereas energy, carbohydrate and fat intakes from complementary feeding did not differ by group over time. At 9 months of age, mean intakes of total protein were significantly higher for the meat group compared with the cereal group (p < 0.001). From 5 to 9 months of age, the weight-for-age z-score and length-for-age z-score increased in the meat group and decreased in the cereal group (p for group by time < 0.05). The change in weight-for-length z-score did not differ between groups. Total protein intake at 9 months of age and baseline weight-for-age z-score were important predictors of changes in the weight-forage z-score (R2 = 0.23, p = 0.01). Conclusion: This analysis of breastfed infants in a Westernized setting resulted in two major findings. First, compared with a lower-protein cereal-based diet, high-protein intake provided primarily from meats as complementary foods from 6 to 9 months of age was associated with greater linear growth and proportional weight gain, but without excessive gain in adiposity. Second, despite

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significantly different distributions of macronutrient intakes at 9 months of age, the combined intake of breast milk and complementary foods resulted in caloric intakes that were indistinguishable between the two groups, which reinforced the notion of the ability of breastfed infants to effectively regulate energy intake. Therefore, a higher intake of protein from meats can be safely recommended for breastfed infants for whom rich sources of bioavailable zinc and iron are important during the complementary feeding period. Comments

In the present study the authors investigated the effect of meat protein as complementary food on growth and metabolic profiles in breastfed infants. It was a secondary analysis from a different trial in which exclusively breastfed infants (5–6 months of age) were randomly assigned to receive commercially available pureed meats (meat group; n = 14) or infant cereal (cereal group; n = 28) as their primary complementary feedings for 5 months. Anthropometric measures and diet records were collected monthly from 5 to 9 months of age; intakes from complementary feeding and breast milk were assessed at 9 months of age. In this study the authors challenged the current recommendation to limit protein to 15% of energy during later infancy and the second year of life. They showed that: ‘In breastfed infants, higher protein intake from meats was associated with greater linear growth and weight gain but without excessive gain in adiposity, suggesting that potential risks of high protein intake may differ between breastfed and formula-fed infants and by the source of protein.’ However, it was neither a prospective randomized study, nor was the study powered for that question. Prospective randomized well-designed studies which investigate the amount and quality of the protein in complementary diet of breastfed and formulafed infants in the second half of their first year of life are therefore needed.

Evidence that estrogen hastens epiphyseal fusion and cessation of longitudinal bone growth by irreversibly depleting the number of resting zone progenitor cells in female rabbits Nilsson O1,2, Weise M1, Landman EBM1,2, Meyers JL1, Barnes KM1, Baron J1 1

Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA; 2Center for Molecular Medicine and Pediatric Endocrinology Unit, Department of Women’s and Children’s Health, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden Endocrinology 2014;155:2892–2899

Background: Longitudinal bone growth occurs at the growth plate by endochondral bone formation. The rate of longitudinal bone growth declines with age, and growth plate cartilage undergoes programmed senescence. As a final step in this program, the growth plate undergoes epiphyseal fusion. Previously it was shown that estrogen hastens epiphyseal fusion and cessation of longitudinal bone growth by accelerating the program of growth plate senescence, including both functional and structural changes. Because senescence appears to involve the depletion of resting zone progenitor cells, the aim was to test the hypothesis that estrogen accelerates senescence by accelerating this depletion, and to determine whether any resulting diminution in the number of these chondrocytes would reverse after the estrogen treatment stopped, or whether the depletion would persist after cessation of estrogen, and thus represent an irreversible depletion of the progenitor cells.

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Methods: Ovariectomized rabbits were exposed to physiological doses of estradiol or vehicle for 5 weeks to determine the effects on the number of resting zone cells. Additional sets of animals were treated with estradiol or vehicle for 5 weeks, after which the treatment was stopped and the number of resting zone chondrocytes was determined after an additional 5-week period. Also other structural and functional components of growth plate senescence were assessed to determine whether the accelerating effects of estrogen on other components of growth plate senescence were reversible or irreversible. Results: Transient exposure to estrogen accelerated the normal decline in growth plate height and in the number of proliferative and hypertrophic chondrocytes. Five weeks after discontinuation of estrogen treatment, these structural parameters remained advanced, indicating an irreversible advancement in structural senescence chondrocytes, and hastened epiphyseal fusion. Estrogen also caused a more rapid decline in functional parameters of growth plate senescence, including growth rate, proliferation rate and hypertrophic cell size. Once the estrogen treatment was discontinued, the growth rate, chondrocyte proliferation rate and hypertrophic cell size all normalized, suggesting that estrogen has a reversible, suppressive effect on growth plate function. In addition, estrogen accelerated the normal loss of resting zone chondrocytes with age, which was maintained after the estrogen treatment stopped, suggesting an irreversible depletion. Conclusions: Estrogen has two distinct effects on the growth plate. First, estrogen reversibly suppresses growth plate function, including proliferation in the proliferative zone, hypertrophic cell size and consequently the rate of longitudinal bone growth. Second, estrogen irreversibly advances structural senescence of the growth plate and hastens epiphyseal fusion, and accelerates depletion of progenitor cells in the resting zone, providing a potential mechanism underlying the acceleration in growth plate senescence. These findings provide a possible cellular mechanism for the clinical observations that premature estrogen exposure in children leads to premature growth cessation and early epiphyseal fusion. Comments

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For many years clinicians who treat patients suffering from undernutrition have been aware of the race between the nutritional rehabilitation and pubertal changes. Children who start their refeeding at an early age have a better prognosis to reach normal adult height than patients who get into the nutritional catch-up period during puberty. Estrogen is the limiting factor of linear growth both in girls and in boys, where testosterone is turned into estrogen in different tissues including the epiphyseal growth plate by aromatase activity. This article sheds light on the mechanism by which estrogen might interfere with nutritional catch-up growth of children who were diagnosed later in their childhood and adolescence. The present manuscript suggests that if a child needs a nutritional rehabilitation program in late childhood or the beginning of adolescence, suppression of the effect of estrogen on longitudinal bones should be considered. Studies of nutrition rehabilitation programs in the adolescence age group, with or without GnRH analogues, should be designed to verify the clinical relevance of the above study.

