Yearbook of Pediatric Endocrinology 2010

Yearbook of Pediatric Endocrinology 2010
Endorsed by the European Society for Paediatric Endocrinology

Editors

Associate Editors

Jean-Claude Carel Ze’ev Hochberg

Gary Butler Evangelia Charmandari Francesco Chiarelli Stefano Cianfarani Mehul Dattani Nicolas De Roux Ken Ong Orit Pinhas-Hamiel Michel Polak Lars Sävendahl Olle Söder Martin Wabitsch

Diabetes: Clinical and Experimental

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Sponsored by a grant from Pfizer Endocrine Care
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© Copyright 2010 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free and non-aging paper (ISO 9706) by Reinhardt Druck, Basel ISBN 978-3-8055-9601-5 ISSN 1662-3391

Mikael Knip

Editors

Jean-Claude Carel
Pediatric Endocrinology and Diabetology, and INSERM U690, University Paris 7 Denis Diderot, Hôpital Robert Debré, 48, boulevard Sérurier, FR–75935 Paris cedex 19, France Tel. +33 1 40 03 41 05; Fax +33 1 40 03 24 29; E-Mail jean-claude.carel@inserm.fr

Ze‘ev Hochberg
Meyer Children’s Hospital, Rambam Medical Center, Faculty of Medicine Technion-Israel Institute of Technology, POB 9602 IL–31096 Haifa, Israel Fax +972 (0) 4 854 21 57; E-Mail z_hochberg@rambam.health.gov.il

Associate Editors

Gary E. Butler
Department of Paediatrics and Adolescents University College London Hospital, 250 Euston Road, London NW1 2PQ, UK Tel. +44 8451 555 000 ext. 5240, E-Mail g.butler@ich.ucl.ac.uk

Evangelia Charmandari
Division of Endocrinology and Metabolism, Clinical Research Center Biomedical Research Foundation of the Academy of Athens 4 Soranou tou Efessiou Street, GR–11527 Athens, Greece Tel. +30 210 659 7196, Fax +30 210 659 7545, E-Mail evangelia.charmandari@googlemail.com

Francesco Chiarelli
Department of Pediatrics, University of Chieti, Via dei Vestini, 5 IT–66013 Chieti, Italy Tel. +39 0871 358015, Fax +39 0871 574831, E-Mail chiarelli@unich.it

Stefano Cianfarani
Department of Public Health and Cell Biology Tor Vergata University Room E178, Via Montpellier 1, IT–00133-Rome, Italy Tel. +39 06 6859 3074, Fax +39 06 6859 2508, E-Mail stefano.cianfarani@uniroma2.it

Mehul T. Dattani
Developmental Endocrine Research Group Clinical and Molecular Genetics Unit, Institute for Child Health University College London London, WC1N 1EH, UK Tel. +44 207 905 2657, Fax +44 207 404 6191, E-Mail mdattani@ich.ucl.ac.uk

Diabetes: Clinical and Experimental

+972 3 5305015. Fax +972 3 5305055.fr Lars Sävendahl Pediatric Endocrinology Unit. +44 1223 769207. FR– 75015 Paris Tel. Diabetes and Obesity Unit.se Olle Söder Pediatric Endocrinology Unit. Israel Tel. Fax +46 8 5177 5128.de Mikael Knip .se Martin Wabitsch Pediatric Endocrinology. Department of Pediatrics and Adolescent Medicine University of Ulm.savendahl@ki.health. +46 8 517 75124.uk Orit Pinhas-Hamiel Pediatric Endocrine and Diabetes Unit. E-Mail michel. Fax +33 1 40 40 91 95.ong@mrc-epid. Q2:08 Department of Woman and Child Health Karolinska Institutet and University Hospital.il Michel Polak Service d’endocrinologie pédiatrique INSERM EMI 0363.ac. Fax +33 1 44 38 16 48. Germany Tel. Box 285 Cambridge CB2 0QQ. Sweden Tel. rue de Sèvres. E-Mail martin. 48 Boulevard Sérurier FR–75019 Paris.soder@kbh.fr Ken Ong Medical Research Council Epidemiology Unit Institute of Metabolic Science.polak@nck. Safra Children’s Hospital Sheba Medical Center Ramat-Gan IL–52621 Ramat-Gan. Q2:08 Department of Woman and Child Health Karolinska Institutet and University Hospital. +46 8 5177 2369.wabitsch@uniklinik-ulm.deroux@inserm.Nicolas De Roux INSERM U 690. +49 731 5002 7715. Eythstrasse 24 DE–89075 Ulm. France Tel.aphp.gov. Fax +44 1223 330316. Hôpital Necker-Enfants Malades 149.cam. Solna SE–171 76 Stockholm. AP-HP Hôpital Robert Debré. +49 731 50027789. E-Mail Orit.ki. Solna SE–171 76 Stockholm.Hamiel@sheba. E-Mail olle. UK Tel. Laboratoire d’Hormonologie. E-Mail nicolas. +33 1 40 03 19 85. Sweden Tel. Addenbrooke’s Hospital. Fax +46 8 517 75128. +33 1 44 49 48 03/02. E-Mail ken. E-Mail lars.

van den Akker and Evangelia Charmandari 119 Type 1 Diabetes: Clinical and Experimental Francesco Chiarelli and M. Anja Moss. Metabolic Syndrome. Lipids Orit Pinhas-Hamiel 171 Population Genetics and Pharmacogenetics Ken K. Daniel Tews. Dattani 33 Thyroid Michel Polak. Loredana Marcovecchio 139 Obesity and Weight Regulation Martin Wabitsch. Gabor Szinnai.T. Butler 207 Editor’s Choice Jean-Claude Carel and Ze’ev Hochberg 219 Science and Medicine Ze’ev Hochberg and Jean-Claude Carel 237 253 Author Index Subject Index Diabetes: Clinical and Experimental VII . Julia von Schnurbein and Pamela Fischer-Posovszky 155 Type 2 Diabetes Mellitus. Gevers and Mehul T. Ong and Cathy Elks 189 Evidence-Based Medicine in Pediatric Endocrinology Gary E.Table of Contents IX Preface Ze’ev Hochberg and Jean-Claude Carel 1 Neuroendocrinology Carine Villanueva. Carsten Posovszky. Lukas Huihjbregts and Nicolas de Roux 13 Pituitary Evelien F. Michaela Keuper. Aneta Gawlik and Lars Sävendahl 83 Reproductive Endocrinology Olle Söder and Lena Sahlin 99 Adrenals Erica L. Aurore Carré and Mireille Castanet 49 Growth and Growth Factors Stefano Cianfarani 65 Bone. Growth Plate and Mineral Metabolism Terhi Heino. Dov Tiosano. Christian Denzer.

In the Yearbook Preface. Berlin. This Yearbook attempts to provide the 2009–10 chapter of the pediatric endocrine science. and to clinicians who must maintain familiarity with the foundation sciences of medical practice as they evolve. centering on the literal bodily death of the Godhead of Judeo-Christian theology.Preface The approach and fusion of many basic. The task of presenting recent advances in a concise but comprehensive form seems no less important as the difficulty increases. who have done an enormous work to discern this year’s advances and provide their chapters in a timely fashion. useful to basic scientists who wish to understand the clinical issues of modern pediatric endocrinology. as summarized in the 2010 Yearbook of Pediatric Endocrinology. Diabetes: Clinical and Experimental 25 . who endorses the Yearbook. Ze’ev Hochberg (Haifa) Jean-Claude Carel (Paris) Wilson JD: The evolution of endocrinology. Urban & Schwarzenberg. 2005]. We are grateful to our twelve Associate Editors and their coauthors. to clinical scientists who wish to base their research on the most recent developments in the field.62:389–396. population genetics.. only about 1% of which had been published prior to 1889... the Yearbook has been. proteomics and metabolomics. evolutionary biology – all of which require attention in our consideration of the nature and mechanism of disease processes. wrote: Everybody thinks he’s being oh-so-deep when he says science doesn’t have all the answers . published the first textbook on endocrinology that was promptly translated into English: Internal Secretion: The Basic Physiology and Significance for Pathology. translational and clinical aspects of medicine make it increasingly difficult to define the limits of subjects to be included in a short presentation of pediatric endocrine highlights of the year. In fulfilling this task. The book listed more than 8. The problem is that we don’t have all the science. This averages more than 400 papers a year during the first 20 years of the field [Wilson. innate immunology. in 1910. and we acknowledge the generous support by Pfizer that makes the Yearbook project possible for its seventh year in a row. are based on new knowledge and concepts in the diverse fields of genetics and genomics. to the European Society for Paediatric Endocrinology (ESPE). molecular biology. we annually recognize the anniversary of a major scientific breakthrough. Professor of General and Experimental Pathology at the German University in Prague. As such. and continues to be. Science does have all the answers. who is best known for his Godhead Trilogy novels. Artur Biedl.. Clin Endocrinol (Oxf) 2005. 100 years ago. modern diagnosis and therapy depend on such consideration. The enormous advances of modern medical science.. systems biology. we have kept in view the original purpose of a compact and condensed volume. The fiction author James Morrow.500 references.

Ghervan C. Massachusetts General Hospital. Guiochon-Mantel A. Conclusion: GnRH1 mutation is a new genetic cause of normomics isolated hypogonadotropic hypogonadism. Hôpital Robert Debré and Université Paris Didérot. Methods and Results: Screening for GnRH1 mutation was the first hypothesis tested to explain congenital IHH without anosmia. Hôpital de Bicêtre. Methods and Results: GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism Chan YM. large numbers of patients were tested without success. an insertion of an adenine at nucleotide position 18. Both affected patients have the same phenotype with isolated gonadotropic deficiency without anosmia. Both parents and 1 unaffected sibling were heterozygous for the insertion. Lang-Muritano M. Lombes M. Plummer L. Genetic defects have now been described in several genes. was found in 2 siblings from consanguineous parents. Pitteloud N. GnRH itself. Wu CH. In transfected cells this insertion results in an aberrant peptide lacking the conserved GnRH decapeptide. France N Engl J Med 2009. One non-synonymous missense mutation in the eighth amino acid of the GnRH decapeptide. France New gene The most obvious candidate gene in gonadotropic deficiency validated at last Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a condition characterized by a failure to undergo puberty and normal fertility in adulthood. Four heterozygous variants were also described in 4 patients and were not seen in controls. Faculté de Médecine Paris-Sud and Assistance Publique-Hôpitaux de Paris. However. Seminara SB Harvard Reproductive Sciences Center and Reproductive Endocrine Unit. Young J Universite Paris-Sud. The phenotype was reversed by pulsatile GnRH administration. Two papers published this year have reported loss of function mutations in few cases of IHH. bilateral cryptorchidism and absent puberty. A polymorphism . IHH is related to a defect of GnRH secretion or GnRH activity. Amory JK. Brailly-Tabard S. Paris. Millar RP. This frameshift mutation was not seen in 192 controls. Lavoie HB. INSERM UMR-S693. Tsiaras S. The mutation was found in a male with micropenis at birth.360:2742–2748 Mutations in GnRH1 which encode for the preprohormone were screened in a population of 310 hypogonadotropic hypogonadism cases. Crowley WF. Paris.Neuroendocrinology Carine Villanueva. Gaspert A. Lukas Huihjbregts and Nicolas de Roux INSERM U676. USA Proc Natl Acad Sci USA 2009. Jr. to date. Conclusion: This study confirms the pivotal role of GnRH in human reproduction. One homozygous frameshift mutation leading to the synthesis of a peptide truncated at the C-terminal end of the mature peptide. Tello JA. Salenave S. One homozygous frameshift mutation. de Guillebon A. Cerrato F. Boston. Chanson P. One nonsense mutation that causes premature termination within the GnRH-associated peptide and 2 sequence variants that cause non-synonymous amino-acid substitutions in the signal peptide and in the GnRH-associated peptide.. Mass. In the early 1990s. no mutations had been described in the most obvious candidate gene.106:11703–11708 GnRH1 mutations were screened in 290 hypogonadotropic hypogonadism cases. Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation Bouligand J.

139:61–72 Background: It has been clearly demonstrated that male sexual behaviors rely on a specific neural network development that requires the sex hormones testosterone and estrogen.. New mechanism Role of estrogen in brain sexual dimorphism Estrogen masculinizes neural pathways and sex-specific behaviors Wu MV. Male mice lacking a functional AR still display this sexually dimorphic trait. San Francisco. Manoli DS. -galactosidase and placental alkaline phosphatase. The pivotal role of GnRH in the regulation of the gonadotropic axis has been known for more than 20 years. Since estrogen is barely undetectable in the male circulation. University of California-San Francisco. probably by promoting cell survival of aromatase-expressing neurons. This allowed them to highlight a sexual dimorphism of the aromatase-expressing neural network in the bed nucleus of the stria terminalis and medial amygdale. USA Cell 2009. how both hormonal pathways interact to govern this sexually dimorphic neural circuit remains unknown. These papers confirm that the physiological function of GnRH1 in humans is restricted to the regulation of the gonadotropic axis. Harada N. a local conversion of testosterone into estrogen by aromatase in the brain is likely to explain how estrogen determines the male-specific differentiation of aromatase neurons. such as aggressiveness and territorial marking. the gonadotropic deficiency was isolated and other endocrine functions of the anterior pituitary were normal. there was no anosmia. Shah NM Program in Neuroscience. In female neo- 2 Carine Villanueva/Lukas Huihjbregts/Nicolas de Roux . Female mice neonatally exposed to estrogen display an increase of territorial urine marking and aggression as well as a reduced sexual receptivity to males mounting and intromission attempts.which did not fit with the hypothesis of a mendelian genetic disease with recessive transmission was reported and GnRH1 was therefore rejected. The analysis of specific apoptosis markers expression in aromatase neurons of bed nucleus of the stria terminalis and medial amygdale shows a higher level of apoptotic cells in young females relative to their male counterparts. However. Both patients had blunted response to a single GnRH administration which represents an interesting finding. Conclusion: This study shows that the sexually dimorphic expression of aromatase is not controlled by AR. This point had already been described 10 years ago when the first mutation of the GnRH receptor was described in patients with low testosterone and estradiol levels. LH pulses were detected in 1 GnRH-mutated female and correlated to the GnRH pulses. In 2009. The phenotype reported by both groups is very similar. The authors have designed a knock-in mouse line expressing reporter enzymes in aromatase-expressing neurons. The authors therefore speculated that aromatase expression could be the key link between the two hormonal pathways. which govern the acquisition of typical male sexual behaviors. Methods and Results: In order to determine whether estrogens or testosterone participate in aromatase expression regulation. they designed a knock-in mouse model in which aromatase-expressing neurons specifically express the two enzymatic reporters. A similar response was observed in patients with partial gonadotropic deficiency due to GnRH receptor mutation. The authors show a highly sexually dimorphic distribution of aromatase-expressing neurons in terms of number and projections in the bed nucleus of the stria terminalis and the posterodorsal component of the medial amygdale. It confirms that the GnRH test is not appropriate to discriminate hypothalamic or pituitary defects in IHH. The very low frequency of GnRHR1 mutations indicates that it should not be the first gene to be screened in patients with IHH. Fraser EJ. two papers appeared at the same time and both reported a very low frequency of GnRH1 mutation in 310 or 290 IHH cases. neonatal administration of estrogen or testosterone in female mice induced a pattern of brain aromatase expression similar to wild-type males. However. In all cases. Coats JK. normal LH and FSH levels and adequate response to GnRH administration [1]. Honda S. Tollkuhn J. Calif. After 13 days of pulsatile GnRH administration. Testosterone acts via the androgen receptor (AR) and is also metabolized in the brain into estrogens by aromatase.

such as erectile activity.nates. and Institut de Biologie. However. Mutant mice were as receptive to female pheromones as wild-type mice in terms of neuronal activity and olfaction. However. France J Neurosci 2009. ovaries are inactive whereas males display a surge in testosterone that is absolutely required for proper male sexual behavior acquisition. the authors demonstrate the role of central AR in the somatotropic axis. Génétique MoléculaireNeurophysiologie et Comportement. Conclusion: These results show that central AR is involved in male-specific acquisition of sexual and aggressive behaviors. testosterone (T) plays a crucial role in the establishment of malespecific neuronal network. de Gendt K. T signaling is mediated either directly via the androgen receptor (AR) or indirectly via the estrogen receptor (ER) after T aromatization into estradiol. and whether other sexually dimorphic populations of neurons are determined through such a mechanism. It also raises numerous questions on how local conversion of testosterone into estrogen promotes aromatase neurons survival in the BNST and MeA. Neuroendocrinology 3 . the latter protecting the aromatase-expressing neurons from entering apoptosis. the authors show that AR expression in the brain at the time of the androgen surge is very weak and is regulated by ERs. male ARNsDel display only moderately impaired male behaviors. Liere P. Verhoeven G. Because T and AR also exert major peripheral effect on male gonadal differentiation and several other physiological functions. where T signals augment the male-pattern behaviors that have been differentiated under the control of estrogen signaling. T and LH secretions were twofold higher than in wild-type animals with no changes in FSH levels. Here the authors bring evidence that this neonatal surge allows local testosterone aromatization into estrogen. governing typical male sexual behavior. The authors did not detect AR expression in GnRH neurons. Paris. but showed severely impaired masculine behaviors. In this study. suggesting that interneurons such as kisspeptin neurons. and participates in the regulation of the somatotropic axis. thereby maintaining functional AR signaling in the peripheral tissues. Because LH secretion is increased twofold in ARNesCre mice. suggesting that T signaling through AR in the brain plays a crucial role in the establishment of a male-specific neuronal network. Therefore. although the authors report a high proportion of hypofertile males. the underlying mechanisms have always remained unclear. Loss of central AR did not abrogate fertility. Duittoz A. Male ARNesCre mice display strongly impaired masculine behavior. Tronche F.29:4461–4470 Background: In the developing male. This work therefore brings precious insight into these mechanisms. However. the authors designed a powerful genetic model to explore the specific role of central AR in mice. as mutant mice showed reduced IGF-I levels and growth retardation. Mutant males were fertile and phenotypic analyses showed that central T has little influence on the urogenital tract development. Conditional inactivation of androgen receptor gene in the nervous system: effects on male behavioral and neuroendocrine responses Raskin K. confirming previous indirect evidence of T feedback provided by the study of ER knockout male mice [2]. the data strongly suggest the existence of a major T-dependent negative feedback on GnRH release as well as a pituitary positive feedback on LH secretion. which express AR [3]. especially the balanced roles between testosterone and estrogen. Mhaouty-Kodja S Centre National de la Recherche Scientifique (CNRS). The major role of estrogen. Collège de France. Methods and Results: In order to distinguish between the central and peripheral roles of AR. Finally. the balance between central and peripheral influence of T on the determinism of male behavior and neuroendocrine control of reproduction is unclear. mounting and aggressiveness. Juntti et al. Unité Mixte de Recherche. Moreover. Analysis of Kiss1 expression in ARNesCre mice would allow to test this hypothesis. may convey T signal toward GnRH neurons. the authors used the Cre-loxP technology to generate mutant mice specifically lacking AR expression in the nervous system only (ARNesCre). In contrast with ARNesCre mice. [4] recently generated another neuron-specific AR knockout mouse line called ARNsDel. the authors propose that estrogen metabolized from testosterone during development is responsible for a higher expression of AR in the adult brain of males. testosterone and aromatase in the acquisition of male sexual behavior has been known for over 20 years.

where kisspeptin neurons 4 Carine Villanueva/Lukas Huihjbregts/Nicolas de Roux . France Endocrinology 2010. The events occurring in the median eminence of the hypothalamus during the ovarian cycle are a striking example of the dynamic morphological changes controlling neurosecretory axons. Simpson ER. PGE2 treatment induces an increase of retraction of cultured tanycytes. tanycytes do not retract. It is now well established that neuronal signaling at the cellular level is not solely dependent on other neuronal inputs. the kisspeptin neuropeptide encoded by KISS1 has been extensively described as a key part in the activation of the gonadotropic axis at puberty through the modulation of GnRH release. The authors previously provided evidence that endothelial cells of the median eminence play a key role in the modulation of neuroglial remodeling through the nitric oxide (NO) pathway. New Zealand Endocrinology 2009. Prior to the preovulatory surge of LH. therefore allowing GnRH release into the circulation. Dunedin. but the molecular mechanism governing tanycyte retraction in response to GnRH output requirements still remain unclear. Postnatal development of an estradiol-kisspeptin-positive feedback mechanism implicated in puberty onset Clarkson J. a modulator of tanycyte plasticity.150:3214–3220 Background: Over the past years. Department of Physiology. which metabolize PGE2. tanycytes no longer create a physical barrier between GnRH neuron terminal axons. However. The question of how the negative estradiol feedback switches to a positive feedback remains unanswered. Conclusion: The authors show that vascular endothelial cells play a critical role in the neuroendocrine brain plasticity by conveying estradiol signaling toward tanycytes in the ME. When cultured alone or cocultured with ECME in the presence of a NO synthase-dominant negative form. d’Anglemont de Tassigny X. Kasparov S. Beauvillain JC. These results add a new level of complexity to the understanding of estradiol-induced rise of GnRH secretion prior to the LH preovulatory surge. This retraction could be facilitated by an estradiol-dependent increase of cyclooxygenases COX1 and 2. the authors first determined the postnatal profile of kisspeptin expression in the rostral periventricular area of the third ventricule.Role of estradiol in the dynamic control of tanycyte plasticity mediated by vascular endothelial cells in the median eminence de Seranno S. tanycytes and neurons coordinate their activity in response to changing outputs. such as estradiol. Triggering of NO release by L-arginine in estradiol-free cocultures induces tanycytes retracting. resulting in tanycytes retraction. Here the authors suggest that estradiol induces NO release from endothelial cells of the median eminence. This elegant work brings further insight into the mechanisms on how endothelial cells. which prevent GnRH crossing the basal lamina of the brain to reach the pituitary portal circulation. Estradiol upregulates both COX1 and COX2 expression in tanycytes. suggesting a retraction of the surrounding tanycytes. Loyens A. Unité 837. Finally. the mechanisms underlying the increase of KISS1 expression in the hypothalamus prior to the onset of puberty remain unknown. Herbison AE Centre for Neuroendocrinology. they show that in vivo inhibition of COX activity in mice impairs the estrous cycle. suggesting that estradiol triggers tanycytes retraction by inducing a NO release by ECME. Leroy D. Lille. Ultrastructural analysis of mouse hypothalamic explants of the ME showed that PGE2 induces an increase of the distance between GnRH nerve terminals and the basal lamina. University of Otago. Ojeda SR. but strongly relies on the microenvironment formed by the surrounding glia and brain capillaries. Boon WC. leading to an increase of prostaglandin E2 (PGE2) synthesis.151:1760–1772 Background: During low GnRH outputs. Cyclooxygenase (COX)1 and COX2 are known to be involved in NO-induced actin cytoskeleton remodeling of tanycytes. Methods and Results: The authors show that tanycytes cocultured with endothelial cells of the median eminence (ECME) present an important retraction under short estradiol exposure. Estrella C. Prevot V Institut National de la Santé et de la Recherche Médicale. thereby confirming the important role of COX and PGE2 in the regulation of the estrous cycle. Methods and Results: Using immunocytochemistry. GnRH-secreting axons are enveloped by ependymoglial cells named tanycytes.

mice lacking a functional aromatase display a total absence of kisspeptin immunoreactivity in the periventricular area of the third ventricule. Treatment with exogenous estrogen restores kisspeptin wild-type profile of expression. This circuitry provides a mechanism to modulate the pulsatile secretion of GnRH.innervate GnRH neurons. kisspeptin. projections to the lateral and ventral hypothalamic tract and the medial forebrain bundle. Whether estrogen acts directly on kisspeptin neurons remains to be defined. Ariz. In this study. Furthermore. and a decrease in the arcuate nucleus. Some neurons residing in the rat arcuate nucleus (ARC) express neurokinin B (NKB). They show that kisspeptin immunoreactivity in mouse occurs around the postnatal day (P)15 and reaches its maximal level at P30. Kisspeptin expression was not detected before P15. University of Arizona College of Medicine. NK3 receptor and estrogen receptor. Once ovarian function produces sufficient estrogen level. these results account for a positive feedback loop model where estrogen-induced increase of kisspeptin activates GnRH neurons resulting in a rise of gonadotropins. kisspeptin in periventricular area of the third ventricule facilitates GnRH impulse generator. Second. and (4). which corresponds to the onset of puberty. Burke MC. As the kisspeptin/KISS1R system is critical for normal puberty onset. Methods and Results: The projections of these neurons in the ARC were studied using NKB immunochemistry as a marker. Anderson MJ. such as GABA and glutamate. arcuate nucleus was ablated by neonatal injection of monosodium glutamate.. suggesting that the early activation of GnRH neurons soon after birth does not depend on kisspeptin. occurring around P15 in mice. behavior and neuroendocrine processes. Rance NE Department of Pathology. (2) projections into the median eminence. First. (3) projections toward the periventricular zone. However. but rather on other neurotransmitters signaling. the authors bring evidence for an estrogen-driven positive regulation of kisspeptin expression in the hypothalamic region periventricular area of the third ventricule. dynorphin. Neuroendocrinology 5 . USA Neuroscience 2010. Concepts revised Characterization of kisspeptin neurons Forebrain projections of arcuate neurokinin B neurons demonstrated by anterograde tract tracing and monosodium glutamate lesions in the rat Krajewski SJ. how this neuronal network regulates the gonadotropic axis is unknown. Conclusion: The diverse projections of arcuate NKB neurons provide evidence that NKB/kisspeptin/dynorphin neurons could integrate the reproductive axis with multiple homeostatic. Tucson. but it would be very interesting to compare the mechanisms of prepubertal upregulation of kisspeptin in the periventricular area of the third ventricule with the upregulation occurring in the AVPV in adult females. Four major projections pathways are described: (1) local and bilateral projections in the arcuate nucleus. which in turn stimulate gonadal steroids and so on. ultimately leading to the activation of the gonadotropic axis at puberty. McMullen NT. which resulted in a very strong reduction in kisspeptin immunoreactivity at P30 and P60.166:680–697 Background: Current studies indicate that neurokinin-3 (NK3) receptor and kisspeptin receptor signaling play a key role in the regulation of the gonadotropic axis activity in humans. This study reveals a bilateral interconnected network of sex-steroid-responsive neurons in the arcuate nucleus of the rat that project GnRH terminals in the median eminence. neurokinin B fibers were anterogradely labeled using biotinylated dextran amine (BDA) injection into the arcuate nucleus and NKB/BDA immunoreactive axons were labeled. Conclusion: These results show that ovarian estrogen is required for the postnatal increase of kisspeptin expression in periventricular area of the third ventricule neurons during the prepubertal period. Female pups were then ovariectomized.