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Linear growth faltering in infants is associated with Acidaminococcus sp. and community-level changes in the gut microbiota Gough EK1, Stephens DA2, Moodie EE1, Prendergast AJ3, Stoltzfus RJ4, Humphrey JH5, Manges AR6 1Department

of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada; 2Department of Mathematics and Statistics, McGill University, Montreal, QC, Canada; 3Centre for Paediatrics, Blizard Institute, Queen Mary University of London, London, UK; 4Zvitambo Institute for Maternal Child Health Research, Harare, Zimbabwe; 5 Program in International Nutrition, Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA; 6Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; 7Faculty of Medicine, School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada Microbiome 2015;3:24

Note: This manuscript is discussed also in the chapter by Bhutta and Yackobovitch-Gavan [this vol., pp. 120–127]. Background: Children whose length- or height-for-age z-scores is more than 2 SD below the reference population median are termed ‘stunted’. Stunting has short-term effects on morbidity and mortality, leads to poor motor development and cognition, and reduces educational and economic attainment over their life course. Recent studies suggest a role of the intestinal microbiota in child growth. The intestinal microbiota is an ecosystem of gut microbes that helps to modulate nutrient harvesting from the diet, mucosal inflammation and immune response in the gut. Observational studies in humans have demonstrated a relationship between the intestinal microbiota and severe acute malnutrition. No study has evaluated the gut microbiota as a determinant of chronic malnutrition and linear growth. The hypothesis was that differences in the relative abundance of identified genera are independently associated with prospective deficits in linear growth. Recent analyses have aimed to determine whether changes in gut microbiota networks and relative abundance are associated with stunting status in order to identify potential microbiota members that contribute to linear growth faltering. Methods: A secondary analysis of available data from two twin cohorts of undernourished children from low-income settings (Malawi and Bangladesh) was performed in order to identify bacterial genera whose relative abundances explain linear growth. Previous analyses from these cohorts showed that acute malnutrition was associated with differences in gut microbiota functional gene abundances and maturation. In a case-control analysis, estimated covariance network models of gut microbial interactions from relative genus abundances and network analysis methods were used to select genera associated with stunting severity. In longitudinal analyses, associations between these selected microbes and linear growth were determined using between-within twin regression models to adjust for confounding and introduce temporality. Results: Less diverse gut microbiota with greater covariance network density were associated with stunting severity, and an increase in the relative abundance of Acidaminococcus sp. was associated with lower future linear growth in two very different, well-characterized cohorts of children. Conclusions: This study applied a novel use of statistical learning and network methods to identify and interpret changes in graphical models of microbiota covariance patterns. They suggest that reduced microbiota diversity and changes in covariance network density are associated with stunting severity and that overgrowth of Acidaminococcus, and possibly other glutamatefermenting microbes, may contribute to future growth deficits in already malnourished children.

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Comments

In the last few years the understanding that the ecosystem of microbes in the human gut has influences on human life has increased dramatically. It has been shown that the intestinal microbiota has a role in nutrient harvesting from the diet, coping with mucosal inflammation and on the immune response in the gut. The causal effect of intestinal microbiota has been documented in experimental models. In this article, the authors (using relatively small numbers of twins) have shown that the growth of the length of infants is associated with the composition of the gut microbiota. Clinicians are constantly struggling to understand the causes of idiopathic short stature (ISS) all over the world. Many different mechanisms have been suggested to explain the ISS phenomena. It is clear that ISS is an entity that has many causes of a common final outcome of short stature. The present study suggests that the ecosystem of microbes in the human gut might influence longitudinal growth. More studies with bigger cohorts in different geographical areas are needed to evaluate the association between the ecosystem of microbes in the human gut and longitudinal growth, and especially in children with ISS.

References 1 Farooqi A, Hägglöf B, Sedin G, Gothefors L, Serenius F: Growth in 10- to 12-year-old children born at 23 to 25 weeks’ gestation in the 1990s: a Swedish national prospective follow-up study. Pediatrics 2006; 118:e1452–e1465. 2 Pierrat V, Marchand-Martin L, Guemas I, Matis J, Burguet A, Picaud JC, Fresson J, Alberge C, Marret S, Roze JC, Kaminski M, Larroque B, Ancel PY;

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Epipage Study Group: Height at 2 and 5 years of age in children born very preterm: the EPIPAGE study. Arch Dis Child Fetal Neonatal Ed 2011; 96:F348– F354. 3 Grimberg A, Huerta-Saenz L, Grundmeier R, Ramos MJ, Pati S, Cucchiara AJ, Stallings VA: Gender bias in US pediatric growth hormone treatment. Sci Rep 2015;5:11099.

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Koletzko B, Shamir R, Turck D, Phillip M (eds): Nutrition and Growth: Yearbook 2016. World Rev Nutr Diet. Basel, Karger, 2016, vol 114, pp 21–49 (DOI: 10.1159/000441810)

Obesity, Metabolic Syndrome and Nutrition Shlomit Shalitin 1  Tadej Battelino 2  Luis A. Moreno 3 1

The Jesse Z. and Sara Lea Shafer Institute of Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel; 2 UMC-University Children’s Hospital, Medical Faculty, University of Ljubljana, Ljubljana, Slovenia; 3 GENUD (Growth, Exercise, Nutrition and Development) Research, University School of Health Sciences, University of Zaragoza, Zaragoza, Spain

Over the span of the last decades there has been an alarming increase in childhood obesity, which tends to track into adulthood. Childhood obesity is associated with significant risk for the development of comorbidities such as type 2 diabetes, dyslipidemia, hypertension, metabolic syndrome and early cardiovascular events. Early life may be a ‘critical period’ when appetite and regulation of energy balance are programmed, with lifelong consequences for obesity risk. Insight into the potential impact of modifying early-life risk factors on later obesity can be gained by evaluating their combined effects [1]. The association between breastfeeding status and childhood overweight is inconclusive. However, it seems that a longer duration of exclusive breastfeeding is associated with a lower risk of becoming overweight [2]. The encouragement and support of breastfeeding and other healthy feeding practices are especially important for low socioeconomic children who are at increased risk of early childhood obesity [3]. Infant formula with lower protein content may also reduce BMI and obesity risk later [4]. There is no clear association between the timing of the introduction of complementary foods and childhood overweight or obesity, but some evidence suggests that very early introduction (before 4 months), may increase the risk of childhood overweight [5]. Studies have revealed an association of hypovitaminosis D with insulin resistance [6] and cardiometabolic risk factors from childhood [7]. Recently it was reported that the fat mass and obesity-associated (FTO) genotype effects are more pronounced among children with insufficient vitamin D levels [8]. The consumption of sugar-sweetened beverages (SSBs) is another risk factor for obesity [9, 10] with an association of higher SSB consumption and metabolic syndrome components in overweight/obese and glucose-intolerant children [11]. Additionally, dietary pattern, food content [12, 13]

and frequency [14], amount of food intake [15] and breakfast consumption [16], and TV viewing and other screen activities [17] may also have an impact on body weight and on markers of the metabolic syndrome. This chapter reviews a selection of important articles published between July 2013 and June 2015 focused on the relation between nutrition, obesity and metabolic syndrome in childhood and in young adults.

Lactation and Early Feeding

Modifiable early-life risk factors for childhood adiposity and overweight: an analysis of their combined impact and potential for prevention Robinson SM1,2, Crozier SR1, Harvey NC1,2, Barton BD1, Law CM4, Godfrey KM1,2, Cooper C1–3, Inskip HM1 1 Medical Research Council (MRC) Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK; 2The National Institute for Health Research (NIHR) Southampton Biomedical Research Centre, University of Southampton and Southampton University Hospitals NHS Trust, Southampton, UK; 3NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Nuffield Orthopaedic Centre, Oxford, UK; 4UCL Institute of Child Health, London, UK

Am J Clin Nutr 2015;101:368–375

Note: This article is discussed also in the chapter by Michaelsen et al. [this vol., pp. 103–119]. Background: There is increasing interest in understanding the role of early environmental factors in the risk of excess weight gain because this is the period in which appetite and the long-term regulation of energy balance are permanently programmed. The objective of this study was to examine the relation between the number of early-life risk factors and obesity outcomes among children in a prospective birth cohort (Southampton Women’s Survey). Methods: Data were available for 991 mother-child pairs with children born between 1998 and 2003. Five risk factors were defined: maternal obesity (prepregnant BMI >30), excess gestational weight gain (Institute of Medicine, 2009), smoking during pregnancy, low maternal vitamin D status (3.5 (OR = 1.39, 95% CI: 1.09–1.77). Results remained significant after adjusting for daily physical activity in moderate-to-vigorous physical activity periods (min/day). Male DBrH consumers, 6–10 years of age, had longer daily periods of moderate-tovigorous physical activity compared with NBrH consumers (32.0 ± 21.4 vs. 27.5 ± 18.8 min/day, p < 0.05). For preschoolers, breakfast consumption was negatively associated with CVD risk factors, but the results of regression models were mostly insignificant. Conclusion: A negative association was found between breakfast frequency at home consumption and CVD risk factors in a large multinational population of school-aged children. Comments

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Skipping breakfast can exacerbate the desire to snack, with more desserts and highfat salty foods. Findings of the current study suggest that mechanisms other than appetite control might counteract this protectiveness of breakfast against elevated CVD risk factors. The limitations of the study include lack of information about the breakfast content and that the dietary 24-hour recalls relied in the majority of the participants on a single 24-hour dietary recall that cannot be enough to capture the weekly breakfast frequency consumption of children. More definitive randomized controlled trials are needed to investigate whether enhancing breakfast consumption among school-aged children could result in higher physical activity levels. Future epidemiological studies need to assess the content of breakfast, and the weekly frequency of breakfast consumption to evaluate the impact of breakfast on CVD risk factors in childhood.