Tac3 encodes neurokinin B which is the ligand of the neurokinin B receptor encoded by Tacr3. Kisspeptin neurons in the ARC drive pulsatile GnRH and LH secretion. The first article provides compelling evidence that the majority of the neurokinin B-immunoreactive axons within the median eminence in rat originate from the arcuate nucleus and modulate GnRH secretion through the neurokinin-3 receptor via non-synaptic transmission. Kisspeptin neurons serve as the central pacemaker that drives GnRH secretion. National Institute of Agrobiological Sciences. Clifton DK. dynorphin and neurokinin B are coexpressed in the same population of neurons. and dynorphin and neurokinin B seem to be involved in the process leading to the rhythmic discharge of kisspeptin in goat. and the estrogen receptor. a similar group of neurons were described in monkeys. The frequency of these bursts is reduced by gonadal steroids. Electrophysiological techniques showed that bursts of multiple-unit activity (MUA) occurring in the medial basal hypothalamus of ovariectomized animals are associated with discrete pulses of LH. Conclusion: Kisspeptin neurons in ARC regulate GnRH secretion. Although Tacr3-invalidated adult mice were fertiles. Mutations in Tac3 and Tacr3 have been recently associated with gonadotropic axis deficiency [Yearbook 2009. 6 Carine Villanueva/Lukas Huihjbregts/Nicolas de Roux . or KOR antagonist. Mogi K. Navarro VM. the authors provide evidence that dynorphin and neurokinin B indeed participate in the regulation of GnRH pulsatile secretion in goat. kisspeptin and dynorphin. These results are consistent with a model in which the pulsatile secretion of GnRH is related to a rhythmic oscillation activity in kisspeptin neurons leading to rhythmic secretion of kisspeptin. these two papers confirm the essential role of neurokinin and dynorphin in the regulation of arcuate nucleus neurons expressing kisspeptin. Tsukuba. dynorphin. Murata K. Japan J Neurosci 2010. Mori Y. Methods and Results: Using immunochemistry. After central administration of neurokinin B. The multiple projections of these neurons suggest that it could also participate in the regulation of other homeostasic. neurokinin B (NKB) or -opiate receptor (KOR) antagonist. the authors have characterized kisspeptin neurons in the goat arcuate nucleus (ARC) and evaluated their role in GnRH secretion regulation. The arcuate nucleus KiSS/NKB/ Dyn neurons network probably acts as a GnRH pulse generator: NKB/NK3R signalling stimulates and the Dyn/Kor signalling inhibits the activation of KiSS/NKB/Dyn neurons.which suggest that this group of neurons also participates in the hypothalamic regulation of estrogen-negative feedback on the mouse gonadotropic axis. a group of sex steroid-responsive neurons expresses neurokinin B. Okamura H Laboratory of Neurobiology. It is therefore fundamental to characterize the neuronal network involved in this regulation and its physiological role in the gonadotropic axis homeostasis. a group of kisspeptin neurons express neurokinin B. The importance of the neurokinin B receptor is underscored by its expression both in arcuate neurokinin B neurons and GnRH terminals in the median eminence. whereas neurokinin B induces multiple-unit activity volleys. electrophysiological techniques show that the multiple unit activity in close proximity of kisspeptin neurons are influenced by neurokinin B and dynorphin A. This co-expression of the three peptides in ARC neurons is thus a conserved mechanism observed in all mammals studied to date.Neurokinin B and dynorphin A in kisspeptin neurons of the arcuate nucleus participate in generation of periodic oscillation of neural activity driving pulsatile gonadotropin-releasing hormone secretion in the goat Wakabayashi Y. Maeda K. Tsukamura H. pp 9–10]. In the human infundibular nucleus. They do not preclude a similar activating-inhibiting loop on the GnRH neurons. electrophysiological techniques and central injection of dynorphin (DynA). Central injection of dynorphin inhibits MUA volleys and pulsatile LH secretion. This study also suggests a physiological function for dynorphin and neurokinin B. Nakada T. In the second article. Ibaraki.30:3124–3132 Background: The pulsatile release of GnRH secretion is essential to drive pulsatile gonadotropin secretion and normal reproduction in mammals. Immunohistochemistry confirmed that kisspeptin. Ohkura S. dynorphin. Steiner RA. behavioral and neuroendocrine circuits. In conclusion.

To support this hypothesis. Yale University School of Medicine and the Ribicoff Research Facilities. van den Pol A. This conditional postnatal deletion was sufficient to cause hyperphagic obesity in Sim1 heterozygotes.106:17217–17222 Background: The link between energy balance and reproduction is critical. Tex. This study demonstrates a role for Sim1 in food intake regulation after birth by modulating the leptinmelanocortin-oxytocin pathway. Sim1 null mice die perinatally and lack anterior periventricular paraventricular and supraoptic hypothalamic nuclei. This study also suggests that Sim1 and its potential target genes act postnatally in paraventricular hypothalamic nucleus and could be potential therapeutic targets for appetite suppression in obese individuals. Gautron L. USA Proc Natl Acad Sci USA 2009. Using stereological cell counting. Kublaoui BM McDermott Center for Human Growth and Development.New hope Sim1 as a new target in obesity Postnatal Sim1 deficiency causes hyperphagic obesity and reduced mc4r and oxytocin expression Tolson KP. which encodes a transcription factor. Methods and Results: The authors designed a mouse line with a conditional postnatal CNS deletion of Sim1 by crossing -calcium/calmodulin-dependent protein kinase II-Cre mice with mice carrying a floxed Sim1 allele. Connecticut Mental Health Center. Dumalska I. University of Texas Southwestern Medical Center. Conclusion: The hyperphagic Sim1-deficient mouse becomes obese because of feeding dysregulation due to changes in the leptin-melanocortin-oxytocin pathway. Morozova E. Single-minded 1 (Sim1) deletions seem to be one of the few causes of monogenic isolated (non-syndromic) obesity but the mechanism involved in the phenotype is unknown. USA J Neurosci 2010. Conn. the phenotype was rescued by oxytocin treatment. Fasting and food restriction up-regulate the hypothalamic melanin-concentrating hormone (MCH) system that promotes feeding and decreases energy expenditure. New Haven. The physiological postnatal functions of this protein have not been well established. MCH knockout mice are lean and have a higher metabolism but remain fertile. Alreja M Department of Psychiatry. Zinn AR. are associated with a monogenic obesity in humans and mice. However. the authors showed no hypocellularity in the paraventricular nucleus of the mutant mice hypothalamus and normal neuronal PVN projections.. New mechanism Molecular Interface between food intake and reproduction Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation. However. In negative energy balance. decreased expression of mc4r could also explain hyperphagia. Dallas. MC4R and oxytocin mRNAs were significantly decreased in this area in both conditional Sim1 homozygotes and germ line Sim1 heterozygotes. Gemelli T. Phenotypic analyzes performed in heterozygote animals did not allow to conclude whether Sim1 is only involved in hypothalamic development or also participates in postnatal physiology of the hypothalamus.. The decrease in oxytocin PVN expression after Sim1 invalidation suggests a possible role of oxytocin deficiency in the hyperphagia observed in this mouse.30:3803–3812 Background: Mutations in single-minded 1 (Sim1). linking energy balance to reproduction Wu M. MCH also regulates other hypothalamic related function such as Neuroendocrinology 7 . Elmquist JK. reproductive processes need to be aborted but molecular mechanisms mediating this link remain unclear. Additional studies are needed to further identify which of Sim1 targets are indeed regulating food intake.

single cell-nested PCR in living brain slices showed that GnRH neurons do not express leptin receptor 8 Carine Villanueva/Lukas Huihjbregts/Nicolas de Roux . Kemp CJ. Tups A. Some of them. MCH has no effect on kisspeptin-insensitive GnRH. Conclusion: Considering the role of MCH in regulating energy balance and of kisspeptin in regulating fertility and pubertal onset. one of which expresses the vesicular glutamate transporter 2 (vGluT2). Centre for Neuroendocrinology. Grattan DR. Finally. Kisspeptin is the major regulator of GnRH secretion and therefore the central regulator of the gonadotropic axis. University of Otago School of Medical Sciences. The most intriguing result reported here is the capacity of melanin-concentrating hormone to specifically target kisspeptin-activated GnRH neurons and not GnRH neurons refractory to kisspeptin activation. Fertility was assessed in males and females with conditional leptin receptor knockout mice from all forebrain neurons or GnRH neurons only.150:2805–1812 Background: Environmental regulation of GnRH neuronal activity determines the reproductive status of the individual. This study reports a combined effect of melanin-concentrating hormone on these two neuroendocrine targets by showing that melanin-concentrating hormone can inhibit the excitatory effect of kisspeptin on vGlutT2-GnRH neurons. drug abuse. MCH blocks the excitatory effect of kisspeptin on vGluT2-GnRH neurons. The next step of this interesting model would be to demonstrate that the inhibitory post-synaptic effect of melanin-concentrating hormone revealed by patch-clamp is associated with a decrease of kisspeptin-induced GnRH secretion. such as insulin. Liu X. It is now clear that kisspeptin is the major regulator of the GnRH secretion and therefore it is involved in the timing of the pubertal onset and in the occurrence of the LH surge leading to ovulation. behavior and mood. Peptides conveying metabolic fuel to brain act at different levels of the gonadotropic axis. Leptin receptor deletion in forebrain neurons prevented the onset of puberty resulting in infertility and blunted estradiol-induced LH surge. Leptin is one of the hormones communicating information about metabolic status to the hypothalamic GnRH neuronal system. Mulligan AC. VGluT2. act directly on GnRH neurons. This inhibitory effect of melanin-concentrating hormone was observed in prepubertal as well as pubertal mice in both sexes. Leptin receptor deletion in GnRH neurons did not impair fertility.sleep. Herbison AE. This result provides an additional evidence of the presence of at least two GnRH neuron populations in the normal hypothalamus. Normal energy balance is critical for normal fertility which occurs only when metabolic fuel is available. target kisspeptins neurons. Using patch-clamp recording in multiple lines of transgenic mice. Methods and Results: To determine whether leptin acts directly on GnRH neurons. MCH may provide a critical link between energy balance and reproduction. Wu et al. others such as leptin. Two subpopulations of GnRH neurons have been described. they demonstrated a strong inhibitory effect of MCH on vGluT2-GnRH neurons. Dunedin. New Zealand Endocrinology 2009. cholinergic or GABAergic neurons located in the same hypothalamic nucleus. The normal fertility in melanin-concentrating hormone knockout indicates that melaninconcentrating hormone effect on the gonadotropic axis is mainly required to curtail reproductive activity in conditions such as food deprivation. Anderson GM Department of Anatomy and Structural Biology. New mechanism Leptin and GnRH secretion Leptin indirectly regulates gonadotropin-releasing hormone neuronal function Quennell JH. Phipps SJ. Methods and Results: In this study. have tested the hypothesis that the link between feeding regulation and reproduction is mediated via a direct postsynaptic effect on vGluT2-GnRH neurons activated by kisspeptin. First. pSTAT3 immunopositive GnRH neurons were counted after intraventricular injection of leptin in males and females rats. MCH fibers are in close proximity to VGluT2-GFP and GnRH-GFP neurons. This inhibitory effect of MCH is mediated via a direct postsynaptic BA2+-sensitive K+ channel mechanism involving the MCHR1 receptor. the authors used three complementary approaches.

Takenoya F. Cone RD. it is shown that NPW expression increases under low leptin levels. Shimomura Y. Intracerebroventricular leptin treatment induced pSTAT3 expression within the AVPV but not in GnRH neurons. NPW seems to be a new example of a peptide having a predominant role in response to specific circumstances. ventromedial. Previous reports have shown that NPW is expressed in different hypothalamic nuclei known as essential areas in the regulation of energy metabolism and feeding behavior. pSTAT3 neuronal knockout is the only component of the leptin signalling pathway that results in infertility and recapitulates the leptin receptor KO phenotype. Neuroendocrinology 9 . activates POMC and inhibits NPY neurons in mice expressing promoter-driven green fluorescent protein. In leptin-deficient mice. The authors studied the effect of leptin on NPW neurons in primary cells culture from adult rats and it will be necessary to confirm this effect using an in vivo approach. Shioda S. Miyazaki. Yamaguchi H. Here. Nakazato M Frontier Science Research Center. Conclusion: GnRH neurons are not direct targets for leptin in rodents.151:2200–2210 Background: Neuropeptide W (NPW) is an anorectic peptide produced in the brain but its interactions with other peptides that regulate feeding are unknown. Leptin regulation of NPW expression is controlled by phosphorylation of STAT3 which induces SOCS3 in NPW-expressing neurons.mRNA. The authors also report that NPW reduces feeding potentially via the melanocortin-4-receptor signaling pathway. anorectic peptides are up-regulated whereas orexigenic peptides are down-regulated by leptin. NPW expression was significantly up-regulated in leptin-deficient and leptin-receptor-deficient mice. The exact intracellular signaling pathways governing this control remain unclear. Mondal MS. Murakami N. leptin replacement rescued NPW hypothalamic levels. Conclusion: NPW plays an important role regulating feeding under the conditions of leptin insufficiency. This study definitively confirms that leptin acts on the GnRH system via afferent interneurons. It is necessary to study whether the role of NPW under normal conditions is similar. lateral and arcuate nuclei. Normal fertility was observed in GnRH neuron conditional leptin receptor deletion. New hormone A new neuropeptide involved in the regulation of food intake Neuropeptide W: an anorectic peptide regulated by leptin and metabolic state Date Y. Kisspeptin neurons are probably one of the candidate interneurons to be tested. University of Miyazaki. This control of leptin on NPW seems to be direct via activation of the leptin receptor in NPW-expressing neurons. Single cell-nested PCR confirmed the absence of leptin receptor mRNA in GnRH neurons and pSTAT3 immunochemistry showed no co-localization with GnRH labelling. Mori M. however. These results add a new complexity in the hypothalamic network regulating feeding behavior in low leptin condition. Methods and Results: NPW is present in several nuclei of the hypothalamus including the paraventicular. Usually. which was a surprising result. Kiyotake. Japan Endocrinology 2010. Ghamari-Langroudi M. Kageyama H. The possibility that leptin receptor could stimulate other signalling pathways than pSTAT3 cannot be excluded.

Yale University School of Medicine. Cresswell JA.New mechanism From the islet to the brain and back Influence of insulin in the ventromedial hypothalamus on pancreatic glucagon secretion in vivo Paranjape SA. a combination of anti-insulin antibody plus GABA receptor agonist muscimol prior to a hypoglycemic clamp or under baseline conditions. Conclusion: Insulin inhibits -cell glucagon secretion both at the level of the pancreas and of the VMH. Bogan JS. McCrimmon RJ.59:1521–1527 Background: The hypothesis that insulin regulates pancreatic -cell glucagon secretion by a central effect on the hypothalamus has not been well investigated. VMH insulin action directly suppressed glucagon response to insulin-induced hypoglycemia independently of intra-islet insulin or input from circulating catecholamines. Local blockade of VMH insulin action increased basal glucagon levels.. USA Diabetes 2010. Que. McNay EC. Altogether. Sherwin RS Department of Internal Medicine. insulin receptor antagonist. Montreal. these data point to the central importance of the hypothalamus in the regulation of metabolic fluxes and their hormonal control. New Haven.. The loss of glucagon response to hypoglycemia in type 1 diabetic patients might result in part from the simultaneous increase in insulin levels both in the VMH and locally in the islet caused by exogenous insulin administration.to 5-fold lower than in the absence of systemic hyperinsulinemia with phloridzin-induced hypoglycemia. Chan O. Division of Endocrinology and Metabolism. Bourque CW Centre for Research in Neuroscience. The authors suggest that the primary site for insulin-mediated glucagon regulation is the islet but highlight a secondary role for central mechanisms. Conn. The authors cannot exclude the possibility that VMH surrounding regions also contribute to the changes observed in glucagon secretion because the cerebral injection is difficult to realize. an effect completely abolished by a simultaneous injection of -aminobutyric acid A receptor agonist. Research Institute of the McGill University Health Center. Methods and Results: To study whether insulin acts within the ventromedial hypothalamus (VMH) to modulate the secretion of glucoregulatory hormones. New mechanism A central clock preventing enuresis Central clock excites vasopressin neurons by waking osmosensory afferents during late sleep Trudel E. Canada Nat Neurosci 2010. This study provides evidence for a role of insulin signalling in the regulation of -cell function in vivo.13:467–474 Background: In addition to its major function in the endocrine axis regulation. Pancreatic glucagon response to central insulin was 4. An insulin central effect appears to occur under hypoglycemia and a basal condition and might contribute to glucose homeostasis disorders. Here. Integrated regulations between circadian rhythms and endocrine homeostasis have been 10 Carine Villanueva/Lukas Huihjbregts/Nicolas de Roux . muscimol. the authors compared the effects of VMH exposure to insulin. Zhu W. anti-insulin antibody. food intake and circadian rhythms. VMH insulin microinjection suppressed glucagon response to phloridzin-induced hypoglycemia. Glucose homeostasis is regulated by insulin and glucagon with a subtle interplay between these two hormones and it is known that insulin exerts a paracrine effect in the islet on glucagon. it is shown that insulin also acts centrally to regulate pancreatic glucagon secretion under fasting and mild hypoglycemic conditions. the hypothalamus is a central regulator of many fundamental behaviors like temperature regulation. Horblitt AM.