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Gender differences in the association between stop-signal reaction times, body mass indices and/or spontaneous food intake in pre-school children: an early model of compromised inhibitory control and obesity Levitan RD1–3, Rivera J1,4, Silveira PP5, Steiner M6, Gaudreau H7, Hamilton J8, Kennedy JL1,2, Davis C9, Dube L10, Fellows L11, Wazana A12, Matthews S3, Meaney MJ7,13; MAVAN Study Team 1Centre

for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, ON, Canada; 2Department of Psychiatry, CAMH, University of Toronto, Toronto, ON, Canada; 3Department of Physiology, University of Toronto, Toronto, ON, Canada; 4Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Toronto, ON Canada; 5Núcleo de Estudos da Saúde da Criança e do Adolescente, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; 6Department of Psychiatry, St Joseph’s Hospital, McMaster University, Hamilton, ON, Canada; 7Douglas Mental Health University Institute, Montreal, QC, Canada; 8Division of Endocrinology, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; 9Department of Kinesiology, York University, Toronto, ON, Canada; 10Department of Management, McGill University, Montreal, QC, Canada 11Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada; 12Institute of Community and Family Psychiatry, Jewish General Hospital, McGill University, Montreal, QC, Canada; 13Department of Psychiatry and Neurology, McGill University, Montreal, QC, Canada Int J Obes 2015;39:614–619

Background: Obesity prevention and treatment in children is improving, but continues to fall well short of established goals. While much of this work has focused on psychosocial factors, neurocognitive correlates of obesity and obesity-related behaviors may also inform prevention and treatment. Poor inhibitory control is associated with overeating and/or obesity. A recent review suggested that the stop-signal reaction time (SSRT), a standardized computer-based measure of inhibitory control, has particularly high reliability in studies of obesity and eating behavior. The aim was to evaluate whether poor inhibitory control, as reflected in higher SSRT scores was associated with BMI z-scores and/or food intake during a laboratory-based snack test in children at 48 months of age, with evaluation of possible gender differences in these associations. Methods: The current sample consisted of preschool children (n = 193) taking part in a longitudinal study of early brain development [Maternal Adversity, Vulnerability and Neurodevelopment (the MAVAN project)]. Linear mixed-effect models were used to examine whether the measured SSRT was associated with BMI z-scores and/or dietary intake during a laboratorybased snack test. Results: There was a significant gender by SSRT interaction effect in predicting 48-month BMI z-scores. Post hoc analysis revealed an association between longer SSRT (poor response inhibition) and higher BMI only in girls. In both genders, longer SSRT was associated with greater intake of carbohydrates and sugars during the snack test. The association between SSRT scores and BMI z-scores in girls was not statistically mediated by carbohydrate or sugar intake. Conclusion: Significant associations were found between inhibitory control as assessed by a SSRT and both BMI z-scores and spontaneous intake of carbohydrates and sugars in preschoolers. Comments

The current results extend a significant body of work that has linked objective measures of inhibitory control and self-regulation to obesity and/or overeating in older children.

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Using the SSRT as a potential biomarker to predict obesity treatment response and/ or relapse is of great interest. In addition to its reliability in studies of eating behavior and obesity, the SSRT is highly standardized and easy to administer; its potential utility in clinical settings as an early marker of vulnerability merits further consideration. Ongoing follow-up of these children will help clarify the implications of these associations for longer-term macronutrient intake, eating-related pathology and/or pathological weight gain over time.

References 1 Robinson SM, Crozier SR, Harvey NC, Barton BD, Law CM, Godfrey KM, Cooper C, Inskip HM: Modifiable early-life risk factors for childhood adiposity and overweight: an analysis of their combined impact and potential for prevention. Am J Clin Nutr 2015;101:368–375. 2 Zheng JS, Liu H, Li J, Chen Y, Wei C, Shen G, Zhu S, Chen H, Zhao YM, Huang T, Li D: Exclusive breastfeeding is inversely associated with risk of childhood overweight in a large Chinese cohort. J Nutr 2014; 144:1454–1459. 3 Gibbs BG, Forste R: Socioeconomic status, infant feeding practices and early childhood obesity. Pediatr Obes 2014;9:135–146. 4 Weber M, Grote V, Closa-Monasterolo R, Escribano J, Langhendries JP, Dain E, Giovannini M, Verduci E, Gruszfeld D, Socha P, Koletzko B; European Childhood Obesity Trial Study Group: Lower protein content in infant formula reduces BMI and obesity risk at school age: follow-up of a randomized trial. Am J Clin Nutr 2014;99:1041–1051. 5 Pearce J, Taylor MA, Langley-Evans SC: Timing of the introduction of complementary feeding and risk of childhood obesity: a systematic review. Int J Obes (Lond) 2013;37:1295–1306. 6 Bril F, Maximos M, Portillo-Sanchez P, Biernacki D, Lomonaco R, Subbarayan S, Correa M, Lo M, Suman A, Cusi K: Relationship of vitamin D with insulin resistance and disease severity in non-alcoholic steatohepatitis. J Hepatol 2015;62:405–411. 7 Kelishadi R, Ardalan G, Motlagh ME, Shariatinejad K, Heshmat R, Poursafa P, Fakhri M, Tajadini M, Taslimi M: National report on the association of serum vitamin D with cardiometabolic risk factors in the pediatric population of the Middle East and North Africa (MENA): the CASPIAN-III Study. Nutrition 2014;30:33–38. 8 Lourenço BH, Qi L, Willett WC, Cardoso MA; ACTION Study Team: FTO genotype, vitamin D status, and weight gain during childhood. Diabetes 2014;63: 808–814. 9 Pan L, Li R, Park S, Galuska DA, Sherry B, Freedman DS: A longitudinal analysis of sugar-sweetened beverage intake in infancy and obesity at 6 years. Pediatrics 2014;134(suppl 1):S29–S35.