Endocrine 1999. Braun RE. Eacker SM. Methods and Results: Clock neurons of the SCN modulate osmosensory synapses onto vasopressin neurons to facilitate osmoregulated vasopressin release during sleep. et al: The androgen receptor governs the execution. Fraser EJ. 2. Misrahi M. Lubahn DB. et al: Differential regulation of KiSS-1 mRNA expression by sex steroids in the brain of the male mouse. De Roux N. Schaison G. Juntti SA.337:1597–1602. This biological rhythm over 24 h is fundamental for a normal endocrine homeostasis. N Engl J Med 1997. In this paper. The experimental approach used by the authors is interesting as they were able to stimulate organum vasculosum laminae terminalis neurons with a hyperosmotic stimulus with or without electrical stimulation of the suprachiasmatic nucleus and then recorded action potentials at distance in magnocellular neurosecretory cells. Their results indicate that the increased release of vasopressin during the end of the sleep cycle is mainly regulated by the release of an inhibitory effect of suprachiasmatic nucleus neurons on osmosensory neurons. The molecular mechanisms linking suprachiasmatic nucleus circadian activity and daily hormonal rhythms are poorly understood. Tollkuhn J.66:260–172. Neuron 2010.11:137–143. This work opens the way to understand how suprachiasmatic nucleus neurons can regulate circadian rhythms of different endocrine axes. Neuroendocrinology 11 . but not programming. Genet R. the molecular mechanisms by which the suprachiasmatic nucleus (SCN) regulates hormonal secretion remain unknown. suprachiasmatic nucleus neurons and vasopressin neurosecretory cells located in the supraoptic nucleus is shown.146:2976–2984. Smith JT. 3. The characterization of the biochemical mechanism of this inhibitory effect will be the next step of this study. Haisenleder DJ. Conclusion: Clock neurons mediate an activity-dependent presynaptic silencing of osmosensory afferent synapses onto vasopressin neurons. Biological rhythms are under the control of the suprachiasmatic nucleus located in the hypothalamus. a molecular mechanism to explain the circadian regulation of the homeostatic circuit involved in osmotic balance is proposed. Endocrinology 2005. Gottsch ML. Osmoregulatory gain is enhanced by removal of this effect during late sleep. A better understanding of these molecular mechanisms may also be important for testing new hypothesis and new treatment for nocturnal enuresis. Previous work has revealed that clock neurons have low firing rates during the late sleep period. et al: A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. A complex biochemical interactions between osmosensory neurons located in the organum vasculosum lamina terminalis. Neurons of this nucleus exhibit daily rhythmic activities that are regulated by cell autonomous molecular feedback loops involving clock genes. Chanson P. Rissman EF: Steroid feedback on gonadotropin release and pituitary gonadotropin subunit mRNA in mice lacking a functional estrogen receptor. This release is facilitated at the end of the sleep cycle to prevent dehydration and enuresis.. Stoll EA. The authors found that excitation of rat vasopressin neurons by osmosensory afferents is facilitated during the late sleep period. suggesting a possible regulation of magnocellular neurosecretory cells by SCN neurons. Wersinger SR. of male sexual and territorial behaviors. Young J. 4. Wu MV.largely described. Tan S. References 1. Dungan HM. Several hormones are produced with a circadian timing and vasopressin is one of them. The circadian rhythm is adjusted to 24 h by external clues like daylight. Soderborg T. However.

as well as the interaction between signaling. Kinoshita E.G188X-OTX2 protein demonstrated reduced (approx. Institute for Child Health. Transient transfection assays were performed using luciferase reporters containing IRBP.b and Mehul T. Ogata T Department of Endocrinology and Metabolism. Hasegawa K.A72fsX86 in case 2 with normal pituitary function and microphthalmia. Fukami M. development and tumor formation. combined pituitary hormone deficiency (CPHD) and APH with an EPP. National Children’s Medical Center. continuing progress is being made to uncover the functions of oxytocin. with no dominant-negative effect. and IRBP (interstitial retinoid-binding protein) promoters. especially its role in behavior and an exciting development is the pharmacological use of oxytocin to affect behavior [1]. cDNA screening identified positive OTX2 expression in the hypothalamus. Tajima T. and sequenced all patients for mutations in OTX2. Yokoya S. and anterior pituitary hypoplasia (APH) and an ectopic/undescended posterior pituitary (EPP). pituitary tumor biology and pituitary signaling. p. and case 4 with microphthalmia and normal pituitary function). but there appears to be considerable variability in the phenotype. Numerous new mutations and their functional implications for pituitary function have been identified.A245V. Japan tomogata@nch. Geversa. Detailed pituitary phenotypes in patients with OTX2 mutations and OTX2 target genes for pituitary function other than HESX1 and POU1F1 remain to be determined. HESX1. Azuma N. p. Kosaka K.go. Moriuchi H. POU1F1. New mutations Heterozygous orthodenticle homeobox 2 mutations are associated with variable pituitary phenotype Dateki S. Human cDNA from a variety of tissues was screened for the presence of OTX2 transcripts. 50%) transactivation function for the four promoters. Two additional missense mutations. Tanaka H.A72fsX86-OTX2 proteins led to loss of transactivation and the p. e. . MRC-National Institute for Medical Research. Tokyo. London b Division of Molecular Neuroendocrinology.T178S and p. Motomura K. Results: The authors identified the following heterozygous mutations: p. Dattania a Developmental Endocrine Research Group. Methods: The authors studied 94 Japanese patients with various ocular or pituitary abnormalities. whereas the p. some mutations do not appear to be associated with eye phenotypes [2].Pituitary Evelien F. anophthalmia/microphthalmia. London. OTX2.g.K74fsX103-OTX2 and p. A number of heterozygous mutations in the gene encoding this protein. UK Significant advances have been made in the field of pituitary development. Recent studies have suggested a positive role of OTX2 in pituitary as well as ocular development and function. Sato N. In addition.86-Mb microdeletion including OTX2 in case 5 with IGHD and APH associated with anophthalmia/microphthalmia. Multiplex ligation-dependent probe amplification (MLPA) was performed for OTX2 intragenic mutation-negative patients. and a 2. p. Adachi M. these were not shown to compromise the function of the protein and may reflect rare sequence variants. Clinical and Molecular Genetics Unit. POU1F1 and GNRH1 promoters.K74fsX103 in case 1 with isolated GH deficiency (IGHD).G188X in 2 unrelated cases (case 3 with microphthalmia. have been identified in association with ocular malformations such as anophthalmia or microphthalmia. Wild-type OTX2 protein transactivated the GNRH1 promoter as well as the HESX1. Muroya K. were also identified in 2 further patients.jp J Clin Endocrinol Metab 2010:95:756–764 Background: Orthodenticle homeobox 2 (OTX2) is a transcription factor that appears to be critical for normal forebrain and eye development.

the phenotype in six patients (aged 6 months to 22 years) with CPHD. hearing impairment. Escher SA Department of Molecular Biology. restricted neck rotation. scoliosis.kristrom@pediatri. the existence of cervical vertebral malformations are revealed. as was significant sensorineural hearing loss. and the gene was sequenced. Sehlin P. found in both human and mouse. Neck anatomy was explored by computed tomography and magnetic resonance imaging. restricted neck rotation and variable hearing impairment. Similarly. Results: A novel recessive splice-acceptor site mutation was found. However. To date. eyes and optic nerves overlap. and is also expressed in the auditory system. which is believed to be a target of OTX2. and believed to be responsible for the rigid neck and the development of scoliosis. this interesting study has screened a sizeable cohort of patients with ocular and/or pituitary abnormalities for mutations in OTX2. one needs to apply caution with respect to this statement. and congenital hearing impairment. Anatomical abnormalities in the occipito-atlantoaxial joints in combination with a basilar impression of the dens axis were found in all patients assessed. The predicted protein encoded by the mutated gene would lack the homeodomain and carboxyl terminus of the normal. although it appears likely that GH deficiency is the commonest endocrine manifestation. The association of previously described LHX3 mutations with CPHD and restricted neck rotation led to the adoption of a candidate gene approach. Mutations in the gene are associated with combined pituitary hormone deficiency (CPHD) in association with a short stiff neck.se J Clin Endocrinol Metab 2009. POU1F1 and IRBP promoters. The authors report considerable variability in the phenotypes associated with the mutations with no clear genotype-phenotype correlations. Sweden berit. Zdunek AM. pituitary. Since transcriptional regulation of the development of the hypothalamus. as does loss of expression of Pou1f1 expression in animals that are conditionally deleted for Otx2. and that OTX2 can transactivate GNRH1 as well as HESX1. with no genotype-phenotype correlations. GNRH1 may also be a target of OTX2. the authors state that since OTX2 transactivates the GNRH1 promoter. homozygous recessive mutations have been identified in 9 unrelated families. Three of the patients also have mild autistic-like behavior. Umeå.umu. and variable sensorineural hearing impairment. functional protein. In addition. Gevers/Mehul T. A novel mutation in the LIM homeobox 3 gene is responsible for combined pituitary hormone deficiency. Scoliosis was identified in 5 of the children. but much remains to be learnt with respect to its role in normal development. Conclusions: This study extends both the mutations known to be responsible for LHX3-associated syndromes and their possible phenotypic consequences. Jonsson H. This is reminiscent of mutations in HESX1. MRI revealed severe anterior pituitary hypoplasia with a cystic structure identified in patient 5. Umeå University. Rydh A. Dattani . Methods: The objective of this study was to determine the cause of. patients examined in the present study also show a severe hearing defect. Genealogical studies revealed a common gene source for all six families dating back to the 17th century. Previously reported traits include CPHD.94:1154–1161 Background: The LIM homeobox 3 (LHX3) LIM-homeodomain transcription factor gene. In vivo studies are needed in animals that are conditionally deleted for Otx2 in the hypothalamo-pituitary region. one cannot extrapolate the binding of OTX2 to the POU1F1 promoter with subsequent transactivation to a direct genetic interaction between OTX2 and POU1F1 – the co-expression of the two genes needs to be shown. It is therefore clear that OTX2 is an important player in hypothalamo-pituitary development in humans. Additionally. and further explore. Cervical lordosis and thoraco-lumbar hyperlordosis were observed in all children by the time the children could stand. including three-dimensional reformatting. Orthodenticle homeobox 2 (OTX2) is critical for normal forebrain and eye development and heterozygous mutations in OTX2 have been associated with anophthalmia or microphthalmia. is required for development of the pituitary and motor neurons.Conclusions: The results imply that OTX2 mutations are associated with variable pituitary phenotypes. 14 Evelien F. and vertebral malformations Kristrom B. The exact role of OTX2 in both murine and human hypothalamo-pituitary development is unclear.

It is important to note that skeletal abnormalities were also noted in 4 patients described by Rajab et al. Eunice Kennedy Shriver National Institute of Child Health and Human Development. However. Previous studies have shown that development of Rathke’s pouch and the generation of distinct populations of hormone-producing endocrine cell lineages in the anterior/intermediate pituitary lobes is regulated by a number of transcription factors expressed in the pouch and by inductive signals from the ventral diencephalon/infundibulum. Westphal H Laboratory of Mammalian Genes and Development. a complete failure of evagination of the neuroectoderm in the ventral diencephalon. Hermesz E.nih. National Institutes of Health. which is formed by evagination of the neuroectoderm in the ventral diencephalon. USA hw@mail. Deletion of Lhx2 resulted in persistent cell proliferation. The posterior lobe is derived from the infundibulum. Md. [6].Initial studies suggested that LHX3 mutations were associated with CPHD excluding ACTH deficiency in association with a short stiff neck and limited rotation [3]. a pocket formed by an invagination of the oral ectoderm. Expression of infundibular markers such as Nkx 2.5. Results: Lhx2 is extensively expressed in the developing ventral diencephalon. However. suggesting a diagnosis of ACTH deficiency. midbrain. Additionally. little is known about factors that regulate the development of the posterior pituitary lobe. it describes the presence of progressive scoliosis from 5 to 6 years of age in the majority of patients. After E15. and confirms the presence of hearing deficit in affected patients. Sox3.1. with a large mass of cells occupying the area between the third ventricle and the anterior/ intermediate lobes of the pituitary. BrdU assays were performed to assess cell proliferation and TUNEL assays performed to detect apoptosis. patient 2 had a low concentration of cortisol in the neonatal period. in addition to other tissues such as the retina. and must now be considered to be a component of the wider LHX3 mutant phenotype. The expression of a number of genes encoding signaling molecules and transcription factors was studied in embryonic sections. Six3. Methods: In this study. Bethesda. This paper nicely describes for the first time the occipito-atlantoaxial abnormalities observed in this cohort of patients. BrdU assays revealed a dramatic increase in cell proliferation in the mutants as compared with wild-type animals at E11. It is important to note that the presence of hypoglycemia led to cortisol replacement in 3 of the 6 individuals.. This study is fascinating as it reports the occurrence of a founder mutation in LHX3 in a northern Swedish population. including the infundibulum and the posterior lobe of the pituitary. the authors investigated the role of the LIM homeobox gene Lhx2 in hypothalamopituitary development in mice.gov Dev Biol 2010:337:313–323 Background: The mammalian pituitary gland originates from two separate germinal tissues during embryonic development. the shape and organization of the pouch and the anterior/intermediate pituitary lobes are severely altered due to the defects in development of the infundibulum and the posterior lobe. the presence of a pituitary microadenoma [5] and the presence of ACTH deficiency with sensorineural hearing impairment [6].5. However. Additionally. Mailloux CM. the phenotypic spectrum has recently expanded to include variability in the presence of the short stiff neck [4]. Lhx2 null mutants (Lhx2–/–) were generated and the phenotype analyzed. E13. Palkovits M.5.5. Rathke’s pouch is formed and endocrine cell lineages are generated in the anterior/intermediate pituitary lobes of the Lhx2 null mutant. E12.5 and E14. the mutant mice die in utero due to a severe defect in definitive erythropoiesis. hindbrain and spinal cord. New genes – pituitary development A role of the LIM-homeobox gene Lhx2 in the regulation of pituitary development Zhao Y. thereby confirming a role for LHX3 in human auditory development. and the cellular retinoic acid binding protein CRABP2 was unaffected in the mutants whereas expression of posterior lobe markers such as calbindin and vasopressin was Pituitary 15 . forebrain. The anterior and intermediate lobes of the pituitary are derived from Rathke’s pouch. and defects in the formation of the distinct morphological features of the infundibulum and the posterior pituitary lobe.

The highly variable clinical phenotypes can now in part be explained due to research performed over the last 20 years. This review describes the current state of knowledge in the field of pituitary development in mouse and human. University College. and features such as phenotypic variability and variability of penetrance remain to be explained. The review describes key processes in murine pituitary development and also the known genetic causes of hypopituitarism in humans.absent in the region corresponding to the posterior lobe. in mice and humans. London Institute of Child Health.30:790–829 Normal hypothalamo-pituitary development is closely related to that of the forebrain and is dependent upon a complex genetic cascade of transcription factors and signaling molecules that may be either intrinsic or extrinsic to the developing Rathke’s pouch. Dattani . Whether it will be implicated in the etiology of hypopituitarism in humans remains to be seen. To date. This comprehensive review attempts to describe the complexity of pituitary development in the rodent. these mutations have led to a greater understanding of the genetic interactions that lead to normal pituitary development. based mainly on naturally occurring and transgenic animal models. Lovell-Badge R. overlying the pouch that failed to grow dorsally in the mutants. It describes in great detail the development of the pituitary and regulation of development by genes encoding signaling molecules such as Sonic Hedgehog and transcription factors such as HESX1. Conclusion: This study thus reveals an essential role for Lhx2 in the regulation of posterior pituitary development and suggests a mechanism whereby development of the posterior lobe may affect the development of the anterior and intermediate lobes of the pituitary gland.uk Endocr Rev 2009. a complete failure of evagination of the neuroectoderm in the ventral diencephalon. UK m. Robinson IC. LHX4. and cell proliferation within the anterior pituitary. and attempts to correlate phenotypes in both mouse and human. An increased number of TUNEL-positive apoptotic cells were present in the large abnormal mass occupying the ventral diencephalon of Lhx2–/– mutants. Gevers/Mehul T. LHX4. a spectrum of disorders that includes syndromic disorders such as septo-optic dysplasia. are associated with hypopituitarism in humans. LHX3. mutations in known genes account for a small proportion of cases of hypopituitarism in humans. SOX2. SOX3. and defects in the formation of the distinct morphological features of the infundibulum and the posterior pituitary lobe. provides inductive signals that are required for the growth and differentiation of Rathke’s pouch. However. Early tissue recombination studies have suggested that the neuroectoderm of the ventral diencephalon. It also reiterates the importance of the inductive interaction between the neuroectoderm and the oral ectoderm. The expression domain of Fgf8 was expanded rostrally. Deletion of Lhx2 resulted in persistent cell proliferation. The normal development of the pituitary gland is a carefully orchestrated process that is dependent on the expression of a number of signaling molecules and transcription factors in a coordinated manner [7]. This exciting work has led to the identification of a further piece of the complex jigsaw. Abnormalities in these processes are associated with congenital hypopituitarism. with or without other syndromic features. of which the commonest is GH deficiency. These factors dictate organ commitment. SOX3. Genetic regulation of pituitary gland development in human and mouse Kelberman D. and isolated hormone deficiencies. leading to neurohypophysis generation.dattani@ich.ucl. although one would predict that the phenotype in affected patients would be extensive given the presence of severely defective erythropoiesis and embryonic death in the Lhx2 mutants.ac. Clinical and Molecular Genetics Unit. The importance of Lhx2 lies in the fact that it is one of the few genes that have been identified to be critical for normal development of the infundibulum and posterior pituitary. with particular emphasis on those factors that. Dattani MT Developmental Endocrinology Research Group. London. LHX3. cell differentiation. Mutations in genes encoding both signaling molecules such as Sonic Hedgehog and transcription factors such as HESX1. It continues to describe the consequences of mutations of these genes in murine and human development of the hypothalamic-pituitary axis and 16 Evelien F. It is clear that normal hypothalamopituitary development is a highly complex phenomenon. Rizzoti K. PROP1 and POU1F1. combined pituitary hormone deficiencies. SOX2. when mutated. PROP1 and POU1F1 have been implicated in the etiology of hypopituitarism.

shown by significant increases in the cyclin-dependent kinase inhibitors. Recent studies postulated that Notch signaling in the pituitary maintains a proliferative zone of cells lining the Rathke’s pouch.150:4386–4394 Background: Growth of the pituitary during development and adulthood is a tightly regulated process. Methods: Expression of cell cycle regulators. pituitaries lacking Hes1 have increased cell cycle exit. but chose to exit the cell cycle instead. Ill. HES–/– mice have hypomorphic pituitaries with reductions in all hormone cell types and absence of -MSH-producing cells that normally appear at a more differentiated stage of pituitary development. Absence of Hes1 leads to dysregulation of cyclindependent kinase inhibitors like p57. Conclusions: These data indicate a role for HES1 in the control of cell cycle exit and in balancing proliferation and differentiation. signal transducers and effectors – play critical roles in executing the effects of Notch signaling. Factors at each step – ligands. pituitary progenitors show an increased cell cycle exit. USA Traetzman@life. p27 and p21.. proliferation and apoptosis in wild-type and Hes1-deficient pituitaries was assessed using immunohistochemistry. HES1 is a repressor of cell cycle inhibitors.5. Hes1 mutant pituitaries have ectopic expression of p21 in Rathke’s pouch progenitors. Ligand binding to DLK1 or other Notch receptors results in regulation of Notch effectors and HES1 is one of these Notch effectors. In line with a role for Notch effectors in the regulation of proliferation and differentiation. The authors hypothesized that with the loss of Hes1. allowing for the properly timed emergence of hormone secreting cell types. an area coincident with increased cell death. We first became interested in HES1 when we were studying regulation of chondrocyte and adipocyte proliferation and differentiation – Pref1 (DLK1) functions as a receptor in the Notch signaling system and needs down-regulation for terminal adipocyte differentiation to occur [9] but is also present in the growth plate and pituitary. p27 and p57. pituitary progenitors are no longer maintained in a proliferative state.5 to e14. and apoptosis in multiple tissues. differentiation. but may also be important for the understanding of pituitary tumor formation. increased cell death and a reduction in cell proliferation resulting in a depletion of the progenitor pool. receptors. allowing cell cycle exit for differentiation to hormone-secreting cells at an appropriate time. Pituitary 17 . This suggests a role for HES1 in the maintenance of a balance between proliferation and differentiation. Furthermore. This study is not only of importance for the understanding of pituitary development. Inappropriate regulation of this process results in a hypomorphic pituitary gland. Notch signaling dictates cell fate and influences cell proliferation. Additionally. Urbana. a transcription factor whose expression is initiated by the Notch signaling pathway. When mutant Hes1 is present.uiuc. Further work is needed to establish whether increased activation of Notch-HES1 signaling in the pituitary may lead to tumor formation.edu Endocrinology 2009. Results: Changes in phosphohistone H3 expression in cells in Rathke’s pouch in early pituitary development [8] indicate decreased proliferation in Hes1-deficient mutants. Rybak S. New mechanisms – pituitary development The notch target gene HES1 regulates cell cycle inhibitor expression in the developing pituitary Monahan P. This study further clarifies its role in pituitary progenitors located in Rathke’s pouch. with or without other syndromic features in humans. is a repressor of cell cycle inhibitors. which normally express HES1. Hairy and enhancer of split (HES1). emphasizing the close relationship between embryonic development and tumor formation. University of Illinois at Urbana-Champaign. Raetzman L Department of Molecular and Integrative Physiology. from e10.the implication of these mutations in the etiology of hypopituitarism.

This paper reports that TLE3 and TLE1 are potential co-repressors. and the similar gene TLE3. through an engrailed homology domain and represses PROP1 activity and TLE1. and the eh1 domain appears to be critical for this repression. This suggests that other co-repressors such as NCoR1 [13] may also enhance the function of HESX1 as a repressor. In vivo studies using transgenic mice tested the functional consequences of ectopic TLE3 and HESX1 expression by driving constitutive expression in pituitary thyrotrophs and gonadotrophs using the Cga promoter. In vitro studies suggest that TLE1 and TLE3 might also play roles independent of HESX1 by interacting with other transcription factors like PROP1. through an engrailed homology (eh1) domain and represses PROP1 activity. Its role as a repressor is undisputed. in addition to ACTH and gonadotrophin deficiency. terminal differentiation of thyrotrophs and gonadotrophs was suppressed by HESX1 alone and by TLE3 and HESX1 together but not by TLE3 alone. Methods: The authors tested the ability of TLE3 to enhance HESX1-mediated repression of PROP1 activation at the POU1F1 promoter in cell culture using 293T cells (human embryonic kidney cells). and is expressed in the developing pituitary in an overlapping yet distinct pattern.000 children born and can be caused by mutations in a number of genes encoding transcription factors such as HESX1. Tle3 is structurally related to Tle1. HESX1 interacts with a member of the groucho-related gene family. SOX2. TLE1. and prolactin. resulting in lack of TSH. Ann Arbor. Although mutations in HESX1 were first identified in 1998 [10]. Dattani . In addition. Ellsworth BS. GH. In vivo. its function remains largely unknown. are expressed in a pattern overlapping that of HESX1. Gevers/Mehul T. Tg(Cga-Hesx1) double transgenic embryos showed a dramatic reduction in the concentration of endogenous CGA protein. probably via a protein-protein interaction. PROP1 and POU1F1. Castinetti F. both TLE3 and TLE1 repressed PROP1 in conjunction with HESX1 with similar efficiencies. TLE1 and TLE3 could each repress PROP1 in the absence of HESX1. Camper SA Department of Human Genetics. and this is underlined by our inability to identify a genetic cause in the vast majority of children with congenital hypopituitarism. HESX1 interacts with a member of the groucho-related gene family. the Tg(Cga-Tle3). Brinkmeier ML. whereas HESX1 alone did not affect the expression of endogenous Cga. 12]. TLE1. SOX3. Mich. 18 Evelien F. as has been previously established for TLE1 [11. It is interesting that the in vivo studies report enhancement of HESX1 function by TLE3. LHX3. Mice with Prop1 deficiency exhibit failed differentiation of the POU1F1 lineage. Interestingly.24:754–765 Background: Pituitary hormone deficiency causes short stature in 1 in 4. these mutants exhibit profound pituitary dysmorphology and overexpress Hesx1 and Tle3.Co-repressors TLE1 and TLE3 interact with HESX1 and PROP1 Carvalho LR. yet its partners and targets have not as yet been clearly established.. LHX4. Results: In the cell culture experiments. although HESX1 can also act as a repressor independently of TLE proteins. Conclusion: This work presents evidence that HESX1 is a strong repressor that can be augmented by the co-repressors TLE1 and TLE3.edu Mol Endocrinol 2010. Much remains to be understood about normal pituitary development and the mechanisms involved. suggesting that the presence of the co-repressor TLE3 in addition to HESX1 was critical for the repression of the endogenous Cga. The ability of HESX1 to interact with TLE3 has not been explored previously. USA scamper@umich. University of Michigan.