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10 Cantoral A, Téllez-Rojo MM, Ettinger AS, Hu H, Hernández-Ávila M, Peterson K: Early introduction and cumulative consumption of sugar-sweetened beverages during the pre-school period and risk of obesity at 8–14 years of age. Pediatr Obes 2015, DOI: 10.1111/ijpo.12023. 11 Wang JW, Mark S, Henderson M, O’Loughlin J, Tremblay A, Wortman J, Paradis G, Gray-Donald K: Adiposity and glucose intolerance exacerbate components of metabolic syndrome in children consuming sugar-sweetened beverages: QUALITY cohort study. Pediatr Obes 2013;8:284–293. 12 Steffen LM, Van Horn L, Daviglus ML, Zhou X, Reis JP, Loria CM, Jacobs DR, Duffey KJ: A modified Mediterranean diet score is associated with a lower risk of incident metabolic syndrome over 25 years among young adults: the CARDIA (Coronary Artery Risk Development in Young Adults) study. Br J Nutr 2014;112:1654–1661. 13 Tognon G, Hebestreit A, Lanfer A, Moreno LA, Pala V, Siani A, Tornaritis M, De Henauw S, Veidebaum T, Molnár D, Ahrens W, Lissner L: Mediterranean diet, overweight and body composition in children from eight European countries: cross-sectional and prospective results from the IDEFICS study. Nutr Metab Cardiovasc Dis 2014;24:205–213. 14 Jääskeläinen A, Schwab U, Kolehmainen M, Pirkola J, Järvelin MR, Laitinen J: Associations of meal frequency and breakfast with obesity and metabolic syndrome traits in adolescents of Northern Finland Birth Cohort 1986. Nutr Metab Cardiovasc Dis 2013; 23:1002–1009. 15 Mendez MA, Sotres-Alvarez D, Miles DR, Slining MM, Popkin BM: Shifts in the recent distribution of energy intake among U.S. children aged 2–18 years reflect potential abatement of earlier declining trends. J Nutr 2014;144:1291–1297. 16 Papoutsou S, Briassoulis G, Wolters M, Peplies J, Iacoviello L, Eiben G, Veidebaum T, Molnar D, Russo P, Michels N, Moreno LA, Tornaritis M; IDEFICS Consortium: No breakfast at home: association with cardiovascular disease risk factors in childhood. Eur J Clin Nutr 2014;68:829–834.

Shalitin  Battelino  Moreno

17 Olafsdottir S, Berg C, Eiben G, Lanfer A, Reisch L, Ahrens W, Kourides Y, Molnár D, Moreno LA, Siani A, Veidebaum T, Lissner L: Young children’s screen activities, sweet drink consumption and anthropometry: results from a prospective European study. Eur J Clin Nutr 2014;68:223–228. 18 Agostoni C, Decsi T, Fewtrell M, Goulet O, Kolacek S, Koletzko B, Michaelsen KF, Moreno L, Puntis J, Rigo J, Shamir R, Szajewska H, Turck D, van Goudoever J; ESPGHAN Committee on Nutrition: Complementary feeding: a commentary by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr 2008;46:99–110. 19 Agostoni C, Braegger C, Decsi T, Kolacek S, Koletzko B, Mihatsch W, Moreno LA, Puntis J, Shamir R, Szajewska H, Turck D, van Goudoever J: Role of dietary factors and food habits in the development of childhood obesity: a commentary by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr 2011;52:662–669. 20 Hunsberger M, Lanfer A, Reeske A, Veidebaum T, Russo P, Hadjigeorgiou C, Moreno LA, Molnar D, De Henauw S, Lissner L, Eiben G: Infant feeding practices and prevalence of obesity in eight European countries – the IDEFICS study. Public Health Nutr 2013;16:219–227. 21 Agostoni C, Braegger C, Decsi T, Kolacek S, Koletzko B, Michaelsen KF, Mihatsch W, Moreno LA, Puntis J, Shamir R, Szajewska H, Turck D, van Goudoever J: Breast-feeding: a commentary by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr 2009;49:112–125. 22 Wilson AC, Forsyth JS, Greene SA, Irvine L, Hau C, Howie PW: Relation of infant diet to childhood health: seven year follow up of cohort of children in Dundee infant feeding study. BMJ 1998;316:21–25. 23 Kelishadi R, Ardalan G, Motlagh ME, Shariatinejad K, Heshmat R, Poursafa P, Fakhri M, Tajadini M, Taslimi M: National report on the association of serum vitamin D with cardiometabolic risk factors in the pediatric population of the Middle East and North Africa (MENA): the CASPIAN-III Study. Nutrition 2014;30:33–38. 24 Goletzke J, Herder C, Joslowski G, Bolzenius K, Remer T, Wudy SA, Roden M, Rathmann W, Buyken AE: Habitually higher dietary glycemic index during puberty is prospectively related to increased risk markers of type 2 diabetes in younger adulthood. Diabetes Care 2013;36:1870–1876. 25 Gopinath B, Flood VM, Rochtchina E, Baur LA, Louie JC, Smith W, Mitchell P: Carbohydrate nutrition and development of adiposity during adolescence. Obesity (Silver Spring) 2013;21:1884–1890. 26 Estruch R, Ros E, Salas-Salvadó J, et al: Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368:1279–1290.