Italy e. Pituitary 19 . Results: Interpretation of the DDAVP test based on percentage and absolute increment of cortisol and ACTH did not in itself give acceptable values of both sensitivity (SE) and specificity (SP). Whether the test can be a useful adjunct to the standard tests in a pediatric population remains to be proven.g.faloia@univpm. Ancona.8%). Boscaro M. SP 92. depression. the diagnosis can be difficult to make. current information on its value is limited and contradictory.5%. with emphasis on subjects with mild hypercortisolism. however.8%). The DDAVP test was performed and compared with standard diagnostic procedures for the diagnosis of Cushing’s syndrome. midnight serum cortisol and serum cortisol after dexamethasone suppression. and midnight serum cortisol in the respective patients make it difficult to distinguish subjects with these two entities. Polytechnic University of Marche. and (3) CD with moderate values of midnight serum cortisol (SE 100%. (2) CD with moderate values of serum cortisol after dexamethasone suppression (SE 86. Faloia E.Important for clinical practice Use of the desmopressin test in the differential diagnosis of pseudo-Cushing state from Cushing’s disease Tirabassi G.3% and an SP of 91.8%).9%.6%. CD diagnosis based on simultaneous positivity for basal serum cortisol >331 nmol/l and absolute ACTH increment >4 pmol/l and its exclusion in subjects negative for one or both measures yielded an SE of 90. 28 with PC. and 31 control subjects (CT) with simple obesity in whom Cushing syndrome had previously been excluded using standard diagnostic tests.it J Clin Endocrinol Metab 2010. Arnaldi G Division of Endocrinology. However. SP 92. The desmopressin (DDAVP) test has been proposed to discriminate Cushing’s disease (CD) from pseudo-Cushing states (PC). even in subjects with mild hypercortisolism. SP 92. serum cortisol after dexamethasone suppression. The diagnosis/exclusion of CD was measured. Papa R. They conducted a retrospective/prospective study that included 52 subjects with CD. severe obesity) that can activate the hypothalamic-pituitary-adrenal axis and is characterized by clinical and biochemical signs typical of Cushing’s syndrome. Pseudo-Cushing state is caused by conditions (e.95:1115–1122 Background: The diagnosis of Cushing disease is generally based upon a combination of urinary free cortisol (UFC). Conclusion: Interpretation of the DDAVP test through a combination of parameters allowed effective discrimination of Cushing disease from pseudo-Cushing. Furlani G. This study has examined the usefulness of the DDAVP test in diagnosing Cushing disease in a large cohort of adult patients and suggests that assessment of percentage and absolute increment of cortisol and ACTH concentration in the DDAVP test allows for discrimination between Cushing disease and pseudo-Cushing. The approach was also highly effective in distinguishing PC from: (1) CD with moderate values of urinary free cortisol (SE 86. alcoholism. The overlapping clinical features with Cushing disease and the similar values frequently determined in tests such as urinary free cortisol. polycystic ovary syndrome. Methods: The authors aimed to study the ability of the DDAVP test to distinguish between CD and PC.

cnrs.e.New hope? Oxytocin-dopamine interactions mediate variations in maternal behavior in the rat Shahrokh DK. High compared with low LG mothers show greater increases in dopamine signal in the nucleus accumbens during bouts of pup LG.ca Endocrinology 2010. Individual differences in pup licking/grooming (LG) are abolished by oxytocin receptor blockade or treatments that equalize dopamine signal in the nucleus accumbens.fr Proc Natl Acad Sci USA 2010. Leboyer M. Meaney MJ Sackler Program for Epigenetics and Psychobiology. This study investigated the behavioral effects of oxytocin. Zalla T.151:2276–2286 Background: Variations in maternal behavior among lactating rats associate with differences in estrogenoxytocin interactions in the medial preoptic area and in dopamine concentrations in the nucleus accumbens. Results: Mothers that exhibit consistently increased pup LG (i. Bron. Retrograde tracing of projections from the ventral tegmental area by stereotactic fluorogold injection into ventral tegmental area followed by oxytocin and fluorogold immunohistochemistry. 20 Evelien F. may be implicated in the social deficit of autism. novel evidence is provided for a direct effect of oxytocin at the level of the ventral tegmental area in the regulation of accumbens dopamine levels. France sirigu@isc. Conclusions: These studies reveal a direct effect of oxytocin on dopamine release within the mesocorticolimbic dopamine system. Results: After oxytocin inhalation. Promoting social behavior with oxytocin in high-functioning autism spectrum disorders Andari E. Diorio J. This supports a role for oxytocin-dopamine interactions in the establishment and maintenance of social bonds. during free viewing of pictures of faces. Unité Mixte de Recherche. Montreal. Canada Michael.107:4389–4394 Background: Social adaptation requires specific cognitive and emotional competences. Douglas Mental Health University Institute. Histology was used to verify proper location of electrodes and cannulae. McGill University. namely the eyes. Sirigu A Centre de Neuroscience Cognitive. Decision behavior in the game. Individuals with high-functioning autism or with Asperger syndrome cannot understand or engage in social situations despite preserved intellectual abilities. high LG mothers) by comparison with low LG mothers show increased oxytocin expression in the medial preoptic area and the paraventricular nucleus of the hypothalamus and increased projections of oxytocin-positive cells from both medial preoptic area and paraventricular nucleus of the hypothalamus to the ventral tegmental area. Dattani . patients exhibited stronger interactions with the most socially cooperative partner and reported enhanced feelings of trust and preference. Zhang TY. Also. Recently. In this paper. Gratton A. and this difference is abolished with infusions of an oxytocin receptor antagonist directly into the ventral tegmental area. Duhamel JR.meaney@mcgill. oxytocin selectively increased patients’ gazing time on the socially informative region of the face. Gevers/Mehul T. Methods: Thirteen subjects with high-functioning autism spectrum disorder were entered in a simulated ball game where participants interacted with fictitious partners and received inhaled oxytocin. Methods: In vivo study of normal rats divided in high LG (>1 SD) or low LG (<–1 SD) dependent on frequency scores for licking/grooming. In situ dopamine concentration was measured using electrochemical probes implanted in the nucleus accumbens. Herbrecht E. visual examination of faces and emotional response using a self-rated scale was assessed. a hormone known to promote mother-infant bonds. it has been suggested that oxytocin. Direct infusion of oxytocin into the ventral tegmental area increased the dopamine signal in the nucleus accumbens. Drugs were injected directly into the ventral tegmental area.

In addition. and that this could explain most of their properties. This work opens doors to the therapeutic use of oxytocin. Zürich. Adrenocorticotropic hormone (ACTH) could not form amyloidlike aggregates on its own but did so in the presence of -endorphin. confirming a pharmacological effect of oxytocin on human behavior. New paradigm Functional amyloids as natural storage of peptide hormones in pituitary secretory granules Maji SK. Vale W. suggesting a therapeutic potential of oxytocin through its action on a core dimension of autism. by the conformational transition into -sheet-rich structure measured by circular dichroism spectroscopy. and by the presence of fibrils in electron microscopy images. These data were Pituitary 21 . Eidgenössische Technische Hochschule. However. These results are promising for the development of pharmacological strategies to increase social interaction and adaptation in patients with autism. Sawchenko P.-sheet-rich protein or peptide aggregates that are associated with pathological conditions including several neurodegenerative diseases such as Alzheimer’s disease and other conditions including type 2 diabetes. patients respond more strongly to others and exhibit more appropriate social behavior and affect. Patients with high-functioning autism spectrum disorders have normal language and intellectual abilities but avoid eye contact. when they are termed ‘functional amyloids’ as demonstrated by fungal prions. the amyloid formation of all 42 peptides and proteins was monitored in the presence of low molecular weight heparin as a representative of GAGs.325:328–332 Background: Amyloid fibrils are highly organized cross. Rivier J. In a simulated game.chem. Given the possible involvement of glycosaminoglycans (GAGs) in the formation of both secretory granules and amyloid fibrils. x-ray fiber diffraction was measured for a subset of hormones. especially since oxytocin has been implicated in the etiology of autism. They were assayed for their capacity to form amyloids by the amyloid-specific dyes thioflavin T and Congo Red using luminescent conjugated polyelectrolyte probes.ch Science 2009. Nilsson KP. Perrin MH. Eisenberg D. The authors hypothesized that peptide and protein hormones in secretory granules may adopt an amyloid-like structure. which is also processed from proopiomelanocortin and secreted together with ACTH in a regulated secretory pathway. Results: Ten of the 42 hormones showed considerable formation of amyloids. Vadodaria K.ethz. Within a population of normal rats. Methods: 42 peptide and protein hormones from multiple species and organs and with a variety of different three-dimensional structures were selected. these patients had reduced oxytocin plasma concentrations compared to normal subjects.riek@phys. Indeed. Switzerland roland. oxytocin-treated subjects scanned the eye region of the face more often and reported greater trust. Jessberger S. the authors were able to differentiate high and low grooming mothers by the number of oxytocin neurons in several hypothalamic nuclei projecting to the ventral tegmental area and showed that oxytocin acts directly on dopamine release in the nucleus accumbens. Schubert D. Normal subjects that receive oxytocin are more inclined to trust other players and to even send them money in simulated investment games [14]. Singru PS. Rissman RA. Furthermore. Most hormones (n = 31) formed amyloid fibrils after 2 weeks of incubation in the presence of heparin. which is involved in mammalian skin pigmentation. which are involved in prion replication. Simon R. Riek R Laboratory of Physical Chemistry. Sawaya MR. the authors mention submitted work that associates activity of dopamine-sensitive pathways (by functional MRI) to maternal responsivity to infant-related stimuli in humans. have less spontaneous interaction with people and show impairments in understanding intentions of others.Conclusions: During oxytocin treatment. The second paper describes a study in which patients with high-functioning autism spectrum disorders (HF-ASD) received inhaled oxytocin. amyloids may also have a normal biological function. and the amyloid protein Pmel17. The first of the papers above reports on the mechanism whereby oxytocin may affect maternal licking and grooming of pups.

Amyloid aggregation thereby sorts the protein/peptide hormones into secretory granule cores. Whether the presence of functional amyloid impacts on disease processes such as autosomal dominant GHD and autosomal dominant diabetes insipidus. Frohman LA. respectively) were used to identify mechanisms that may prevent or delay adenoma formation in the presence of excess GHRH. Diabetes. prolactin and GH in the anterior lobe. Thus. remains to be established. Cordoba-Chacon J. USA RDkineman@uic. Conclusion: This study reports that peptide and protein hormones in secretory granules of the endocrine system are stored in an amyloid-like cross. somatostatin). Further evidence suggested that 22 Evelien F. amyloid aggregation of the prohormone is initiated spontaneously above a critical prohormone concentration and/or in the presence of helper molecules such as GAGs in parallel to a possible prohormone processing. prohormone processing at critical hormone concentrations may initiate the aggregation. the hormone amyloids become surrounded by membrane. membrane surrounding and inert hormone storage. were indicative that their storage in the secretory granules was extensively amyloid-like. Kineman RD Section of Endocrinology. concentrates them to the highest density possible. immunohistochemistry revealed the abundant presence of amyloids in the anterior and posterior pituitary. This study aimed to assess the role of GHRH and somatostatin in pituitary tumor formation. leading to long-term storage. expression of the late G1/G2 marker Ki67 increased. and form mature granules. The authors suggest that. Within the mouse pituitary. Gevers/Mehul T.. and suggests the association of amyloid with hormones. it may play a critical functional role in hormone storage and secretion. ACTH in the intermediate lobe. Soares BS. and subsequently the release of hormones from the granules. Krishnan S. This paper presents a highly novel concept. functional amyloids in the pituitary and other organs can contribute to normal cell and tissue physiology encompassing processes such as granule formation including hormone selection. Co-localization of the amyloid-specific dye Thio S and the hormones ACTH. and excludes nonaggregation prone constitutively secreted proteins. whereas the proportion of 5-bromo-2’-deoxyuridine-labeled cells (an S-phase marker) did not differ from agematched controls indicating that cell cycle progression was blocked.g. They propose that in the Golgi. Results: In hyperplastic pituitaries. Chicago. Secretory proteins and peptides are synthesized in the endoplasmic reticulum and Golgi and then stored in vesicles or secretory granules ready for release into the extracellular space. Methods: Hyperplastic and adenomatous pituitaries of metallothionein promoter-human GHRH transgenic mice (4 and > 10 months.edu Endocrinology 2009. Peng XD. and oxytocin and vasopressin in the posterior lobe.confirmed in the mouse pituitary tumor neuroendocrine cell line AfT20. The authors suggest a possible functional amyloid state of many endocrine hormones in secretory granules of the hypothalamus (e.-sheet-rich conformation.g. New mechanism – pituitary tumors Use of the metallothionein promoter-human growth hormone-releasing hormone (GHRH) mouse to identify regulatory pathways that suppress pituitary somatotrope hyperplasia and adenoma formation due to GHRHreceptor hyperactivation Luque RM. Ill. separate from Golgi. -endorphin. During the aggregation process. although amyloid has been associated with disease processes in the past. and Metabolism. On signaling. and may result in the formation of adenomas relatively late in life. CRF) and pancreas (e. Dattani .150:3177–3185 Background: Hyperactivation of the GHRH receptor or downstream signaling components is associated with hyperplasia of the pituitary somatotrope population. Because the prohormone may aggregate less into an amyloid entity than its hormone counterpart. University of Illinois. secretory granules are secreted and the cross -sheet structure of the amyloid enables a controlled release of monomeric functional hormone. where hormone secretion is abnormal. which then form secretory granules.

Navratil AM. The effects of ERK pathway ablation on LH biosynthesis underlined this gender-specific phenotype. Subsequent studies will undoubtedly assess the role of these genes in pituitary tumor formation in more detail. Results: ERK signaling was found to be required in females for ovulation and fertility. Conclusion: These findings help to elucidate the molecular basis of gender-specific regulation of the hypothalamic-pituitary-gonadal axis and sexually dimorphic control of fertility.. College of Veterinary Medicine. Increased endogenous somatostatin (SST) tone may slow the conversion from hyperplastic to adenomatous tissue since mRNA levels for SST receptors. apoptosis and microtubule formation (mitogen-activated protein kinase kinase1. Cornell University. Roberson MS Department of Biomedical Sciences. Array analysis comparing hyperplastic and adenomatous pituitaries showed differential regulation of genes involved in. Reduction of somatostatin tone plays a role in adenoma formation by modulation of apoptosis and senescence rather than proliferation. USA MSmsr14@cornell. and the next one the role of the less well known pituitary tumor transforming gene (PTTG1). GHRH however seemed to act by affecting cell cycle and cyclin-dependent kinase inhibitors (p27). Fisher PJ. Landreth GE. whereas action of somatostatin was proliferation independent and may be through modulation of apoptotic and senescence pathways. McDonough SP. SSTknockout Tg pituitaries were larger and adenomas formed earlier compared with those of SST-intact Tg mice. this one assessing the role of GHRH-somatostatin balance. consistent with the predicted function of some of the most differentially expressed genes (Casp1. proliferation. adenomatosis polyposis coli binding protein (Mapre1). Adenoma formation was associated with loss of p27 activity. tumor necrosis factor receptor 1b (TNFR2)). Unexpectedly. were elevated in hyperplastic pituitaries. Pituitary 23 . It was not too unexpected that loss of somatostatin tone enhanced tumor formation induced by GHRH overexpression. these changes were independent of changes in proliferation rate within the hyperplastic tissue. Also. GH producing adenomas are often found to overexpress GHRH and this study therefore focused on the role of GHRH in pituitary tumor formation. This study aimed to find genes that allow for or halt pituitary tumor formation despite continuous GHRH stimulation. LH expression being dependent on ERK-dependent up-regulation of the transcription factor Egr1.enhanced p27 activity may contribute to this process. TNFR2) identified by membrane arrays and confirmed by quantitative real-time RT-PCR. These tumors however often develop late in life and do not have 100% penetrance. New York. but loss of p27 is needed for adenomatous transformation. Pituitaries of mice overexpressing GHRH were used and these mice were crossed with mice deficient in somatostatin to study the contribution of somatostatin in slowing tumor formation.edu Mol Endocrinol 2009. but male reproductive function was unaffected. sst2 and sst5. N. MAP2K1.Y. whereas adenomas were associated with a decline in sst1 and sst5 mRNA.23:1092–1101 Background: Males and females require different patterns of pituitary gonadotropin secretion for fertility. suggesting that other factors are needed to allow for uncontrolled growth. This paper and a paper mentioned later in this chapter investigate mechanisms involved in tumor growth. The mechanisms underlying these gender-specific profiles of pituitary hormone production are unknown but there is evidence to suggest that ERK1 and 2 are essential modulators of hypothalamic GnRHmediated regulation of pituitary gonadotropin production and fertility. Miller A. amongst others. New mechanisms – signaling in the pituitary and hypothalamus ERK signaling in the pituitary is required for female but not male fertility Bliss SP. suggesting that endogenous SST controls GHRH-induced adenoma formation primarily via modulation of apoptotic and/or cellular senescence pathways. Conclusions: A block in cell cycle progression is responsible for hyperplasia of pituitaries under continuous GHRH signaling. Xie J. Methods: Mice with a pituitary-specific depletion of ERK1 and 2 were generated and a range of physiological parameters including fertility was assessed.

JNK1–/– mice are protected from insulin resistance and obesity-induced hyperglycemia and are leaner. reflecting the lower levels of LH that are required for Leydig cell function. To resolve the importance of JNK1 signaling in the hypothalamic/pituitary circuitry. Max Planck Institute for the Biology of Aging.bruening@uni-koeln. Germany jens. Spohn G. Moreover. In this work. it suggests that FSH synthesis is less dependent on ERK signaling than LH synthesis. but also in the central nervous system thereby causing neuronal insulin and leptin resistance. Indeed. the in vivo function of this pathway has not been assessed. This work implies ERK signaling as the sexually dimorphic link between genderspecific GnRH pulsatility and LH synthesis. Bruning JC Department of Mouse Genetics and Metabolism. Central JNK1 ablation resulted in increased insulin sensitivity with an increased Akt activation in response to insulin. up until now. Since Nestin is expressed not only in neurons but also in pituitary stem cells. implicating LH deficiency as the primary cause of infertility. Hampel B. the mice also had reduced growth (approx. Gevers/Mehul T. critical role for hypothalamic/pituitary JNK1 signaling in the coordination of metabolic/endocrine homeostasis. JNK1(DeltaNES) mice exhibit improved insulin sensitivity both in the CNS and in peripheral tissues.107:6028–6033 Background: c-Jun N-terminal kinase (JNK) 1-dependent signaling plays a crucial role in the development of obesity-associated insulin resistance.de Proc Natl Acad Sci USA 2010. Obesity causes an increased production of cytokines and inflammatory and stress signaling which results in activation of c-jun terminal kinase (JNK) and thereby insulin resistance. LH expression was only slightly decreased and fertility was unaffected. and protection of diet induced insulin resistance. However. 20%) without increased adiposity as a result of a reduction in pituitary GHRH receptors. and MAPKs ERK1 and ERK2) that is activated upon a range of extracellular stimuli and is activated in gonadotrophs by GnRH. Bronneke HS. The mitogen-activated protein kinase extracellular signal-regulated kinase (MAPK-ERK) signaling system comprises a three-level phosphorylation cascade (MAPK-kinasekinase Raf1. MAPK kinases MEK1 and MEK2. Although thyrotropes and ovaries were also ERK1 deficient. LH synthesis was reduced in gonadotropes and ovulation occurred in response to exogenous LH . Hypothalamic and pituitary c-Jun N-terminal kinase 1 signaling coordinately regulates glucose metabolism Belgardt BF. rendering gonadotropes and thyrotropes ERK1/2 deficient. obesity does not only result in a reduction of insulin sensitivity in classical peripheral tissues. However. However. but lacked luteal tissue. energy expenditure. JNK1(DeltaNES) mice also show reduced somatic growth in the presence of reduced circulating growth hormone and insulin-like growth factor 1 concentrations. Ovaries contained follicles of various maturation. and hepatic glucose production. as well as increased thyroid axis activity. use of a Nestin-Cre mouse will allow for ablation of genes in all pituitary cell lines. mice were generated that have an ablation of JNK1 specifically in neurons. the authors argue that this is unlikely to have affected the phenotype of the mice. Conclusion: These experiments reveal an unexpected. Dattani . improved glucose metabolism. The authors started by showing that high fat feeding not only promotes JNK1 activation in peripheral tissues and CNS but also in the pituitary. Ernst MB. Wunderlich FT. Cologne. Female mice did not have estrous cycle activity and did not mate. and then crossed to ERK1 null mice. Pal M. In addition. Mauer J. Methods and Results: This work demonstrates that JNK activation not only occurs in peripheral tissues. In males. Ablation of the ERK signaling pathway in pituitary gonadotropes led to infertility in female but not male mice. but also in the hypothalamus and pituitary of obese mice. Brodesser S.This paper aims to further our understanding of the sexually dimorphic control of reproductive function at the molecular level. pituitary GH and peripheral 24 Evelien F. Mice with P-lox elements surrounding the ERK2 locus were crossed with -GSU-Cre mice resulting in deletion of ERK2 in gonadotropes and thyrotropes. Recent yearbooks discussed in length the new concept of glucose homeostasis and body weight being under control of hypothalamic circuits regulating food intake. The authors therefore generated mice in which JNK1 was ablated in Nestin-expressing cells and confirmed ablation of JNK in both the hypothalamus and pituitary. the authors generated mice with a conditional inactivation of JNK1 in nestin-expressing cells (JNK1(DeltaNES) mice). as well as protection from hepatic steatosis and adipose tissue dysfunction upon high-fat feeding. Schauss AC.

Results: As expected. with an increase in TRH.5-kDa hGH after GHRH stimulation and exert Pituitary 25 . Lochmatter D. New mechanisms – GH deficiency Growth hormone (GH)-releasing hormone increases the expression of the dominant-negative GH isoform in cases of isolated GH deficiency due to GH splice-site mutations Petkovic V. TRH receptors. so having a dominant-negative effect. Robinson IC. can be due to heterozygous splice site mutations that weaken recognition of exon 3 leading to aberrant splicing of GH-1 transcripts and production of a dominant-negative 17. increased amount of 17. Diabetology. Switzerland primus. this study aimed to mimic the in vivo situation in vitro by transfecting wt-GH and three different exon 3 splice site mutations (GH-IVS+2. GH-IVS+6. disrupts the Golgi apparatus and prevents normal production and secretion of the 22-kDa isoform. Since the main driver of GH production is GHRH. a phenotype that is reminiscent of healthy ageing (increased insulin sensitivity accompanied by reduced glucose. and Metabolism. Eble A. GH-ISE+28) were transfected in rat pituitary cells expressing human GHRH receptor (GC-GHRHR).5-kDa protein. Splice site mutations in the GH-1 gene. result in deletion of exon 3. Significant variation in severity and age of onset exists in patients with IGHD type II [15]. Conclusion: The severity of IGHD II depends on the position of the splice site mutation and the production of increasing amounts of 17. a chronic up-regulation of GHRH would lead to an increased stimulatory drive to produce more 17. which is overexpressed in IGHD. GC-GHRHR cells coexpressing wt-hGH and each of the splice site mutants displayed reduced hGH secretion and intracellular GH content when compared with cells expressing only wt-hGH. combined with an increase in central insulin sensitivity and increased thyroid activity. but the exact reason is unclear. and GH levels).5-kDa GH isoform. which was not observed after GHRH-induced increase in wt-hGH. Due to the absence of GH and IGF-I-negative feedback in IGHD II. Bern. Mice expressing a high-copy number of a transgene mimicking the GH-IVS+1 mutation exhibit a dwarfed phenotype. like GH-IVS+1. TSH .IGF1. upon GHRH stimulation. with some patients showing progressive hypopituitarism. Unexpectedly the thyroid axis was also affected. thereby accelerating autodestruction of somatotrophs in a vicious cycle. resulting in production of a 17. and GH-ISE+28) which cause variable IGHD II in human patients.5kDa GH from the severest mutant alleles. confirming the dominant-negative effect of 17.5-kDa isoform on the secretion of 22-kDa GH. The results show that the three hGH splice site mutants produce different amounts of 17. insulin.mullis@insel. which reduces the storage and secretion of wt-GH in the most severely affected cases. University Children’s Hospital. Furthermore. This isoform is retained in the ER. This work therefore revealed an unexpected role of hypothalamic and pituitary JNK1 in the regulation of GH secretion and growth. the phenotype being less severe in low-copy number mice. and show disruption of somatotrophs and invasion of macrophages in the pituitary. the autosomal dominant form of isolated GH deficiency. Mullis PE Department of Pediatric Endocrinology. GH-IVS+2. GH-IVS+6 and GH-ISE+28.5-kDa isoform produced after GHRH stimulation in cells expressing GH-splice site mutants reduced production of endogenous rat GH. Previous studies suggested that the extent of mis-splicing varies with different mutations and the level of GH expression and/or secretion. wt-hGH and/or different hGH-splice site mutants (GH-IVS+2. aiming to study this clinical phenomenon using basic research tools. Fluck CE. in a rat pituitary cell line stably expressing GHRH receptors. depending on the GH-1 gene alterations. and also have deficits of other pituitary hormones.151:2650–2658 Background: IGHD II. GH-IVS+6.ch Endocrinology 2010. Methods: To study the functional relation between mutations and GH secretion. This study is a good example of bedside to bench work. and T3. Godi M.5-kDa GH isoform.