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27 Martinez-Gonzalez MA, Bes-Rastrollo M: Dietary patterns, Mediterranean diet, and cardiovascular disease. Curr Opin Lipidol 2014;25:20–26. 28 Salas-Salvadó J, Bulló M, Babio N, et al: Reduction in the incidence of type 2 diabetes with the Mediterranean diet: results of the PREDIMED-Reus nutrition intervention randomized trial. Diabetes Care 2011; 34:14–19. 29 Núñez-Córdoba JM, Valencia-Serrano F, Toledo E, et al: The Mediterranean diet and incidence of hypertension: the Seguimiento Universidad de Navarra (SUN) Study. Am J Epidemiol 2009;169:339–346. 30 Kastorini C-M, Milionis HJ, Esposito K, et al: The effect of Mediterranean diet on metabolic syndrome and its components: a meta-analysis of 50 studies and 534,906 individuals. J Am Coll Cardiol 2011;57: 1299–1313. 31 Babio N, Bulló M, Basora J, et al: Adherence to the Mediterranean diet and risk of metabolic syndrome and its components. Nutr Metab Cardiovasc Dis 2009;19:563–570. 32 Kesse-Guyot E, Ahluwalia N, Lassale C, et al: Adherence to Mediterranean diet reduces the risk of metabolic syndrome: a 6-year prospective study. Nutr Metab Cardiovasc Dis 2013;23:677–683. 33 Ryan MC, Itsiopoulos C, Thodis T, Ward G, Trost N, Hofferberth S, et al: The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. J Hepatol 2013;59:138–143. 34 Hakanen M, Lagstrom H, Kaitosaari T, Niinikoski H, Näntö- Salonen K, Jokinen E, et al: Development of overweight in an atherosclerosis prevention trial starting in early childhood. The STRIP study. Int J Obes (Lond) 2006;30:618–626. 35 Kontogianni MD, Vidra N, Farmaki AE, Koinaki S, Belogianni K, Sofrona S, et al: Adherence rates to the Mediterranean diet are low in a representative sample of Greek children and adolescents. J Nutr 2008; 138:1951–1956. 36 Kesse-Guyot E, Ahluwalia N, Lassale C, Hercberg S, Fezeu L, Lairon D: Adherence to Mediterranean diet reduces the risk of metabolic syndrome: a 6-year prospective study. Nutr Metab Cardiovasc Dis 2013; 23:677–683. 37 Lissner L, Lanfer A, Gwozdz W, Olafsdottir S, Eiben G, Moreno LA, et al: Television habits in relation to overweight, diet and taste preferences in European children: the IDEFICS study. Eur J Epidemiol 2012; 27:705–715. 38 Koletzko B, Toschke AM: Meal patterns and frequencies: do they affect body weight in children and adolescents? Crit Rev Food Sci Nutr 2010; 50: 100– 105.

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Koletzko B, Shamir R, Turck D, Phillip M (eds): Nutrition and Growth: Yearbook 2016. World Rev Nutr Diet. Basel, Karger, 2016, vol 114, pp 50–65 (DOI: 10.1159/000441922)

Term and Preterm Infants Johannes B. van Goudoever 1  Dominique Turck 2 1

Department of Pediatrics, Emma Children’s Hospital-AMC and VU University Center, Amsterdam, The Netherlands; 2 Unité de Gastro-Entérologie, Hépatologie et Nutrition, Clinique de Pédiatrie, Hôpital Jeanne de Flandre et Faculté de Médecine, Université de Lille, INSERM U995, Lille, France

Nutrition in early life has a major impact on later health and disease. Nowadays we are aware of the impact of appropriate macro- and micronutrient nutritional strategies already starting before conception and extending throughout pregnancy and into early childhood. In the present chapter we focus predominantly on articles that have been published last year on short-term outcomes, whereas the chapter entitled ‘Early nutrition and its effects on growth, body composition and later obesity’ by Michaelsen et al. [this vol., pp. 103–119] focusses on later outcomes. Here we include preterm and term infants and show the recent developments on growth and nutrition. Rates of premature delivery are still around 6–11% and with increased survival rates, there has been growing attention on the processes of care during a child’s stay in the neonatal intensive care unit (NICU) that optimize their shortand long-term outcomes. Appropriate growth of a prematurely born infant may have a significant impact on his or her developmental and growth outcomes after discharge from the NICU. We have selected papers on growth and early nutrition in both welldeveloped areas of the world and in developing countries, as these deserve more attention as well. Therefore, we included a small study on an alternative way of fat absorption by massage from Iran, discuss the recent developments of growth charts and the way of advancing feeding in a low-income setting. Additionally, we discuss recent developments in fat emulsions used in NICUs, but put emphasis on the use of human milk as well. The studies with term infants which are discussed here focus on protein, oligosaccharide and milk fat globule membrane content, but timing of introduction and quality of complementary feeding are also important and have been discussed in other recently published articles. Together, these articles improve our knowledge and show our advancement in understanding the role of appropriate nutrition in the first weeks of life. These recently published articles also raise new (mechanistic) questions, requiring all our efforts to continue to perform research in all parts of the world.

General Core data necessary for reporting clinical trials on nutrition in infancy Koletzko B1, Fewtrell M2, Gibson R3, van Goudoever JB4, Hernell O5, Shamir R6, Szajewska H7; Consensus Group on Outcome Measures Made in Paediatric Enteral Nutrition Clinical Trials (COMMENT); Early Nutrition Project 1Department

of Paediatrics, Dr. von Hauner Children’s Hospital, Ludwig Maximilians University of Munich, Munich, Germany; 2Institute of Child Health, London, UK; 3FOODplus Research Centre, The University of Adelaide, Glen Osmond, SA, Australia; 4Department of Pediatrics, Emma Children’s Hospital, Academic Medical Center and VU University Medical Center Amsterdam, Amsterdam, The Netherlands; 5Department of Clinical Sciences, Paediatrics, Umeå University, Umeå, Sweden; 6Schneider Children’s Medical Center of Israel, Sackler Faculty of Medicine, Tel Aviv University, Petach Tikva, Israel; 7Department of Paediatrics, Medical University of Warsaw, Warsaw, Poland Ann Nutr Metab 2015;66:31–35

This paper presents an updated and revised summary of the ‘core data set’ that has been proposed to be recorded and reported in all clinical trials on infant nutrition by the recently formed Consensus Group on Outcome Measures Made in Paediatric Enteral Nutrition Clinical Trials (COMMENT). This core data set was developed based on a previous proposal by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee on Nutrition in 2003. It comprises confidential data to identify subjects and facilitate contact for further follow-up, data to characterize the cohort studied and data on withdrawals from the study, and some additional core data for all nutrition studies on preterm infants. Comments

This article sets the scene for reporting outcomes whenever nutritional trials are conducted. It enables comparisons between different trials which makes the interpretation of these trials easily accessible. This set of data could (and should) be used by the various researchers who are developing research projects in this field, grant organizations who are financing the studies, and editorial boards and reviewers who are involved in making these results public.

Attrition in long-term nutrition research studies: a commentary by the ESPGHAN Early Nutrition Research Working Group Fewtrell MS1, Domellöf M2, Hojsak I3, Hulst JM4, Kennedy K1, Koletzko B5, Mihatsh W6, Stijnen T7 1Childhood

Nutrition Research Centre, UCL Institute of Child Health, London, UK; 2Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden; 3University Children’s Hospital, Zagreb, Croatia; 4Erasmus MC, Sophia Children’s Hospital, Rotterdam, The Netherlands; 5Metabolic and Nutritional Medicine, Ludwig-Maximilans-Universität München, Dr. von Hauner Children’s Hospital, University of Munich Medical Center, Munich, Germany; 6Munich Municipal Hospitals, Harlaching Hospital Department of Paediatrics, Munich, Germany; 7Leiden University Medical Center, Leiden, The Netherlands J Pediatr Gastroenterol Nutr 2015, Epub ahead of print

Long-term follow-up of randomized trials and observational studies provide the best evidence currently available to assess long-term effects of nutrition, and such studies are an important compo-

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nent in determining optimal infant feeding practices. However, attrition is an almost inevitable occurrence with increasing age at follow-up. There is a common assumption that studies with less than 80% follow-up rates are invalid or flawed, and this criticism seems to be more frequently applied to follow-up studies involving randomized trials than observational studies. In this paper, we explore the basis and evidence for this ‘80% rule’ and discuss the need for greater consensus and clear guidelines for analyzing and reporting results in this specific situation. Comments

Long-term follow-up studies are difficult to conduct and many studies are faced with a substantial loss to follow-up. This article discusses how the loss to follow-up should be addressed, indicating that studies with a higher than 20% loss can still provide us with important knowledge.

Preterm Infants

BMI curves for preterm infants Olsen IE1,2, Lawson ML3, Ferguson AN3, Cantrell R3, Grabich SC3, Zemel BS4,5, Clark RH6 1

School of Nursing, University of Pennsylvania, Philadelphia, PA, USA; 2Department of Biology and Physics, College of Science and Mathematics, Kennesaw State University, Kennesaw, GA, USA; 3 Department of Statistics and Analytical Sciences, College of Science and Mathematics, Kennesaw State University, Kennesaw, GA, USA; 4Division of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of Philadelphia, PA, USA; 5 Department of Pediatrics, The University of Pennsylvania School of Medicine, Philadelphia, PA, USA; 6Pediatrix Medical Group Inc., Sunrise, FL, USA Pediatrics 2015;135:e572– e581

Background: Most preterm infants experience growth failure postnatally, which is not only shown by weight gain rates, but also by body composition changes. The objective of this study was to create and validate intrauterine weight-for-length growth curves using the contemporary, large, racially diverse US birth parameters sample used to create the Olsen weight-, length- and headcircumference-for-age curves. Methods: Data from 391,681 US infants (Pediatrix Medical Group) born at 22–42 weeks’ gestational age (born 1998–2006) included birth weight, length, head circumference, estimated gestational age and gender. Results: A total of 254,454 singleton infants (57.2% male) who survived to discharge were used for this exercise. BMI was the best overall weight-for-length ratio for both genders and a majority of gestational ages. Gender-specific BMI-for-age curves were created (n = 127,446) and successfully validated (n = 126,988). Conclusions: BMI was different across gender and gestational age. We provide a set of validated reference curves (gender-specific) to track changes in BMI for prematurely born infants cared for in the neonatal intensive care unit for use with weight-, length- and head-circumference-for-age intrauterine growth curves.