As is true for tumor formation of most tissues. 17]). VEGF and c-myc) (see Yearbook 2009. Methods: Immunofluorescence. Melmed S Department of Medicine. but little is known about proximal regulatory mechanisms. Overexpression of PTTG in mice facilitates pituitary tumor development and hPTTG1 overexpression in human tumors correlates with tumor invasiveness. transfection of E2F1 small interfering RNA lowered hPTTG1 levels 24 h later in HCT116 than in H1299 cells. which results in the most severe clinical presentation of the three. Gevers/Mehul T. results in the most severe dominant negative effect on endogenous wt-GH production and secretion. Bannykh S. USA SMelmed@csmc. including identification of potential binding sites in the hPTTG1 promoter. The presence of endogenous p53/p21 constrained the induction. Moreover. There is no dominant effect at the transcriptional level. Up-regulation of GHRH likely results in a vicious circle of increased 17. Pituitary tumors account for approximately 15% of intracranial tumors in adults. suppressing Rb by small interfering RNA concordantly elevated E2F1 and hPTTG1 protein levels. Quite a lot is known about downstream targets and action of PTTG (for example upregulation of bFGF. E2F1 overexpression enhanced endogenous hPTTG1 mRNA and protein levels up to 3-fold in H1299 cells. UCLA.5kDa GH production and somatotroph destruction and further up-regulation of GHRH. In contrast. PTTG is a proto-oncogene.23:2000–2012 Background: Rb(retinoblastoma protein)/E2F is dysregulated in murine and human pituitary tumors. is required for pituitary tumorigenesis. indicating that p53 delays E2F1 action on hPTTG1. chromatin immunoprecipitation. This study demonstrates how carefully designed in vitro experiments may not only be able to explain the mechanism of a disease. Los Angeles. and facilitates cell cycle progression. and PTTG1 deletion attenuates pituitary tumor development in Rb+/– mice.5-kDa protein in the proteosomal degradation pathway results in impaired cell function and storage and secretion of wt-GH and finally leads to somatotroph destruction. Dattani .. Conclusion: These results elucidate a mechanism for abundant tumor hPTTG1 expression. Pituitary [16. The GH-IVS+2 mutation. Transfection of E2F1 and its partner DP1 dose-dependently activated hPTTG1 transcription up to 3-fold in p53-devoid H1299 cells but not in p53-replete HCT116 cells. recurrence and prognosis. RNA down-regulation with siRNA. essential for proper chromatoid separation. Pituitary tumor transforming gene (PTTG1).edu Mol Endocrinol 2009. indicating that hPTTG1 may act as a direct E2F1 target. whereas decreasing either p53 or p21 in HCT116 cells restored E2F1-induced hPTTG1 transactivation and expression.different degrees of a dominant negative effect on endogenous wt-GH production. Wawrowsky K. but accumulation of the 17. This paper examines the regulation of PTTG1 by E2F1. Calif. aberrant cell cycle regulation plays a major role in pituitary tumor formation. Retinoblastoma protein (Rb) controls G1/S phase cell phase transition and Rb+/– mice spontaneously develop pituitary tumors. E2F1 specifically bound the hPTTG1 promoter. This paper now convincingly identifies E2F1 as a direct regulator of hPTTG in several ways. Results: E2F1 and PTTG1 were concordantly overexpressed in most of 46 Rb+/– murine pituitary tissues and also in over half of 80 human pituitary tumors. Gutman S. but also predict severity and progress of disease. This paper enhances our knowledge of Rb-E2F1-hPTTG1 signaling and the requirement of hPTTG1 for pituitary tumorigenesis. transient transfection of cultured cells. a securin protein. Follow-up on Yearbook 2009 – pituitary tumorigenesis E2F1 induces pituitary tumor transforming gene (PTTG1) expression in human pituitary tumors Zhou C. E2Fs are key interacting factors for Rb proteins and are universal regulators of G1/S transition and cell cycle progression [18]. Cedars-Sinai Medical Center. 26 Evelien F. whereby Rb inactivation releases E2F1 to induce hPTTG1.

at least in mice [19]. located in the hypothalamus and pituitary. thereby eliminating all octanoylated ghrelin from blood. Normal mice were able to cope and maintain normoglycemia in contrast to the Goat–/– mice that became hypoglycemic and died. In Goat–/– mice however. which on stimulation led to release of growth hormone from the pituitary. fasting blood glucose initially declined equally. USA joe. In both lines. its receptor or both. Infusion of either ghrelin or GH normalized blood glucose in Goat–/– mice and prevented death. Ghrelin was identified more than a decade ago as the endogenous ligand for the growth hormone secretogogue receptor. Yancopoulos GD. Ghrelin is unique in that its third amino acid. Here. Brown MS Department of Molecular Genetics. In this paper. which is processed to ghrelin.107:7467–7472 Background: Ghrelin is able to enhance food intake and growth hormone secretion from pituitary cells. Conclusion: An essential function of ghrelin in mice is elevation of GH levels during severe calorie restriction. Xie X. These data suggest a role for ghrelin in the release of GH during times of calorie restriction to preserve normoglycemia likely through the effect of GH on gluconeogenesis. and Ghrelin O-acyltransferase (GOAT) attaches octanoate to proghrelin. but experiments in this paper went one step further to expose the mice to prolonged severe nutrient restriction. Goldstein JL. Ghrelin is an octanoylated peptide. Pharmacological studies have since shown ghrelin’s potential to increase food intake. Methods: Goat knockout mice (Goat–/–) were generated and used in physiological experiments.edu Proc Natl Acad Sci USA 2010. The enzyme is located in the stomach and small intestine and lacks.goldstein@southwestern. has no significant impact on growth or appetite. It has been much harder to identify the physiological role of ghrelin since deletion of ghrelin. Sleeman MW. is modified by the attachment of a medium chain fatty acid. much like ghrelin or Ghs-r null mice. WT mice showed normal physical activity. and this modification is necessary for its action. glucose stabilized in WT mice at 58–76 mg/dl. The evidence presented reminds us also that GH is pivotal in preserving normal bloodglucose levels. When subjected to 60% calorie restriction. Liang G. glucose continued to decline. After 4 days. any other function. and GH treatment of Goat–/– mice prevented hypoglycemia without raising IGF1 or ghrelin. compared to Goat–/– mice.. At this point. In addition. This is supported by the lower concentrations of GH observed in the GOAT knockout mice and the rescue of blood glucose by infusion of GH or ghrelin. as far as is known. reaching 12–36 mg/dl on day 7. Mice fed a normal ad libitum diet did not show any abnormalities. the authors eliminate the Goat gene in mice. Valenzuela DM. whereas Goat–/– mice were moribund. octanoate. Dallas. serine. both WT and Goat–/– mice lost 30% of body weight and 75% of body fat within 4 days. the authors take a new approach to show the physiological role of ghrelin by generating mice that lack the enzyme GOAT. Results of this study suggest that ghrelin is important for the maintenance of the blood-glucose concentrations needed for survival during prolonged nutrient restriction. GH rose progressively in calorie-restricted WT mice and less in Goat–/– mice. but its essential function is obscure since elimination of the gene encoding ghrelin or its receptor produces only mild phenotypes in mice. serum GH concentration was much further increased when glucose concentration declined in WT mice. gut motility and growth hormone release. University of Texas Southwestern Medical Center. thereby preserving blood glucose and preventing death. Results: Goat–/– mice grew and maintained the same weights as wild-type (WT) littermates on normal or high fat diets. Li RL.Concept revised Ghrelin O-acyltransferase (GOAT) is essential for growth hormone-mediated survival of calorie-restricted mice Zhao TJ. Goat–/– mice indeed did not have detectable acyl-ghrelin. Pituitary 27 . Tex. Murphy AJ. which is required for the octanoylation of ghrelin.

The pituitary was normal in Gli1–/– mice but there was a missing adenohypophysis in 4 of 5 Gli2–/– and Gli1+/–. GnRH-1 cells develop independent of the adenohypophyseal placode and are associated early with the formation of the nasal placode.Gli2–/–. depending on the species. Within the CNS. it has been suggested that the GnRH-1 progenitor cells are located in an intermediate area between the anterior respiratory cells and the OE sensory cells. At E18. it was reported that when the adenohypophysis was missing or reduced. However. single [(Gli2–/–). the preoptic area. or neural crest.5. single knockouts (KOs) and double knockouts (35 and 65% respectively). It is clear that the neuroendocrine GnRH cells migrate from extra-central nervous system (CNS) locations into the forebrain. you-too and detour. Wray S Cellular and Developmental Neurobiology Section. In the mouse. with subsequent localization to the presumptive nasal cavity and olfactory placode. However. although olfactory structures were intact [20]. it is important to note that the murine genetic models that they have used may not be associated with GnRH-1 cell abnormalities as the genes that have been mutated may be implicated at later stages of pituitary 28 Evelien F. For a subset of embryos. Gevers/Mehul T. Ablation experiments suggested that the GnRH-1 lineage was developmentally associated with the respiratory area of the nasal placode. The authors of this study have used these mutants in the mouse to try and establish the lineage of GnRH-1 neurons. the proportion of the GnRH-1 population in nasal areas versus the forebrain was the same in controls (30 and 70%). Standard immunohistochemistry was performed and GnRH-1 cells counted in embryos in three areas: nasal region.Gli2–/– mice.New mutant mouse models Use of mutant mouse lines to investigate origin of gonadotropin-releasing hormone-1 neurons: lineage independent of the adenohypophysis Metz H. it was reported that absence or hypoplasia of the adenohypophysis was associated with absence or reduction of GnRH neurons. the embryonic origin of GnRH-1 and GnRH-3 cells is controversial and has been suggested to be nasal placode. Analysis of the mutants revealed that several diencephalic regions were normal in both single. Their data seem to confirm that the origin of the GnRH-1 cells may be independent of the adenohypophsis. yet with intact olfactory structures. nasal-forebrain junction. National Institute of Neurological Disorder and Stroke.. GnRH-1 cells within the forebrain showed a similar distribution. so were the hypothalamic GnRH neurons. At E15. There was no difference in the brain distribution among genotypes. or the hypothalamus. In mammals. in Gli single and double KOs. Bethesda. The origin of GnRH-1 cells has been the subject of much debate.gov Endocrinology 2010. Gli1+/–. Methods: In this report. (Gli1–/–) and (Lhx3–/–)] and double (Gli1–/–. Gli2–/– mice had complete loss of the adenohypophysis. in two zebrafish KOs in the Sonic Hedgehog pathway. forebrain GnRH-1 cells were further characterized as being in the olfactory bulb/rostral forebrain region. and double KOs. again dependent on the species examined.nih. GnRH-1 transcripts were identified in the primitive streak and later in the anterior neural ridge which gives rise to the anterior pituitary. However. cells were detected in the olfactory bulb/rostral forebrain. Results: Mutant mice with either missing or disrupted anterior pituitaries (Gli2–/–. National Institutes of Health.151:766–773 Background: Mutant mouse lines have been used to study the development of specific neuronal populations and brain structures as well as behaviors. Dattani . Gli2–/–) mutant mice were used to examine the lineage of GnRH-1 cells.and double-Gli KOs. but was structurally normal. you-too (Gli2–/–) and detour (Gli1–/–). Lhx3–/– mice were characterized by the presence of an undifferentiated anterior pituitary that was still connected to the oral ectoderm. the GnRH-1 cells are first identified in the nasal placode which also gives rise to the nonsensory respiratory epithelium. and forebrain. Conclusion: These results indicate that in mice. the olfactory epithelium and the vomerulonasal organ. GnRH is essential for vertebrate reproduction. The vomerulonasal organ was reduced in size in Gli2–/–. adenohypophyseal (anterior pituitary) placode.5. however there was no difference in GnRH-1 cell number or distribution. USA wrays@mail. Gli1–/–/Gli2–/– and Lhx3–/–) exhibited a normal GnRH-1 neuronal population and these cells were still associated with the developing vomerulonasal organ. preoptic area and hypothalamus. In the chick. This distribution was similar to control mice. In two zebrafish knockouts. Md. and all Gli1–/–. with either GnRH-1 or GnRH-3 controlling release of gonadotrophins from the anterior pituitary.

and cell activity at single-cell resolution in mouse pituitary glands in situ.mollard@igf. oxygen partial pressure. and cell activity at single-cell resolution in mouse pituitary glands in situ. the supply and consumption of oxygen by the vasculature and GH cells. These methods involved the modification of a fluorescent stereomicroscope with long working distance objectives to image at wide field and single cell resolution an exposed pituitary gland deep in its in vivo environment. Results: Single capillaries were identified in close proximity to structural GH cell network motifs. which was temporally associated with increases in blood flow rates and oxygen supply by capillaries. Conclusion: These data suggest that GH pulse generation is not simply a GH cell network response. Desarmenien MG. in zebrafish. Hodson D. Cassou M. The pulsatile release is dependent upon a carefully orchestrated pattern of GHRH and somatostatin secretion. Carmignac D. New image Cellular in vivo imaging reveals coordinated regulation of pituitary microcirculation and GH cell network function Lafont C. oxygen partial pressure. Montpellier. the mutants are associated with a small pituitary. Lecoq J. Mennessier G. Molino F. there is a general reduction in all the anterior pituitary hormones [7]. They developed optical imaging methods that can monitor directly in vivo the relationship between the blood vasculature and GH cell network function.fr Proc Natl Acad Sci USA 2010.crns. macromolecules injected into the extracellular parenchyma moved rapidly to the perivascular space. with corresponding changes in oxygen supply and oxygen consumption. However. yet poorly understood processes leading to pulsatile GH secretion It is clear that the secretion of GH by the GH cell network is dependent upon the fine regulation of hypothalamic inputs by the pituitary microcirculation. Institute of Functional Genomics. These elegant studies have begun to shed light on the highly complex.107:4465–4470 Background: Growth hormone (GH) exerts its actions via coordinated pulsatile secretion from a GH cell network into the bloodstream. Lacampagne A. Coutry N. Many unanswered questions remain. Charpak S. but were then cleared more slowly in a size-dependent manner into capillary blood. whereas the rest of the pituitary hormones are largely unaffected apart from occasional GH deficiency. and will probably impact on our understanding Pituitary 29 . Le Tissier P. and the dynamic uptake of secreted products by the efferent blood capillaries. as well as oxygen consumption. Mollard P Department of Endocrinology. The authors also report a time-limiting step for hormone output at the perivascular level. El Yandouzi T. France patrice.development. Fernandez-Fuente M. in vivo techniques in transgenic GH-eGFP mice to measure local blood flow. In this work. Injection of GHRH led to stimulation of both GH cell network activities and GH secretion. Hence. for example mutations of SOX2 in humans are associated with hypogonadotrophic hypogonadism in association with a small anterior pituitary gland. were exploited to monitor directly the relationship between the blood vasculature and GH cell network function in vivo. in the mouse. The study of these processes in an in vivo setting will revolutionize our understanding of GH secretion. whereas Gli1–/– mutants are not associated with an abnormal pituitary in the mouse. Christian H. a restricted distribution gradient evolved within the pituitary parenchyma. Robinson IC. Methods: The authors have developed in vivo approaches using transgenic GH-eGFP mice to measure local blood flow. hence. but is shaped by a tissue microenvironment context involving a functional association between the GH cell network activity and fluid microcirculation. one cannot rule out a very early common origin of GHRH-1 and pituitary progenitor cells. Fontanaud P. Additionally. When secretagogue (GHRH) distribution was modeled with fluorescent markers injected into either the bloodstream or the nearby intercapillary space. Practically nothing is known about how the network receives its inputs in vivo and releases hormones into pituitary capillaries to shape GH pulses. species differences may account for some of the discrepant results.

and selectively targets 30 Evelien F. a newly described homolog of MRAP. b-. a commonly used food additive in South Asian cooking. MRAP2. William Harvey Research Institute. This is an excellent review that highlights the importance of the various components of melanocortin receptor (MCR) signaling. London. MCRs act as receptors for a-. Milwaukee.uk Mol Endocrinol 2010. UK a.e. Standard treatment includes surgery and. MC2R as the receptor for ACTH. This review facilitates the understanding of MCR signaling and its relation with disease. Dattani . Reviews Minireview: the melanocortin 2 receptor accessory proteins Webb TR. Recent work has started to reveal which MRAP domains are involved in MC2R functional expression. Clark AJ Centre for Endocrinology. i. possibly by inhibiting constitutively activated NF B.g. Raff H.24:475–484 The melanocortin 2 receptor (MC2R) accessory protein. St. The review covers the similarities and differences of MRAP and MRAP2.j. Woodliff J. Luke’s Medical Center. and g-MSH and ACTH and have a diverse range of functions – MC1R in skin pigmentation. has potent growth inhibitory effects on cell proliferation. Curcumin. Wisc. moderate signaling intensity. Kansra S Department of Endocrinology. Aurora St. Food for thought – curcumin Growth suppression of mouse pituitary corticotroph tumor AtT20 cells by curcumin: a model for treating Cushing’s disease Bangaru ML.of the pathophysiology associated with GH deficiency and related disorders. in children with tumors. dopamine receptor agonists. is one of a growing number of G-protein-coupled receptor accessory proteins that have been identified in recent years. e. MRAP. both of which have undesirable side effects and frequent recurrence of the tumor. direct receptor trafficking and targeting.. if not successful.5:e9893 Background: Pituitary corticotroph tumors secrete excess adrenocorticotrophic hormone (ACTH) resulting in Cushing’s disease. is also able to support the cell surface expression of MC2R.ac.clark@qmul. Gevers/Mehul T. The mechanism of MRAP action is only beginning to be understood although it is clear that MRAP is required for MC2R function. and mutations cause ACTH resistance. and also discusses their MC2R independent function and ability to modulate function of other MCRs. Pharmacotherapy using PPAR agonists.edu PLoS One 2010. congenital GH deficiency and those who have impaired GH secretion as a result of traumatic brain injury and radiotherapy. MRAP interacts directly with MC2R and is essential for its trafficking from the endoplasmic reticulum to the cell surface. and new data have shown a potential role for both MRAP and MRAP2 in the regulation of the other melanocortin receptors. In addition. MC3R and MC4R in energy homeostasis. familial glucocorticoid deficiency. radiotherapy. Bartholomew’s and The Royal London School of Medicine and Dentistry. MRAPs act as accessory proteins for MC2R and are required for MC2R to travel to the cell surface and for ACTH signaling. their structure and function in ACTH signaling. Metabolism & Clinical Nutrition. GPCR accessory proteins modulate GPCR function. retinoic acid or somatostatin analogs is still experimental. and modify receptor structure and ligand binding. USA skansra@mcw. where it acts as the receptor for the pituitary hormone ACTH.

Results: Using the mouse corticotroph tumor cells. Hunter CS. Zalla T. Further. Although rare in children.107:4389–4394. 10. curcumin down-regulated the pro-survival protein Bcl-xL. apoptosis (bcl-2). Herbrecht E. et al: Four novel mutations of the LHX3 gene cause combined pituitary hormone deficiencies with or without limited neck rotation. Hansen LH. and these studies suggest that Bcl-xl plays a major role in regulating cell survival in pituitary corticotrophs. Andari E. 8. In the Indian population. Constitutive activation of NF B has been reported in cell lines as well as tumor samples. any effective alternative therapies need to be explored. Endocr Rev 2009. Walvoord EC. Leboyer M. which has previously been used in Indian cooking. Monahan P. Thomas PQ. although the in vivo effects have not as yet been established in humans. et al: Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency.92:1909– 1919. especially before use in children and adolescents. as an anti-tumor agent. Rajab A. Maghnie M.91:747–753. The curcumin-induced growth inhibition was accompanied by a dose-dependent decrease in constitutive NF B activity. Biebermann H. osteoporosis and hypertension. and increased PARP cleavage. Brickman JM.19:125–133. and may be linked to tumor progression as well as drug resistance. the authors report that curcumin had a robust. Teisner B. et al: Novel mutations in LHX3 are associated with hypopituitarism and sensorineural hearing loss. Gupta R. cyclin D family). Kelberman D. The results are certainly interesting. Pavlakis S. 3. and Mcl-1) are target genes of NF B. the molecular mechanisms that mediate this effect of curcumin are still unknown. Nat Genet 2000. Mol Endocrinol 1998. Conclusion: The ability of curcumin to inhibit NF B and induce apoptosis in pituitary corticotroph tumor cells suggests that it might be used as a novel therapeutic agent for the treatment of Cushing’s disease. However. Martinez-Barbera JP. Robinson IC. Billestrup N: Characterization of the inhibitory effect of growth hormone on primary preadipocyte differentiation. [21] confirmed these data and also showed the in vivo effectiveness of curcumin in suppressing pituitary tumorigenesis. 5. Curcumin may therefore modify Bcl-xL levels and hence act as a tumor suppressor. surgery and radiotherapy. Increased expression of the pro-survival protein Bcl-2 is commonly observed in pituitary tumors. The proposed mechanism of action of curcumin is interesting. Kumar P. References 1. potential side effects will need to be considered. 4. Schnabel D. The pro-survival Bcl-2 family of proteins (Bcl-2. it is estimated that the average daily consumption of curcumin is 60–100 mg. Dattani MT. it can be associated with life-long complications and impact on normal growth and development and also lead to diabetes mellitus. Palme C.25:182–186. The treatment of Cushing syndrome is not straightforward and often needs a combination of medical treatment.g.12:1140–1149. Shaikh H.93:4351–4439. Kelberman D. Subsequently. 9. Rybak S.tumor cells. et al: Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Pfaeffle RW. which led to increased apoptosis. Proc Natl Acad Sci USA 2010. although no toxic effects are known at present. Marshall I. Raetzman LT: The notch target gene HES1 regulates cell cycle inhibitor expression in the developing pituitary. Nielsen JH. Anhalt H. Ahlmann M. 2. Pituitary 31 . Madsen B. AtT20 cells. J Clin Endocrinol Metab 2008.30:790–829. Bcl-xl plays a central role in pituitary cell survival and apoptosis. Marcos E. Savage JJ. Nat Genet 1998. de Castro SC.17:2150–2159. Hum Mol Genet 2008. In this study. Martensson IL. Zunich J. Lovell-Badge R. Bcl-xL. Diaczok D. Dattani MT: Genetic regulation of pituitary gland development in human and mouse. Pearce K. et al: Clinical case seminar: a novel LHX3 mutation presenting as combined pituitary hormonal deficiency. curcumin decreased secretion of ACTH and its effects are irreversible. Sobrier ML. Radovick S: A novel dominant negative mutation of OTX2 associated with combined pituitary hormone deficiency. Duhamel JR.g. irreversible inhibitory effect on cell proliferation and clonogenic property. The authors recently demonstrated that curcumin inhibited growth and induced apoptosis in prolactinand growth hormone-producing tumor cells. Romero C. Savage JJ. and complete inhibition was observed with 20 µM. It suppresses the TNF -induced activation of IKK that leads to the inhibition of TNF-dependent phosphorylation and degradation of I B and subsequent nuclear translocation of the p65 subunit of NF B to regulate expression of genes implicated in cell cycle progression (e. Bhangoo AP. and cell migration and invasion (e. Sirigu A: Promoting social behavior with oxytocin in highfunctioning autism spectrum disorders. J Clin Endocrinol Metab 2007. J Clin Endocrinol Metab 2006. significant inhibition of colony formation was observed with concentrations of 5 µM. depolarized the mitochondrial membrane. Hence. Additionally. Rizzoti K.150:4386–4394. offering new hope to the treatment of Cushing disease. Netchine I. Krude H. Hunter CS. 7. Endocrinology 2009. MMP2 and MMP9). 6. Finally. curcumin had a concentration-dependent suppressive effect on ACTH secretion from AtT20 cells. in vitro. Schaaf et al. the authors have investigated the use of the potent proliferation inhibitor curcumin.

et al: A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction.11. Chesnokova V.23:7973– 7981.15:3193–3207. et al: Isolated autosomal dominant growth hormone deficiency: an evolving pituitary deficit? A multicenter follow-up study. Nature 1998.435:673– 676.112:1192–1201. Salemi S. Stifani S. Olson L. Kosfeld M. Xu L. Slack RS: Specific in vivo roles for E2Fs in differentiation and development. Carvalho LR. Ju B. Ben-Shlomo A. Hochberg Z (eds):. Dasen JS. 17. et al: Curcumin inhibits the growth. 21. Dasen JS. Vuissoz JM. 12. Besson A. Mullis PE.91:200–210.105:17498–174503.90:2089–2096.257:140–152. Stalla GK. Mendonca BB. Nature 2005. Kovacs K. McClellan KA. 20. Eble A. Whitlock KE. Lavinsky RM. Connell SO. Wawrowsky K. Marcal N. pp 13–26. Herman TS. Schaaf C. 19. et al: Temporal regulation of a paired-like homeodomain repressor/TLE corepressor complex and a related activator is required for pituitary organogenesis. Bannykh S. Ahmed S. J Clin Endocrinol Metab 2005. J Clin Invest 2003. et al: Signal-specific co-activator domain requirements for Pit-1 activation. Fischbacher U. Schilling T. 14. 2009. Secco A. Wolf CD. 32 Evelien F. McInerney EM. Smith RG: Deletion of ghrelin impairs neither growth nor appetite. Proc Natl Acad Sci USA 2008. Neuroendocrinology 2010. 16. Onofri C. Robinson IC. Mullen TM.6:2917– 2927. Karger. et al: p21(Cip1) restrains pituitary tumor growth. Cell Cycle 2007. in Carel J-C.395:301–306. Genes Dev 2001. Flynn SE. Yearbook of Pediatric Endocrinology 2009. Basel. Shan B. 18. Dev Biol 2003. Arzt E. 13. Dattani . Loche S: Pituitary. Heinrichs M. Fehr E: Oxytocin increases trust in humans. Woods KS. 15. induces apoptosis and modulates the function of pituitary folliculostellate cells. Danio rerio. Barbera JP. Boyce ML: Gonadotropin-releasing hormone (GnRH) cells arise from cranial neural crest and adenohypophyseal regions of the neural plate in the zebrafish. Zonis S. Gevers/Mehul T. Maghnie M. Zamparini AL. Mol Cell Biol 2003. Sun Y. Zak PJ.

New York. Department of Medicine and Department of Pharmacology. N. NIS-mediated I− transport uses the downhill Na+ gradient generated by the Na+. conversely. Reyna-Neyra A. Abbott GW Greenberg Division of Cardiology. Basel. these symptoms were elicited in Kcne2+/+ pups by feeding exclusively from Kcne2–/– dams.and KCNQ1linked human cardiac arrhythmias. USA gwa2001@med. The alopecia. the concept of the year is the introduction of potassium channels in the scene of thyroid hormone biosynthesis.K+-ATPase by the presence of a constitutively active potassium channel. As supposed from their co-expression with the sodium/iodide symporter (NIS) at . Kcne2-deficient mice had hypothyroidism. goiter and cardiac abnormalities including hypertrophy. in mice impaired thyroid iodide accumulation up to 8-fold. thyrocytes are non-excitable. and reduced fractional shortening. Koba W. Purtell K. France b Paediatric Endocrinology. where they create a TSH-stimulated constitutively active potassium current. INSERM U845. by supplementing dams with T4 before and after they gave birth or by feeding the pups exclusively from Kcne2+/+ dams. Université Paris Descartes. halved milk tetraiodothyronine (T4) content and halved litter size. Lerner DJ. For us. Results: Targeted disruption of Kcne2. polarized epithelial cells expressing ion transporters essential for the function of the thyroid gland.K+-ATPase at the basolateral membrane of the thyrocyte. Paris. Carrasco N. They showed that both subunits were expressed in human and murine thyrocytes. The concept of the year was the introduction of potassium channels as limiting factor of iodine accumulation in the murine thyroid by closing the gap between the sodium/iodide symporter (NIS) and the Na+. a thyrocyte K+ channel. impaired maternal milk ejection. dwarfism. environmental factors. Mechanism of the year in thyroidology Kcne2 deletion uncovers its crucial role in thyroid hormone biosynthesis Roepke TK. where it is covalently incorporated into thyroglobulin. Aurore Carréa and Mireille Castanetb a Pediatric Endocrinology and Gynecology. Hôpital Necker Enfants Malades. Weill Medical College of Cornell University. AP-HP.15:1186–1194 Background: Analogous to parietal cells and colonic crypt cells in the gastrointestinal tract. Switzerland The chapter aims at giving a representative choice of high-standing articles answering timely questions in the fields of thyroid physiology and disease covering areas as genetics. Time and future yearbooks will be able to estimate the clinical relevance of this report for understanding normal thyroid function and its disease. The authors identified the presence of a heterodimeric thyrocyte potassium channel. development and cancer. Paroder M. thyrocyte K+ channel required for normal thyroid hormone biosynthesis. These data provide a new potential therapeutic target for thyroid disorders and raise the possibility of an endocrine component to previously identified KCNE2. I− enters thyrocytes via the basolaterally located Na+/I− symporter (NIS) and exits apically into the colloid. The thyroid hormones (TH) triiodothyronine (T3) and tetraiodothyronine (thyroxine. constitutively active. Conclusion: The authors show that the potassium channel subunits KCNQ1 and KCNE2 form a thyroidstimulating hormone-stimulated. The role of K+ channels in the thyroid has not been described so far.. pharmacology.Thyroid Michel Polaka.cornell. composed of the two subunits KCNQ1 and KCNE2. the precursor of T3 and T4. King EC. Gabor Szinnaib. dwarfism and cardiac abnormalities were alleviated by triiodothyronine (T3) and T4 administration to pups.edu Nat Med 2009. fibrosis. or T4) are critical for normal growth and development of the fetus and newborn as well as for regulation of metabolism in virtually all tissues at all ages.Y. alopecia. University Children’s Hospital. Fine E.

there has not been a systematic and comparative evaluation of the adverse events associated with antithyroid drug use.3–6. a hallmark of loss-off-function mutations in KCNE2 and KCNQ1. and as published by the same group in a past paper. USA scott. they identified high reporting ratios for severe liver injury and vasculitis in the pediatric and adolescent age group for propiothiouracil vs. 34 Michel Polak/Gabor Szinnai/Aurore Carré/Mireille Castanet .5–24. deletion of Kcne2 resulted in an I– accumulation defect. Kcne–/– mice were hypothyroid and developed goiter.edu J Clin Endocrinol Metab 2010. Methods: They used a data mining algorithm to analyze more than 40 years of safety data in AERS. The prevalence of severe liver failure was estimated to be approximately 1:2. the authors detected higher-thanexpected reporting of severe hepatotoxicity and vasculitis in children and adolescents with propylthiouracil but not with methimazole.000 children. Szarfman A Yale Pediatric Thyroid Center.1) in the group less than 17 years of age. Vasculitis was also observed for propylthiouracil in children and adolescents. focusing on hepatotoxicity events. Epub ahead of print Background: The antithyroid drugs propylthiouracil and methimazole are estimated to be used in more than 6. Silver Spring. Results: The algorithm identified higher-than-expected reporting of severe liver injury in pediatric patients treated with propylthiouracil but not with methimazole. derived from those FDA data. pp. However. This detailed paper reinforces the preliminary message of last year’s letter of the authors in the New England Journal of Medicine that propylthiouracil should not be used anymore in children with Graves’ disease [1]. This algorithm allows ultimately calculating adjusted observed to expected ratios for every drug-adverse event combination in AERS. Although the concept of closing the gap between the NIS and the Na+. The authors have already reported in a letter format the hepatotoxic effect of propylthiouracil in children and have pleaded not to use this drug anymore in pediatric Graves’ disease [1]. Conn. US Food and Drug Administration. By use of a data mining algorithm of more than four decades of safety data of the FDA’s AERS.8 (3.the basolateral membrane.rivkees@.000 children and adolescents per year in the USA. Consequently. Kcne–/– mice further had cardiac hypertrophy. Propylthiouracil had a high adjusted reporting ratio for severe liver injury (17.or KCNQ1-associated cardiac arrhythmias. Conclusions: Within the US Food and Drug Administration’s AERS. 90% CI 11. Objective: The authors’ aim was to assess safety and hepatotoxicity profiles of propylthiouracil and methimazole by age in the US Food and Drug Administration’s Adverse Event Reporting System (AERS). As subclinical hypothyroidism is also associated with prolonged QTc.yale. thorough clinical description of thyroid function in patients with mutations is warranted to further support the hypothesis of a ‘thyroid’ component to some KCNE2. Yale University School of Medicine. Whether further potassium channels are expressed in human thyrocytes and could be involved in human thyroid biosynthesis. The highest ratio values for methimazole were with mild liver injury in the group 61 years and older (4. Over the years that these medications have been used. the first step of thyroid hormone biosynthesis. methimazole. reaching higher ratio values than hepatotoxicity signals. remains unanswered for the moment. 27–40) Protect the liver when using antithyroid drugs in children Dissimilar hepatotoxicity profiles of propylthiouracil and methimazole in children Rivkees SA. This statement. reports of adverse events involving hepatotoxicity have appeared. Md.K+-ATPase by the presence of a constitutively active potassium channel is new and innovative. impaired ventricular repolarization.8)). New Haven.. and Center for Drug Evaluation and Research. human mutations in KCNE2 have been identified in patients with long QT syndrome (LQT subtype 6). but hypothyroidism was not reported in these patients so far. which consisted of cholestasis. Follow-up on a Yearbook 2009 paper (see Thyroid section.

indicating that intra-amniotic TSH levels did not reliably reflect fetal thyroid function. returning to normal in 4. Université Paris Descartes. Methods: This study was a retrospective study of 12 prenatally treated fetuses diagnosed between 1991 and 2005 in France. laboratory. This paper also highlighted the utility of systematic analyse adverse events reports in large databases using methods that decrease false-positive rates due to small numbers while preserving stable signals with a small number of reports. Results: The practice of the prenatal treatment was found to vary widely in terms of L-thyroxine dosage (200–800 µg/injection). safety. Luton D. using intra-amniotic injections in a large cohort with non-immune fetal goitrous hypothyroidism. Clinical trials. the safety of both drugs in pregnant women as well as their potential teratogenic effects should therefore be under close scrutiny from now on and further data should be gathered before formal recommendations can be issued. clinical. Fortunately.does not apply to adult patients [2]. all babies had hypothyroidism. During pregnancy. Thyroid 35 . Vuillard E. However.polak@nck. A statement was issued to use propylthiouracil during organogenesis for the first 8 weeks of development and then to switch to methimazole [2]. Conclusion: The authors confirmed the feasibility and safety of intra-amniotic L-thyroxine treatment for non-immune fetal goitrous hypothyroidism. at birth. They also could show that amniocentesis seemed inadequate for monitoring fetal thyroid function in comparison with fetal blood sampling. However. and effectiveness of intrauterine L-thyroxine treatment. new treatments Pro and contra for in utero treatment of congenital hypothyroidism Experience with intra-amniotic thyroxine treatment in non-immune fetal goitrous hypothyroidism in 12 cases Ribault V.fr J Clin Endocrinol Metab 2009. Castanet M. further studies are needed to determine the optimal management of this disorder. thyroid size decreased in 8 of 9 cases and amnioticfluid TSH levels decreased in the 6 investigated cases. Paris. Guibourdenche J. At birth. number of injections (1–6). no adverse events were recorded. France michel. Objective: The authors wished to evaluate the feasibility.aphp. Necker Enfants Malades AP-HP. and frequency (every 1–4 weeks). In the treatment of pregnant women with active Graves’ disease we are faced with a dilemma: propylthiouracil may appear as the drug of choice as methimazolerelated fetal malformations were reported in some studies but not in all [3–5]. Prenatal treatment to prevent these adverse outcomes is appealing. but experience is limited and the risk-to-benefit ratio controversial. and ultrasound data were evaluated. However. Bertrand AM. Polak M. During pregnancy.94:3731–3739 Background: Non-immune fetal goitrous hypothyroidism is a rare condition that can induce obstetrical and/or neonatal complications and neurodevelopmental impairments such as those still seen in some patients with congenital hypothyroidism. goiter size and thyroid hormone levels were compared before and after prenatal treatment. the French Fetal Goiter Study Group Pediatric Endocrinology.

6 ± 5. The authors rightly conclude that ‘to determine the indications and optimal modalities of the prenatal treatment of non-immune fetal goitrous hypothyroidism. Intra-amniotic thyroxine was injected at 25 weeks when amniotic fluid volume increased. 36 Michel Polak/Gabor Szinnai/Aurore Carré/Mireille Castanet .ca J Pediatr 2010. Normal newborn screening results can be falsely reassuring and may contribute to a delay in diagnosis of hypopituitarism despite classic clinical features. Important for clinical practice Everlasting questions on congenital hypothyrodism screening Newborn screening results in children with central hypothyroidism Nebesio TD. Van Vliet G. The average total thyroxine level in the remaining 34 subjects was 9. and children with normal newborn screening results were initially examined at an average age of 16. Indianapolis. Francoeur D. 8]. Fetal goiter size decreased in 8 of 9 investigated cases and intra-amniotic TSH levels decreased. larger and well-designed studies are needed and would be best conducted via international cooperation of multidisciplinary medical teams’. Grignon A. Canada Johnny.8 ± 3.edu J Pediatr 2010. Department of Pediatrics.156:1026–1029 Hypothyroidism was documented by cordocentesis at 19 weeks in a fetus with non-immune goiter. No differences were found in the two groups for birth history. Pohlenz J. the second paper reports a case with a review of the literature..037). as expected but not adapted for those with low T4 levels. 57% of children had septo-optic dysplasia. Conclusions: Most children with congenital central hypothyroidism have normal thyroid function at birth. others would favor an approach using research protocols to target fetal hypothyroidism treatment itself [7.4 µg/dl. McKenna MP. Some authors propose to use intra-amniotic thyroxine treatment only in case of fetal goiter that may impede vaginal delivery or result in the development of polyhydramnios. Methods: Medical records of children with central hypothyroidism observed in their pediatric endocrinology clinics from 1990 to 2006 were reviewed. Children with an abnormal newborn screening results were initially examined by a pediatric endocrinologist at an average age of 4. 8 children (19%) had a low total thyroxine level (<5. The feasibility of intrauterine treatment of fetuses affected by hypothyroidism has been shown.7 months (p = 0. Psychomotor outcome was normal.156:990–993 Background: The authors wished to investigate newborn screening results in children with congenital hypopituitarism. USA tdnebesi@iupui. Deladoëy J Endocrinology Service and Research Center and Department of Pediatrics.Non-immune goiter and hypothyroidism in a 19-week fetus: a plea for conservative treatment Stoppa-Vaucher S. The incompletely solved question is when should we apply those new tools? While the first paper reports a multicenter retrospective experience with in utero treatment. CHU Sainte-Justine and Université de Montréal. Results: 42 subjects (22 boys) were identified. hypoglycemia (36% overall).9 ± 26. Montréal. The diagnosis of fetal thyroid function disturbances is now possible in utero [6–8].. Nabhan ZM. Ind. or micropenis (43% of boys). Alos N.0 months. all with central hypothyroidism. and 98% had multiple pituitary hormone deficiencies.0 µg/ dl) on the newborn screening test. Thyrotropin levels were within the reference range in all children. jaundice (53% overall). They also wished whether there were differences between children who had abnormal results and children with normal newborn screening results. The authors argue that intra-amniotic thyroxine should not be used to treat the hypothyroidism but only to correct the development of polyhydramnios. Eugster EA Indiana University School of Medicine.deladoey@umontreal. Hermanns P. Riley Hospital for Children. due to central hypothyroidism in a screening program that uses T4 determination. Que.

0 mU/l.cheetham@nuth. would have been missed using the 20 mU/l cut-off. evolving in mild permanent thyroid dysfunction later in life. Clinical re-evaluation after L-T4 withdrawal of a representative group of 140 CH children at 3–5 years was also performed.uk Arch Dis Child 2010. Wastell H. Results were compared with those virtually obtained with the previous cut-off (20 mU/l). As the value used varies from 5 to 10 mU/l. Chiumello G. 120 were term infants with 67 of these (0. Results: 148 of 65. Methods: The authors’ regional blood spot TSH cut-off is 6 mU/l.org] advocated the use of low bloodspot TSH (b-TSH) threshold for newborn screening of congenital hypothyroidism (CH) [9]. The incidence of CH in this Italian population appears to be double than previously thought with a clear-cut prevalence of functional defects over dysgenetic ones. Cheetham T Institute of Human Genetics. Italy luca. UK tim.to 5-fold increased risk of GIS CH.1% of all infants tested) having a TSH between 6. Ward Platt MP.nabc. but abnormalities of thyroid function requiring treatment will be detected. Passoni A.1 and 10. Royal Victoria Infirmary. Methods: Retrospective study of 629. Objective: The authors wished to determine the impact on CH epidemiology and classification generated by the introduction of lower b-TSH cut-off than the on they previously used. Re-evaluation at 3–5 years showed a permanent thyroid dysfunction in 78% of 59 CH toddlers with GIS.nhs.0 mU/l. The survey of endocrinologists highlighted significant differences in practice. Milan.0 mU/l on initial testing.0 mU/l and 53 a TSH >10. Beck-Peccoz P. Persani L Laboratory for Neonatal Screening.0 mU/l and then >6 mU/l on second sampling were sent to pediatric endocrinologists to determine approaches to management.it Clin Endocrinol (Oxf) 2009.A 7-year experience with low blood TSH cut-off levels for neonatal screening reveals an unsuspected frequency of congenital hypothyroidism Corbetta C. One with a TSH >10 mU/l and 1 infant with a TSH <10 mU/l on the second blood spot have been diagnosed with CHT.042 newborns screened with b-TSH cut-offs of 12 (years 1999– 2002) or 10 mU/l (2003–2005). we examined the implications of altering this threshold. Turner S. including 12/141 dysgenesis. All term infants (>35 weeks) whose first TSH was 6–20 mU/l had a second TSH measured.95:169–173 Background: The UK Newborn Screening Programme Centre recommends that a blood spot thyroid-stimulating hormone (TSH) cut-off of 10 mU/l is used to detect congenital hypothyroidism (CHT). Vigone MC. In contrast to current classification. Conclusions: A reduced threshold of 6 mU/l will increase the number of false positive term infants by 126%. Conclusions: The use of low b-TSH cut-off allowed the detection of an unsuspected number of children with neonatal hypothyroidism. Pearce M.persani@unimi. Avis E. Of the 67 term infants with a TSH between 6. Calebiro D.71:739–745 Background: The guidelines of the National Academy of Clinical Biochemistry [www. Newcastle upon Tyne. The authors suspected but did not confirm that the additional expense involved in setting a lower threshold is justified.446 infants (0.446). Weber G. Thyroid 37 .1 and 10. 32% CH newborns had thyroid dysgenesis and 68% had a gland in situ (GIS). Difficulties in selecting an appropriate neonatal thyroid-stimulating hormone screening threshold Korada SM. Premature birth was present in 20% of cases being associated with a 3. Positive or suspected cases were defined as a TSH >6 mU/l throughout the study period (1 April 2005 to 1 March 2007).1 and 10. Results: Low b-TSH cut-offs allowed the detection of 435 newborns with confirmed CH (incidence 1:1. Newcastle University. 4 continued to have a TSH >6 mU/l. Cortinovis F.23%) had a first blood spot TSH >6. Department of Paediatrics. Buzzi Children Hospital. 45% of CH infants. The biochemical details of infants with a TSH between 6.