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van Goudoever  Turck

Comments

BMI is a relatively new measure for premature infants with limited information about the association between abnormally high or low BMIs and outcomes of preterm infants. However, the use of BMI curves in older children and adults are a standard way of assessment. These gender-specific BMI curves developed from a large sample need to be interpreted with caution as we do not know the impact of their use. Since nutritional intake is mostly determined by the prescribing team, a low or high BMI might merely be a reflection of unit policy. Furthermore, length measurements are difficult to perform and subject to error. However, the construction of these curves provides a valuable base from which we can build ideal curves in the future.

A randomised controlled trial of high vs low volume initiation and rapid vs slow advancement of milk feeds in infants with birth weights ≤ 1000 g in a resourcelimited setting Raban S1, Santhakumaran S2, Keraan Q1, Joolay Y1, Uthaya S3, Horn A1, Modi N3, Harrison M1 1Division

of Neonatal Medicine, Department of Paediatrics, University of Cape Town, South Africa; of Neonatal Medicine, Department of Medicine, London School of Hygiene and Tropical Medicine, London, UK; 3Section of Neonatal Medicine, Department of Medicine, Imperial College, London, UK 2Section

Paediatr Int Child Health 2015, Epub ahead of print

Background: Optimal feeding regimens for infants ≤1,000 g have not been established and remain a concern throughout the world. A controlled trial was designed to establish the safety and efficacy of high versus low volume initiation and rapid versus slow advancement of milk feeds in a resourcelimited setting. Methods: Infants ≤1,000 g birth weight were randomized to one of four arms: low (4 ml/kg/day) or high (24 ml/kg/day) initiation, and slow (24 ml/kg/day) or rapid (36 ml/kg/day) advancement of exclusive feeds of human milk (mother’s or donor) until a weight of 1,200 g was reached. After this point, formula was used to supplement insufficient mother’s milk. The primary outcome was time to reach 1,500 g. Results: 200 infants were recruited (51: low/slow, 47: low/rapid, 52: high/slow, 50: high/rapid). Infants on rapid advancement regimens reached 1,500 g the fastest (hazard ratio = 1.48, 95% CI: 1.05–2.09, p = 0.03). The rapid advancement groups also regained birthweight more rapidly (hazard ratio = 1.77, 95% CI: 1.26–2.50, p = 0.001). There was no apparent effect of high versus low initiation volumes, but there was some evidence of interaction between interventions. There were no significant differences in other secondary outcomes, including necrotizing enterocolitis, feed intolerance and late-onset sepsis. Conclusions: In this small pilot study, higher initiation feed volumes and larger daily increments appeared to be well tolerated and resulted in more rapid early weight gain. These data provide justification for a larger study in resource-limited settings to address mortality, necrotizing enterocolitis and other important outcomes. Comments

Although this study can be considered a pilot study because of the number of infants included (n = 200), the impact of the outcome can be huge. This study shows that feeding advancement can be increased, although safety should be established in a larger study. If proven effective, this will reduce hospital time considerably, while all efforts should be made to monitor long-term outcomes as well.

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The value of routine evaluation of gastric residuals in very low birth weight infants Torrazza RM1, Parker LA2, Li Y3, Talaga E4, Shuster J5, Neu J1 1Division

of Neonatology, Department of Pediatrics, University of Florida, Gainesville, FL, USA; of Nursing, University of Florida, Gainesville, FL, USA; 3Department of Pediatrics, University of Florida, Gainesville, FL, USA; 4Shands Hospital, University of Florida, Gainesville, FL, USA; 5Department of Health Outcomes and Policy, College of Medicine, University of Florida, Gainesville, FL, USA 2College

J Perinatol 2015;35:57–60

Background: Gastric residual evaluation prior to feedings in premature infants is a controversial topic with many different approaches around the world. The purpose of this study was to compare the amount of feedings at 2 and 3 weeks of age, number of days to full feedings, growth, and incidence of complications between infants who underwent routine gastric residual evaluation versus those who did not. Methods: Sixty-one premature infants were randomized to one of two groups. Group 1 received routine gastric residual evaluation prior to feeds whereas group 2 did not. Results: There was no difference in amount of feeding at 2 (p = 0.66) or 3 (p = 0.41) weeks of age, growth, days on parenteral nutrition, or complications. Although not statistically significant, infants without routine gastric residual evaluation reached feeds of 150 ml kg–1 per day 6 days earlier and had 6 fewer days with central venous access. Conclusion: Routine gastric residual evaluation may not improve nutritional outcomes in premature infants.

A randomised trial of re-feeding gastric residuals in preterm infants Salas AA1, Cuna A2, Bhat R3, McGwin G Jr4, Carlo WA5, Ambalavanan N5 1Department

of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA; 2Department of Pediatrics, University of Missouri-Kansas City, Kansas City, MO, USA; 3Department of Pediatrics, University of Maryland, Baltimore, MD, USA; 4Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA; 5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA Arch Dis Child Fetal Neonatal Ed 2015;100:F224–F228

Background: To determine whether refeeding of gastric residual volumes reduces the time needed to achieve full enteral feeding in preterm infants. Methods: Parallel-group randomized controlled trial in a regional referral neonatal intensive care unit with 72 infants of gestational age 230/7 to 286/7 weeks receiving minimal enteral nutrition (