38 Michel Polak/Gabor Szinnai/Aurore Carré/Mireille Castanet . They aimed to recommend optimal treatment in these forms of neonatal thyroid impairment.Neonatal hyperthyrotropinemia: population characteristics. 8%. The first paper analyzed the sensitivity of combined T4/TSH bloodspot screening for detection of neonatal central hypothyroidism. more cases were found when lowering the bloodspot TSH cutoff value to 12. 11]. several cases of thyroid dysgenesis were found in both cohorts. Israel amzung2@bezeqint. Bistritzer T. thyroid imaging results and optimal thyroxine doses between HT and CH and between the two forms of HT. screening and confirmatory T4 and TSH levels. retrospective study was conducted in six pediatric endocrinology units.72:264–271 Background: Neonatal hyperthyrotropinemia (HT). Of interest. Barkan S. Tenenbaum-Rakover Y.net Clin Endocrinol (Oxf) 2010. Patients with permanent HT had a higher prevalence of abnormal thyroid imaging but were indistinguishable by other parameters from patients with transient HT. The worrisome question is: What happened to the children with such intermediate levels of TSH on screening at the time when the threshold was higher: were they picked up at a later age with mild hypothyroidism. This article reminds us that the possibility of late congenital hypothyroidism diagnosis should be on our mind despite normal screening results and that the clinical skills to suspect such a diagnosis should still be taught. 10 or 6 mU/l. These four articles targeted questions related to screening of congenital hypothyroidism and extend our current knowledge. modes of diagnosis. diagnosis. Conclusion: The authors recommended obtaining thyroid imaging to distinguish between the two forms of HT. should we be worried for their cognitive development? The fourth paper raised the question of the follow-up of children with neonatal hyperthyrotropinemia (HT) based on a retrospective analysis. Hanukoglu A. Only 8 (19%) of a retrospective single-center cohort of 42 children with central hypothyroidism were detected by decreased T4 values in the newborn screening. This rate of normal newborn screening results of T4 in central hypothyroidism is much higher than stated in previous reports [10. On the other hand. During treatment. The diagnosis of central hypothyroidism was based on classic clinical and laboratory features rather than dynamic testing. Results: Newborns with HT had lower BW and GA than those with CH. Kaplan Medical Center. As expected. Pinhas-Hamiel O.005). 43 HT patients and 83 CH patients were included in the study. They draw our attention to this peculiar group of patients in whom a targeted dose of thyroxine and a close follow-up is necessary. p = 0. defined by elevated TSH and normal T4. They also advised that early cessation of therapy in transient HT can prevent iatrogenic hyperthyroidism in these patients. gestational age (GA). Objective: The authors assessed perinatal parameters and diagnostic measures that may distinguish between transient and persistent HT. management and outcome after cessation of therapy Zung A. the authors demonstrated a significant incidence of iatrogenic hyperthyroidism due to treatment.5 years. Although most HT patients were re-evaluated after 2. Hershkovitz E. is either transient or persistent. Zadik Z Pediatric Endocrinology Unit. 79 and 55% of transient and persistent HT patients respectively experienced elevated levels of free T4. compared with congenital hypothyroidism (CH). Of interest. but those with persistent HT had a higher prevalence of abnormal thyroid imaging (69 vs. Proponents of a T4 screening claim that this would identify central hypothyroidism. many patients with glands in situ were identified with a high incidence of permanent thyroid dysfunction at follow-up. The authors evaluated differences in birth weight (BW). Transient (n = 18) and persistent HT (n = 25) patients were indistinguishable by most parameters. 6 transient HT patients stopped therapy and showed full recovery within the first year of life. Rehovot. Two papers questioned the threshold of the bloodspot TSH levels for the neonatal screening of congenital hypothyroidism. Methods: A multi-centre.

org J Clin Oncol 2010. surgical approach and long-term follow-up for medullary thyroid carcinoma. Methods: Relevant articles were identified using a systematic PubMed search and supplemented with additional published materials. Francis GL. Ringel MD. extent of surgery. Eng C. Link MP Department of Pediatric Hematology/Oncology. as well as for MEN2-associated pheochromocytoma and hyperparathyroidism. Recommendations are stratified according to more experience with clinical outcome of patients with specific RET mutations. Columbus. Whittemore AS. Evans DB.Pediatric thyroid cancer A new bible and long-term data Medullary thyroid cancer: management guidelines of the American Thyroid Association American Thyroid Association Guidelines Task Force. the application of these recommendations in clinical life. Schlumberger M. The management guidelines further propose a large series of recommendations dealing with diagnosis. This paper updates the 2001 consensus guidelines for treatment of MEN2 and MTC patients based on the important advances of knowledge over the last 10 years in the application of ‘codon-specific prophylactic thyroidectomy’ which is the gold standard for kindred in MEN2 families. long-term follow-up and management (including the frequency of follow-up and imaging). Cincinnati. USA richard. management of persistent or recurrent MTC (including the role of tumor marker doubling times. Gagel RF. especially also by pediatric endocrinologists. initial diagnosis and therapy of clinically apparent disease (including preoperative testing and imaging.19:565–612 Background: Inherited and sporadic medullary thyroid cancer (MTC) is an uncommon and challenging malignancy. The American Thyroid Association (ATA) chose to create specific MTC Clinical Guidelines that would bring together and update the diverse MTC literature and combine it with evidence-based medicine and the knowledge and experience of a panel of expert clinicians. Second malignant neoplasms in survivors of pediatric Hodgkin’s lymphoma treated with low-dose radiation and chemotherapy O’Brien MM. and optimal medical practice. While the paper shows the way for the optimal management. and directions for future research. rational. Division of Endocrinology. Agency for Healthcare Research and Quality. Ohio. USA maureen. Balise RR. Evidence-based recommendations were created and then categorized using criteria adapted from the United States Preventive Services Task Force. especially with rare ones. Results: The authors addressed initial diagnosis and therapy of preclinical disease (including RET oncogene testing and the timing of prophylactic thyroidectomy). Gharib H. Cincinnati Children’s Hospital Medical Center. The Ohio State University. Conclusion: 122 evidence-based recommendations were created to assist in the clinical care of MTC patients and to share what the authors believed to be current.28:1232–1239 Background: Survivors of childhood Hodgkin’s lymphoma (HL) are at risk for second malignant neoplasms (SMNs). and handling of devascularized parathyroid glands). will need to be evaluated in the future. from controversies concerning counseling of prenatal testing to management of persistent or recurrent metastatic disease. It is theorized that this risk may be attenuated in patients treated with lower doses of Thyroid 39 . The Arthur G. James Cancer Hospital. Donaldson SS. initial evaluation and treatment of postoperative patients (including the role of completion thyroidectomy). Kloos RT. Diabetes and Metabolism. Pacini F. and treatment of patients with distant metastases and hormonally active metastases). The 122 recommendations give answers based on the current state of the art to all clinical situations encountered in the care of affected families.kloos@osumc. Wells SA Jr Department of Internal Medicine. Moley JF. Ohio.ed Thyroid 2009.obrien@cchmc.

but not for thyroid cancer. 18 patients developed one or more SMNs.86). We report the first long-term outcomes of a cohort of pediatric survivors of HL treated with chemotherapy and low-dose radiation. breast and thyroid carcinomas occurred with similar frequency and latency as found in studies of children with HL who received high-dose radiation. was obtained from retrospective chart review and patient questionnaires.5 Gy involved-field radiation with optional 10-Gy boosts to bulky sites. During 1940–1969. 5% had incomplete tumor resection. Conclusion: Despite treatment with low-dose radiation.9 (95% CI 14. USA hay. and 78% had nodal metastases. 21. the recurrence rates at local.001) higher than after bilateral lobar resection (BLR). Mayo Clinic. median follow-up was 20. the mean (±SE) 5-year disease-free and overall survival were 76 ± 12% and 85 ± 10% with median follow-up 5 years from SMN diagnosis. but later death from non-thyroid malignancy is disconcerting. and distant sites were 7. 73% of those who died from non-thyroid malignancy had received postoperative therapeutic irradiation. 40 Michel Polak/Gabor Szinnai/Aurore Carré/Mireille Castanet . 5 thyroid carcinomas. 2007. The patients were aged 3–20 years (median 16 years). show that low-dose irradiation of the thyroid in the context of pediatric Hodgkin’s lymphoma results in a significant risk for thyroid carcinoma on follow-up. median follow-up was 29 years. Methods: The authors studied 215 PTC patients younger than 21 years of age who were managed during 1940 through 2008. 15 of 22 deaths (68%) resulted from non-thyroid malignancy. Minn. children treated for HL remain at significant risk for SMN. it did not diminish the 25-year regional recurrence rate of 16% seen after BLR alone (p = 0.7) at 20 years after HL diagnosis.edu World J Surg. Gonzalez-Losada T. Long-term outcome in 215 children and adolescents with papillary thyroid cancer treated during 1940 through 2008 Hay ID. regional. for a causespecific mortality at 40 years of only 2%.6 years. but from 30 through 50 years. the authors expect a reduction of second malignant neoplasms such as breast cancer by further dose reduction and shielding procedures. and 5%. For those with second solid tumors. Reinalda MS. At 20 years. and 4 sarcomas. Only 2 fatal events from PTC occurred at 28 and 30 years.2 cm.. Few studies with long-term outcome exist and second primary malignancies have rarely been analyzed.34:1192–1202 Background: Controversy exists regarding the aggressiveness of initial therapy in childhood papillary thyroid cancer (PTC). As decreasing intensity of clinical follow-up of these patients often coincides with the transition from the pediatric oncologist and endocrinologist to the adult endocrinologist or general practitioner. Methods: Pediatric patients with HL (n = 112) treated at Stanford from 1970 to 1990 on two combined modality treatment protocols were identified. Honetschlager JA.001) higher than predicted. The standard incidence ratio for any SMN was 22. Treatment included six cycles of chemotherapy with 15–25. Richards ML. Although reflecting the consequence of past therapies. PTC recurred in 32% by 40 years. Results: 110 children completed HL therapy. Conclusion: Survival from childhood PTC should be expected. including 4 leukemias. 86% had nodes removed at initial surgery.7 cases per 10. respectively. Rochester. the risk of second malignant neoplasias needs to be well communicated to the patient and the responsible physicians. local and regional recurrence rates after unilateral lobectomy (UL) were significantly (p < 0.000 person-years. O’Brien et al. The most accurate follow-up remains to be determined but it should most probably include yearly thyroid ultrasound.ian@mayo. radioiodine remnant ablation (RRA) was administered within 18 months to 32%. They advocate an ‘aggressive surveillance’ of these patients.5–26. 2010. Cumulative incidence of first SMN was 17% (95% CI 10.2–35) with an absolute excess risk of 93. During 1950–2008. 6 breast carcinomas. All-causes mortality rates did not exceed expectation through 20 years. Six percent had distant metastases at presentation.radiation. Results: Median primary tumor size was 2. Sarcomas. After complete surgical resection. the number of deaths was significantly (p < 0. All 4 secondary leukemias were fatal. Follow-up through September 1. Thompson GB Division of Endocrinology and Internal Medicine. Recurrence and mortality details were taken from a computerized database.

they showed that radioiodine remnant ablation did not diminish the 25-year regional recurrence rate.aphp. locoregional recurrence. Paris. as both gain and loss of function on surfactant protein promoters were associated with interstitial lung disease. hypotonia. respectively). NKX2-1-p. Feldmann D b. Han et al. The data presented showed for the first time in vivo and in vitro that patients with NKX2-1 mutations with lung disease suffered from disturbed surfactant protein metabolism. Carré Aa. In contrast.31:E1146–1162 Background: NKX2-1 (NK2 homeobox 1) is a critical regulator of transcription for the surfactant protein (SP)-B and -C genes (SFTPB and SFTPC. This result was surprising and suggests that irradiation of this patient group should be avoided as far as possible. while SFTPB activation was only significantly reduced in HeLa cells. Counil Fb. the lung disease remained the ‘white spot’ of the disease. Université Paris 6 and Université Paris Descartes and b Hôpital Trousseau and Necker Enfants Malades. Epaud Ra a INSERM UMR 938 and U845. Jaubert Fb.786_787del2 (p. Broutin Ib. the authors found decreased amounts of SP-B and SP-C by Western blot in bronchoalveolar lavage fluid (patient with p. Castanet Mb. Lacking a more thorough description of the patients treated with radioiodine and the selection process of those receiving such a procedure may have induced such results. In accordance with their in vitro data. Conclusion: ILD in patients with NKX2-1 mutations was associated with altered surfactant protein metabolism. France michel. Szinnai Gb. also called ‘brain-lung-thyroid syndrome’ [13].L263fs induced neither SFTPB nor SFTPC promoter activation and had a dominant negative effect on wild-type (WT) NKX2-1. Tron Eb.epaud@trs. The current use of radioiodine has been validated in others studies [12].aphp.R165W activated SFTPC.493C>T (p. Since the first descriptions of NKX2-1/TITF1 (NK2 homeobox 1/thyroid transcription factor 1) mutations leading to the clinical triad of congenital hypothyroidism. For the neonatologists and pneumologists it is of importance to search for NKX2-1 mutations in newborns presenting neonatal surfactant deficiency syndrome with mild hyperthyrotropinemia. childhood PTC certainly has an excellent prognosis. Clement Ab. neck nodal metastases. distant metastases. to a significantly greater extent than did WTNKX2-1. probably due to altered interaction of transcriptional activators and inhibitors. Polak Ma. However.fr Hum Mutat 2010.L263fs) and features of altered surfactant protein metabolism on lung histology (patient with NKX2-1-p. single institutional cohort. The majority (73%) of these patients received postoperative therapeutic irradiation. the differences between survival after surgery alone and after surgery plus RRA to the endpoints of local recurrence. and all-sites recurrence were shown to be statistically insignificant.fr. This study further highlighted the variability of the transactivation capacity of mutated NKX21. Owing to an extensively long followup period of 40 years. New genetic studies for known and unknown genes NKX2-1 mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in ‘brain-lung-thyroid syndrome’ Guillot La.polak@nck. in this large.L263fs) in infants with closely similar severe interstitial lung disease (ILD). R165W). In contrast. ralph. and both gain and loss of function of the mutated NKX2-1 genes on surfactant protein promoters were associated with ILD in ‘brain-lung-thyroid syndrome’. surfactant deficiency syndrome and benign hereditary chorea. The data of the paper are consistent with experimental evidence documenting the importance of NKX2-1 in pulmonary surfactant metabolism. Whether isolated lung disease due to NKX2-1 mutations in analogy with Thyroid 41 .R165W) and c. Further.In general. Functional analyses using A549 and HeLa cells revealed that NKX2-1-p. in the thyroid both mutations led to loss of function. and congenital hypothyroidism. revealed an unexpectedly high mortality of patients treated for PTC below age 21 years due to second primary tumors of solid organs other than thyroid between 30 and 50 years of age. Results: The authors identified and functionally characterized two new de novo NKX2-1 mutations c.

Berlin. Grueters A. reporting a patient with transient congenital hypothyroidism and compound heterozygosity for a novel hemizygous missense mutation and a partial deletion of DUOX2. suggesting the existence of other pathophysiological factors. raises the question whether transiency and permanency of congenital hypothyroidism relate exclusively to monoallelic or biallelic inactivation of the gene or whether disease phenotype is dependent on residual function of the mutated DUOX2 protein. comprehensive screens failed to detect mutation carriers in a significant number of patients with non-syndromic TD. Results: The authors report here a novel genetic defect causing congenital hypothyroidism in a FrenchCanadian patient. Belgium xdedeken@ulb.isolated hereditary benign chorea exists and whether NKX2-1 mutations should be screened in such patients after exclusion of mutations of surfactant B and C remains to be shown. Compound heterozygosity for a novel hemizygous missense mutation and a partial deletion affecting the catalytic core of the H2O2-generating enzyme DUOX2 associated with transient congenital hypothyroidism Hoste C. Campus Erasme. suggesting dyshormonogenesis. Ropers HH. ullmann@molgen.be Hum Mutat 2010. The transient congenital hypothyroidism phenotype prompted the authors to screen for mutations in DUOX2 and DUOXA2 genes using the PCR-amplified direct sequencing method. Thyroxine treatment was given from 1 month to 17 years.ac. Miot F. Further work on more patients affected with DUOX2 gene mutations is awaited to clarify this fundamental question. formerly THOX2) gene have been shown to cause transient and permanent dyshormonogenetic congenital hypothyroidism. Charité University Medicine and Max Planck Institute for Molecular Genetics. the patient had high TSH and low total T4 levels.Gly1518Ser). The deleted fragment encompasses the entire COOH-terminal end which is responsible for the NADPH-oxidase activity. Ullmann R Institute for Experimental Pediatric Endocrinology. 42 Michel Polak/Gabor Szinnai/Aurore Carré/Mireille Castanet . Germany heiko. De Deken X IRIBHM. Mueller I. Mutations in the dual oxidase 2 gene (DUOX2. Although several candidate genes have been implicated in thyroid development. termed thyroid dysgenesis (TD). They found complete inactivation of DUOX2 caused by a partial genomic deletion of one allele inherited from the mother associated with a paternally inherited missense mutation (c. transient forms were associated with heterozygous mutations. Van Vliet G. Université Libre de Bruxelles. p.mpg. The biochemical requirement of H2O2 for thyroid hormone synthesis has been known for decades. Mutations in the DUOX2 gene have been described in transient and permanent congenital thyroid dyshormonogenesis. represents 80% of permanent congenital hypothyroidism cases. The Gly1518Ser DUOX2 protein is expressed at the cell surface of transfected cells albeit at low level.de J Clin Endocrinol Metab 2010. Brussels. 99mTc scan showed a normally shaped orthotopic but mildly enlarged thyroid gland. Krude H. Two homologous proteins (dual oxidase 1 and 2) containing functional domains of NADPH oxidoreductases were identified in thyroid follicular cells. Rigutto S. Biebermann H. after which it was stopped for re-evaluation and the patient remained euthyroid. Conclusion: This study provides further evidence that the permanent or transient nature of congenital hypothyroidism is not directly related to the number of inactivated DUOX2 alleles.krude@charite. So far. H2O2 is used by thyroperoxidase to oxidize iodide for thyroid hormonogenesis. This interesting case. Screening chromosomal aberrations by array comparative genomic hybridization in 80 patients with congenital hypothyroidism and thyroid dysgenesis Thorwarth A. but it is non-functional.31:E1304–1319 Background: Dual oxidases (DUOX) 1 and 2 are components of the thyroid H2O2-generating system. At neonatal screening. and permanent forms with homozygous mutations in DUOX2 [14].4552G>A. Epub ahead of print Background: A spectrum of defective thyroid morphology.de.

Thus. After 28 weeks. Cognitive performance was assessed through 4 subtests from the Wechsler Intelligence Scale for Children. the authors aimed at assessing de novo chromosomal rearrangements which conceivably represents one of the molecular mechanisms participating in its etiology. future studies may have to shift the focus from singling out specific genes to the identification of deregulated pathways as the underlying cause of the disease. 17]. Ruffman T Department of Human Nutrition. The authors performed an array CGH screen of 80 TD patients to determine the role of CNVs in the etiology of the disease. New methods for microarray-based genotyping of single nucleotide polymorphism (SNP) markers as well as parallel methods assessing rare and common DNA deletions or duplications across the genome as copy number variants (CNVs) permitted breakthrough identification of susceptibility genes for nonmendelian diseases [16. the study of DNA CNVs may turned out to be productive to find the etiologies of TD [15]. Environment Iodine supplementation improves cognition in mildly iodine-deficient children Gordon RC. Little is known about the consequences of milder forms of iodine deficiency on neurodevelopment. Conclusions: The high rate of chromosomal changes in TD argues for an involvement of CNVs in the etiology of this disease.4 µg/l). A recent large-scale analysis of CNVs in eight common human diseases puts the contribution of CNVs in comparison with SNP-based studies for detection of new genetic hot spots into perspective [18. placebo-controlled. thyroglobulin: 8. searched for the first time for common chromosomal changes in a representative cohort of patients with thyroid dysgenesis. Their results add to current knowledge the fact that a high rate of chromosomal changes was found in these patients.-C. and dietary data were collected from each child at baseline and after 28 weeks. Objective: The authors aimed to determine whether supplementing mildly iodine-deficient children with iodine improves cognition. pp.5 µg/l). the absence of recurrent CNVs further supports the notion that thyroid dysgenesis is rather a heterogenous disease than a monogenetic one. 219–236]. Skeaff SA. Results: At baseline. whereas the placebo group remained iodine- Thyroid 43 . Carel. anthropometric.ac. Dunedin.nz Am J Clin Nutr 2009. New Zealand sheila. Methods: The introduction of array comparative genomic hybridization (CGH) has provided the ability to map DNA copy number variations (CNVs) genome-wide with high resolution. and the regions flanking the CNVs were not enriched for segmental duplications.skeaff@otago. The study of Thorwarth et al. Rose MC. Methods: A randomized. As in others types of endocrine disorders as well as in others fields of medicine. Gray AR. Biochemical. Children were randomly assigned to receive a daily tablet containing either 150 µg iodine or placebo for 28 weeks. Results: They identified novel CNVs that have not been described as frequent variations in the healthy population in 8.Objective: Due to the sporadic occurrence of TD.75% of all patients. also see Science and Medicine section by Z.90:1264–1271 Background: The effects of severe iodine deficiency during critical periods of brain development are well documented. Hochberg and J. iodine status improved in the supplemented group (UIC: 145 µg/l. However. children were mildly iodine-deficient (median urinary iodine concentration (UIC): 63 µg/l. Future approaches aiming to decipher the genetic basis of thyroid dysgenesis should consider this new piece of knowledge. double-blind trial was conducted in 184 children aged 10–13 years in Dunedin. thyroglobulin concentration: 16. Morgan KM. New Zealand. University of Otago. These CNVs exclusively affected patients with athyreosis or thyroid hypoplasia and were non-recurrent. Yet the lack of recurrent aberrations suggests that the genetic causes of TD are heterogenous and not restricted to specific genomic hot spots.

Iodine treatment significantly improved performance in 4 of 7 cognitive and motor tests.uk J Clin Invest 2010. [19]. with marked hyperphagia particularly evident in children. Shulman GI. Henning E. is characterized by elevated levels of circulating thyroid hormones (including thyroxine). Farooqi IS. and hyperphagia Mitchell CS. The strength of this paper is to highlight the fact that not only in moderately but even in mildly iodine-deficient areas. Raised energy expenditure and hyperphagia are recognized features of hyperthyroidism. Energy intake in RTH subjects was increased by 40%.petersen@yale. Curran S.ac. The re-emergence of iodine deficiency in New Zealand is believed to be a consequence of lower concentrations of iodine in milk because of the discontinuation of iodine-containing sanitizers in the dairy industry. Gordon et al.011).cam. but the effects of comparable hyperthyroxinemia in RTH patients are unknown. as determined by 13C/31P magnetic resonance spectroscopy. Conclusion: These data demonstrate that basal mitochondrial substrate oxidation is increased and energy production in the form of ATP synthesis is decreased in the muscle of RTH patients and that resting 44 Michel Polak/Gabor Szinnai/Aurore Carré/Mireille Castanet . and an increased consumption of processed foods not made with iodized salt.480) or symbol search (p = 0. Murgatroyd P. Schoenmakers N. The overall cognitive score of the iodine-supplemented group was 0.040)) but not for letter-number sequencing (p = 0. Rothman DL. and an important health issue also in industrialized countries. Mild iodine deficiency remains the most common thyroid disease worldwide. Dufour S.6 µg/l).023) and matrix reasoning (p = 0.edu. The elimination of iodine deficiency by the year 2005 was a World Fit for Children target.19 SD higher than that of the placebo group (p = 0.bio. Conclusion: Iodine supplementation improved perceptual reasoning in mildly iodine-deficient children and suggests that mild iodine deficiency could prevent children from attaining their full intellectual potential. and variable tissue refractoriness to thyroid hormone action. present us with convincing data on the impact of iodine supplementation of children in a mildly iodine-deficient area. yet a large proportion of children worldwide still have inadequate iodine intakes. Rates of muscle TCA cycle flux were increased by 75% in adults with RTH. They used a similar study design (duration of supplementation. Institute of Metabolic Science. thyroglobulin: 11. Halsall D. The authors show significant association between iodine supplementation and improvement in 2 of 4 cognitive tests relative to placebo. Chatterjee K. Northcott S. Addenbrooke’s Hospital. Mitochondrial coupling index between ATP synthesis and mitochondrial rates of oxidation (as estimated by the ratio of ATP synthesis to TCA cycle flux) was significantly decreased in RTH patients. a dominantly inherited disorder usually associated with mutations in thyroid hormone receptor.120:1345–1354 Background: Resistance to thyroid hormone (RTH). Cambridge.608).deficient (UIC: 81 µg/l. Petersen KF University of Cambridge Metabolic Research Laboratories. Results: The authors showed that resting energy expenditure (REE) was substantially increased in adults and children with THRB mutations. UK kitt. iodine supplementation is beneficial for cognitive function in schoolchildren.(THRB). Owen P. The impact of iodine supplementation on moderately iodine-deficient children was first shown in an elegant randomized controlled double-blind study by Zimmermann et al. failure of feedback suppression of thyrotropin. muscle mitochondrial uncoupling. Befroy D. Iodine supplementation significantly improved scores for 2 of the 4 cognitive subtests (picture concepts (p = 0. cognitive testing) at a lower supplementation dose in analogy to the previous paper. declining use of iodized salt. kkc1@mole. Thyroid hormone resistance revisited New pathophysiological insights Resistance to thyroid hormone is associated with raised energy expenditure. Raymond-Barker P. Keogh J. Lazarus J. Savage DB. whereas rates of ATP synthesis were unchanged.

D2. a TH receptor agonist. measured by an ad libitum test meal and found a 75% increase in RTH children compared to controls. reaching levels present in hyperphagic patients with monogenetic obesity syndromes. USA refetoff@uchicago. suggesting that resting mitochondrial uncoupling in skeletal muscle is a major contributor to increased resting energy expenditure in patients with RTH. resulting in increased deiodinase 1 (D1). these observations suggest that mitochondrial uncoupling in skeletal muscle is a major contributor to increased REE in patients with RTH. The potential clinical utility of this analog to patients with MCT8 mutations requires further studies. mice were given three different doses of DITPA. liver T3 content is high.-rich organs such as skeletal muscle and myocardium are the main determinants of thyroid hormone-mediated changes in the whole body expenditure in humans. This paper reports on extensive studies of energy balance in patients with thyroid hormone resistance (RTH). Dumitrescu AM. for its dependence on Mct8 in Mct8KO and wild-type (Wt) mice tissues. they have decreased brain T3 content and high deiodinase 2 (D2) activity.. The authors studied an unselected group of 54 adults and 13 children from 35 unrelated families harboring 25 different THRB gene mutations. The higher dose of T4 suppressed TSH in the Wt mice. and D1 in both Wt and Mct8KO mice.5-diiodothyropropionic acid (DITPA). After depletion of endogenous TH. but produced a thyrotoxic effect on liver D1 in both genotypes. they analyzed food intake. In conclusion. the authors documented significantly increased resting energy expenditure and basal metabolic rate in patients with RHT. Methods: The authors generated a Mct8-deficient mouse (Mct8KO) manifesting the human thyroid phenotype. using both ventilated hood and chamber calorimetry.(THRB) [20]. In contrast. they revealed a 75% increase in substrate oxidation but an identical level of ATP synthesis in the muscle of RHT patients compared to controls. providing general insight into thyroid hormone-dependent energy metabolism in humans. the authors suggest that thyroid hormone receptor. Second. First. University of Chicago. Ill. Although these mice have no neurological manifestations.150:4450–4458 Background: Mutations of the thyroid hormone (TH) cell membrane transporter MCT8. The higher dose fully normalized all measurements and other parameters of TH action. Third. The intracellular hypothyroidism in the brain due to the abolished activity of the thyroid hormone transporter MCT8 cannot be corrected by physiological or supraphysiological substitutive doses of Thyroid 45 . produce severe mental and neurological impairment in men. suggesting that in this tissue TH entry is Mct8 independent. reflecting TH deprivation. New hope? A thyroid hormone analog with reduced dependence on the monocarboxylate transporter 8 for tissue transport Di Cosmo C. brain D2. on chromosomeX. Effects were compared with treatment with two doses of L-T4.edu Endocrinology 2009. RTH is characterized by a variable degree of tissue hyposensitivity to thyroid hormones usually associated with mutations in the thyroid hormone receptor. physiological doses of L-T4 normalized serum TSH. Chicago. normalized TSH and brain D2 in Mct8KO mice. respectively. by investigating the role of skeletal muscle mitochondrial energy metabolism. In contrast and as in serum. due to tissue selective retention of THRB sensitivity to elevated thyroid hormone levels. Conclusions: DITPA is relatively MCT8 independent for entry into the brain and corrects the TH deficit in Mct8KO mice without causing thyrotoxic effect in liver.oxidative phosphorylation is uncoupled in this disorder. Furthermore. Weiss RE. Refetoff S Department of Medicine. Liao XH. and liver D1 in Wt mice but not the Mct8KO mice. They tested the effect of 3. DITPA produced similar effects on TSH. Results: As expected. The raised energy expenditure was positively correlated with heart rate and thyroid hormone levels being intermediate in RTH patients compared to euthyroid control and thyrotoxic subjects.

Almholt K. would be of great therapeutic importance. Jacobsen SD. GLP-1 receptor agonists stimulated calcitonin release. Results: The GLP-1 receptor was localized to rodent C-cells. Måløv.and long-term animal and human pharmacological studies to show relevant species-dependent differences of GLP-1 receptor expression as well as calcitonin release to liraglutide between rodents (rat and mouse) and humans and primates. Drucker DJ. New concerns? Glucagon-like peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation Bjerre Knudsen L. Zdravkovic M Department of Biology and Pharmacology Mgt. The FDA approved liraglutide for treatment of type 2 diabetes in January 2010. thyroid C-cells in rats and mice differ markedly from primate and human C-cells in their response 46 Michel Polak/Gabor Szinnai/Aurore Carré/Mireille Castanet . show that the transport of DITPA into the brain and liver is less dependent on MTC8. Di Cosmo et al. Solberg H. Moreover. Gotfredsen C. Egerod FL. Novo Nordisk A/S. Thi TD. Mølck AM. such as the 3. the potential effect on the severe human neurological phenotype remains to be proven. they provide evidence that DITPA acts in brain without producing thyrotoxic effects in peripheral tissues. One major safety concern was the potential deleterious effect of liraglutide on thyroid C-cells. up-regulation of calcitonin gene expression. Further. Longterm liraglutide exposure in rodents was associated with thyroid C-cell hyperplasia and tumors. Although. Denmark lbkn@novonordisk. Nowak J. de Boer AS. and subsequently C-cell hyperplasia in rats and.151:1473–1486 Background: Liraglutide is a glucagon-like peptide-1 (GLP-1) analog developed for type 2 diabetes. relevant species-specific differences have to be considered. In conclusion. GLP-1 receptor agonists with prolonged half-life have been developed for the treatment of type 2 diabetes. In this context. humans and/or cynomolgus monkeys had low GLP-1 receptor expression in thyroid C-cells. Conclusion: The findings delineate important species-specific differences in GLP-1 receptor expression and action in the thyroid. in mice. such as the liver. these results are an important step forward to a clinical study of this pharmacological compound in patients with MTC8 mutations. Indeed the data support a GLP-1 receptor-mediated mechanism for these changes in rodents. 20 months of liraglutide treatment (at >60 times human exposure levels) did not lead to C-cell hyperplasia in monkeys. In contrast. whether thyroid hormone analogues. and GLP-1 receptor agonists did not activate adenylate cyclase or generate calcitonin release in primates. no C-cell hyperplasia was observed in primates during and after 87 weeks of treatment and basal plasma calcitonin levels were not increased in patients with type 2 diabetes receiving liraglutide in three different doses compared to placebo at repeated measurements during 2 years. Andersen S. In this context. could be less dependent on the active transport by MTC8 for their passage from the blood to the central neurons. Madsen LW.thyroid hormones in patients with MTC8 mutations.5-diiodothyropropionic acid (DITPA). to a lesser extent. Moses AC. the question. Novo Nordisk Park. Hegelund AC. and there was no difference in the proportion of patients with calcitonin levels increasing above the clinically relevant cutoff level of 20 pg/ml. Mean calcitonin levels in patients exposed to liraglutide for 2 years remained at the lower end of the normal range.com Endocrinology 2010. Nevertheless. As the MTC8 knockout mouse model does not display a neurological phenotype like MTC8-deficient humans. Two-year highdose exposure studies confirmed C-cell hyperplasia and development of C-cell adenoma in rodents. Jacobsen H. the authors combined short. the long-term consequences of sustained GLP-1 receptor activation in the human thyroid remain unknown and merit further investigation. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that promotes glucose-dependent stimulation of insulin secretion. as the long-term exposure was associated with thyroid C-cell hyperplasia and tumors in rodents. In contrast. Nielsen HS.

to GLP-1 receptor activation supporting the arguments of the FDA for approval of the drug. Hurles ME. Ricard M. Mammi I. Zhang F. Conte-Devolx B. Melhus H: Severe embryopathy and exposure to methimazole in early pregnancy. J Clin Endocrinol Metab 2005. Longterm safety monitoring is nevertheless required by the FDA by monitoring the annual incidence of medullary thyroid cancer of over the next 15 years. the interested reader is referred to the article by Parks and Rosebraugh [21]. Di Gianantonio E. Gu W. Liascovich RC. Acta Paediatr 2002. Laboratory support for the diagnosis and monitoring of thyroid disease. 20.90:6093–6098. present and future. J Clin Endocrinol Metab 2002. Rivkees SA.109:959–964. Schlumberger M. Ku CS. Krainz PL. J Hum Genet 2010 (in press). Skeels MR. 17. Grimci L: Iodine supplementation improves cognition in iodine-deficient schoolchildren in Albania: a randomized.10:451–481. Van Vliet G: Therapeutic approach of fetal thyroid disorders. De Rosa LF. disease. Reprod Toxicol 2007. J Clin Invest 2008. J Pediatr 1986.109:475–480. 14. et al: Management of Graves’ disease during pregnancy: the key role of fetal thyroid gland monitoring. Bozo M. et al: Laboratory medicine practice guidelines. et al: The role of propylthiouracil in the management of Graves’ disease in adults: report of a meeting jointly sponsored by the American Thyroid Association and the Food and Drug Administration. Loy EY. et al: Choreoathetosis. Barbero PM. Nat Clin Pract Endocrinol Metab 2008. Pacini F: How the availability of recombinant human TSH has changed the management of patients who have thyroid cancer. Biebermann H. Hurles ME. Thyroid 47 . Collins FS: A HapMap harvest of insights into the genetics of common disease.360:1574– 1575. J Clin Invest 2002. Sesser DE.87:947–949. Bikker H. Thyroid 2003. N Engl J Med 2002. De Pouvourville G. Yamagami Y: Hypothalamo-pituitary hypothyroidism detected by neonatal screening for congenital hypothyroidism using measurement of thyroid-stimulating hormone and thyroxine. 6. 7.464:713–720. Am J Clin Nutr 2006.74:1–5. For the complete discussion of the safety issue of liraglutide by the FDA.362:774–777. and evolution. Salim A.1:97–108. Adachi M. Le Gac I.118:1590–1605. 10. Bahn RS. 5. controlled. Karlsson FA. Moreno JC. Mattison DR: Ending propylthiouracil-induced liver failure in children. 21. Cardin N. et al: Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism. Bridson J. Polak M. 19. Van Vliet G.19:673–674. Horm Res Paediatr 2010. Polak M. 16. Manolio TA. Baloch Z. Luton D. Hanna CE. Annu Rev Genomics Hum Genet 2009. Kempers MJ.91:172–177. Krude H.000 cases of eight common diseases and 3. 4. 12. and pulmonary alterations due to human NKX2-1 haploinsufficiency. References 1. Am J Med Genet 1999. Craddock N. Tenconi R: Methimazole embryopathy: delineation of the phenotype. Aguirre MA. 9. double-blind study. N Engl J Med 2009.83:108– 114. 13. Lupski JR: Copy number variation in human health. Carayon P. Brooks LD. Chia KS: The discovery of human genetic variations and their use as disease markers: past. Refetoff S: Resistance to thyroid hormone. Pawitan Y. Connolly K. Parks M. Rev Endocr Metab Disord 2000. hypothyroidism.000 shared controls.13:3–126.347:95–102. 2. Ritzen EM: Treating fetal thyroid and adrenal disorders through the mother. Tachibana K. LaFranchi SH: Detection of congenital hypopituitary hypothyroidism: ten-year experience in the Northwest Regional Screening Program. Pelo E. Rosebraugh C: Weighing risks and benefits of liraglutide – the FDA’s review of a new antidiabetic therapy. 8. Weiss RE. 15. Nat Clin Pract Endocrinol Metab 2007. Cooper DS. Zimmermann MB. Axelsson O. Rohner F.4:675–682. Basile RT. 18. et al: Genome-wide association study of CNVs in 16. N Engl J Med 2010. 11.23:253–255.3:641–650. Burch HS. Valdez RM. Vuillard E. Suwa S. Nature 2010. 3. Thyroid 2009. Schutz B. Alba LG: Methimazole embryopathy: a contribution to defining the phenotype.83:43–46. Asakura Y. Clementi M. Miyahira RS.

Jira PE. In the last 12 months. Methods: 55 prepubertal children (with a mean ± SD age of 5. other equally valuable studies have been neglected. Italy This collection of articles aims to provide a wide spectrum of studies on the subject of growth and growth factors. the choice of articles has been fully arbitrary and. Important for clinical practice Efficacy and safety of long-term continuous growth hormone treatment in children with Prader-Willi syndrome de Lind van Wijngaarden RF. Haring DA. Among experimental studies. given the limited number of papers to be selected. Hoorweg-Nijman JJ. van Leeuwen M. they nonetheless provide the basis for further clinical and experimental research. Bakker B. applied to single clinical cases or large cohorts of patients. Hokken-Koelega AC Dutch Growth Research Foundation. Lean body mass transiently increased during therapy.94:4205–4215 Background: Prader-Willi syndrome (PWS) is a rare. Rotterdam. complex disorder characterized by failure to thrive. Rotteveel J. Finally. Although most of these papers have not yet yielded conclusive results.2 years) with PWS were recruited in the trial with GH therapy and followed for 4 consecutive years. reduced IGF-I levels and good response to GH therapy have been described in children with PWS. Height and head circumference significantly increased during the first 3 years of therapy achieving a value not significantly different from 0 SDS. Festen DA. Drop SL. Tor Vergata University. learning disabilities. Houdijk EC. Schroor EJ. Body composition was evaluated by dualenergy x-ray absorptiometry.nl J Clin Endocrinol Metab 2009. Siemensma EP. Wishing you a good reading. short stature. van Trotsenburg AS. other endocrine dysfunctions. All children had a genetically confirmed diagnosis of PWS by positive methylation test and were naive to GH treatment at the time of inclusion. early obesity starting during the second year of life. Children were treated with rhGH 1 mg/m2 daily. GH insufficiency. Results: Fat body mass decreased only during the first year of therapy. Otten BJ. has elucidated the mechanisms underlying some conditions characterized by severe short stature. The purpose of this multicenter prospective study was to test efficacy and safety of GH therapy during a 4-year follow-up. The Netherlands r. New therapeutic tools for treating growth impairment have been tested in phase 1 and 2 clinical trials. the founder of modern auxology: ‘the appetite comes reading’. Pilon JW. abnormal behavior. Bindels-de Heus GC. and psychiatric problems. I would like to wrap up this short introduction quoting a sentence written on the office door of James Muorilyan Tanner. Bocca G. inevitably. The long-term efficacy of GH treatment on adult height and body composition of patients with PWS has not yet been established. Body proportions expressed by the . Wit JM. Odink RJ. Hypothalamic dysfunction may account for many features of the syndrome.Growth and Growth Factors Stefano Cianfarani Molecular Endocrinology Unit – DPUO Bambino Gesù Children’s Hospital – ‘Rina Balducci’ Center of Pediatric Endocrinology. the research in the field of growth factors has provided important achievements. Vreuls RC. hypotonia. pharmacological modulation of IGF system has been attempted to inhibit cancer growth. and remained higher than +2 SDS after 4 years of therapy. I favored those with major clinical implications.delindvanwijngaarden@erasmusmc. Molecular biology. Of course.9 ± 3. remaining lower than –2 SDS after 4 years. particularly focusing on those with direct or potential clinical implications. van Mil EG. New relationships between the IGF system and predisposition to cardiovascular disease have been described. Erasmus University Medical Center/Sophia Children’s Hospital. Rome.

the relationships with metabolic markers disappeared. which might indicate that more free IGF-I was present in the systemic circulation. The major cause of death in PWS children is respiratory failure [3]. further research on longer-term effects of high IGF-I levels is warranted. frequently sampled intravenous glucose tolerance test with tolbutamide was performed in a subgroup of study subjects. IGFBP-2 correlated positively with insulin sensitivity. van de Sande AG. The aim of this study was to assess IGFBP-2 levels in a cohort of young adults and children born SGA. Evidence suggests that IGFBP-2 may alter the activity of intracellular kinases that regulate insulin signaling by both IGF- 50 Stefano Cianfarani . After adjustment for fat mass. the safety of GH treatment in this high-risk population has been questioned and warnings have been added for the use of rhGH. alterations of body composition and microcephaly. Body composition was assessed by dual-energy x-ray absorptiometry. the finding of the sharp increase of IGF-I even above the upper normal range raises concern. Conclusion: In SGA young adults. Therefore. IGFBP-3 also increased but to a less extent ultimately leading to a marked increase of the IGF-I/IGFBP-3 molar ratio. GH therapy had no significant effect on bone maturation. Furthermore. HOMA-IR. cholesterol and triglycerides. fasting insulin. such as short stature. The Netherlands s.nl J Clin Endocrinol Metab 2010. In addition. type 2 diabetes. Whereas IGFBP-2 did not correlate with birth size. Although there is no direct evidence for a causative role of GH therapy. Conclusions: GH long-term therapy proved to be safe and effective in improving height. GH significantly increased IGF-I up to more than +2 SDS with peak after the first year of therapy. fat mass. Results: SGA young adults showed reduced concentrations of IGFBP-2 independently of catch-up growth in height. since 2002 [1]. Methods: 151 young adults and 147 children born SGA were studied. Rotterdam. body composition. a significant number of deaths in children with PWS treated with GH have been reported [2]. IGFBP-2 may represent an indicator of the cardiovascular risk.dekort@erasmusmc. especially during the first 6–12 months of therapy. Hand and foot length as well as arm span did not normalize during treatment. Concentrations of IGFBP-2. IGFBP-2 correlated negatively with BMI. IGFBP-2 has been reported to modulate intracellular insulin signaling. Leunissen RW. and the results of this study look reassuring. Although there is no clear evidence of a connection between GH treatment and risk of death. No correlation between IGFBP-2 and cardiovascular risk markers was seen in SGA children.sitting height to height ratio improved during treatment and did not significantly differ from 0 SDS after 4 years. thus suggesting that IGFBP-2 levels associate with FM and that a lower FM is associated with lower insulin levels and less insulin resistance. in this group.95:864–871 Background: Subjects born small for gestational age (SGA) are at risk of developing insulin resistance. head circumference and lipid profile in children with PWS. On the other hand. blood lipid profile assessment and blood pressure evaluation. Glucose and insulin levels remained unchanged during GH therapy whereas LDL cholesterol decreased significantly. and IGFBP-2 levels are inversely related to insulin concentrations and insulin resistance. Subjects underwent anthropometry. However. binding both IGF-I and IGF-II. increase after a prolonged period of fasting. insulin secretion. A modified. This study substantially confirms previous reports showing the effects of GH therapy on a series of features typically associated with PWS. no major side effect was observed during the 4-year follow-up in this large cohort of patients. Serum insulin-like growth factor-binding protein-2 levels and metabolic and cardiovascular risk factors in young adults and children born small for gestational age de Kort SW. metabolic syndrome and cardiovascular disease in adulthood. IGF-I is a potent stimulator of lymphoid tissue growth and the excessive and rapid increase in IGF-I at the start of GH treatment could induce tonsillar and adenoid hypertrophy which may concur in increasing the risk of sleep-obstructive apnea. indicating that IGFBP-2 concentrations are metabolically regulated. van Doorn J. Hokken-Koelega AC Erasmus MC Sophia. it was inversely related to fat mass. IGF-binding protein 2 (IGFBP2) belongs to the family of 6 IGFBPs which bind IGF-I and IGF-II. blood pressure.

On average. but. Tor Vergata University. The mean differences in final height and overall height again between treated and untreated subjects were 0. Finally. studies in adult patients have shown a relationship between IGFBP-2 and cardiovascular risk factors. GH therapy has been shown to be effective in reducing the adult height deficit. Italy Pediatrics 2009. the quality of most studies is affected by the recruitment of small study cohorts.dependent and IGF-independent mechanisms. most trials have reported short-term results only. the use of historical controls. Moderate-quality evidence was the score assigned to all four RCTs.25 SDS (approx. No significant difference in adult height between the two dose regimens was observed. this report re-opens the debate on the cost/benefit ratio and. Rome. long-term. and only in short SGA children. Conclusions: Despite the approval of GH therapy for improving adult height of short children born SGA. This systematic review has important clinical practice implications representing a comprehensive meta-analysis appraising the effect of long-term GH therapy on adult height of short children born SGA. no indicator has so far been identified. Methods: A meta-analysis of all RCTs conducted up to the achievement of adult height and published until November 2008 was performed.85 SDS (approx. and based on correlation analyses.3:E519–E531 Background: The indication for growth hormone (GH) therapy in children born small for gestational age (SGA) has been approved worldwide. there is no evidence for supporting the use of doses higher than 33 µg/kg per day. the magnitude of the growth-promoting effect is relatively low. However. including a total of 270 treated and 155 untreated children (controls). no single. On the other hand. it may be argued that insulin sensitivity is mildly impaired in children born small for gestational age [4]. 6 cm) and 1. unfortunately. parents and physicians. In addition. The search for a reliable marker of metabolic risk in children and adolescents with low birth weight looks worthwhile. SGA children can expect to gain between 6 and 8 cm from years’ long daily injections of GH. Department of Public Health and Cell Biology. Cianfarani S ‘Rina Balducci’ Center of Pediatric Endocrinology. randomized. well-powered study conducted up to the achievement of adult height has been published so far. thereby modulating insulin sensitivity. Although GH seems effective in improving adult height. Although the results are in adults. Furthermore. Impact of growth hormone therapy on adult height of children born small for gestational age Maiorana A. whereas strong recommendation was assigned to 2/4 trials. The quality of trials and strength of recommendation were assessed using the Endocrine Society grade recommendations [5]. The positive predictive factors for GH efficacy were younger age and number of prepubertal years of therapy. it has to be pointed out that the whole set of independent variables (including IGFBP-2) only explained 20% of variance. although the meta-analysis shows a wide individual variability in the response. Although the primary outcome measure for evaluating the efficacy of such therapy is adult height. and. the individual variability in the response to GH therapy should prompt further investigations aimed at identifying those who can substantially benefit from a long-term treatment. Although international and national drug agencies have approved the use of GH in this condition. the findings are suggestive for a potential use of IGFBP-2 in quantifying the metabolic risk in this population. more importantly. The aim of this systematic review was to examine the evidence that long-term randomized controlled trials (RCTs) of GH treatment in children born SGA may improve adult height. controlled (in parallel). Children with birth weight and/or length below –2 SD score (SDS) and pre-therapy height less than –2 SDS treated with two dose regimens (33–67 µg/kg per day) met the inclusion criteria. Adult height and total height gain expressed in SDS were considered as the primary outcome measures. This study represents the first report on the association between IGFBP-2 levels and markers of cardiovascular risk in normal height and short SGA adults. often. It is noteworthy that such relationships were not present in SGA children. Growth and Growth Factors 51 . 8 cm) respectively. Results: Four RCTs were identified. Efforts to evaluate metabolic risk are more meaningful in young adulthood but early predictors would be welcome. provides the evidence-based achievements that can be reasonably expected by children. In addition.

IGFBP1–6. Rosenfeld RG Department of Pediatrics. Portland. de Wit CC. IGF-I receptor gene (IGF1R) was investigated in a family with severe short stature. referred for short stature (height: –3. IGF-I circulating levels were low in patient A. Broekman AJ. USA J Clin Endocrinol Metab 2009. This study investigated copy number variations in 18 growth-related genes in short children born SGA. dysmorphic features including proximal implanted thumbs. He was on treatment with methylphenidate for a diagnosis of attention-deficit hyperactivity disorder. ALS. NMD regulates approximately 10% of human mRNAs [10].nl J Clin Endocrinol Metab 2009. to date. GRB10. these patients seem to respond to GH therapy. Ruivenkamp CA. Interestingly. IGF1R. Oreg.94:4717–4727 Background: Children born small for gestational age (SGA) represent a widely heterogeneous population. Johnson BD. probably due to partial GH deficiency. IGF2. Rotterdam. independently of GH responses to provocative tests and IGF-I levels. whereas patient B had attention-deficit hyperactivity disorder. Wit JM.94:1740–1747 Background: To date. however. functional studies on dermal fibroblasts were performed to investigate the IGF1R signal transduction pathway. In 2 subjects a deletion of the IGF1R gene was identified. These patients are characterized by severe pre. Finally. Methods: Multiplex ligation-dependent probe amplification (MLPA) was used to test whether copy number variations in growth-related genes (SHOX. Both subjects showed reduced birth length. only few cases of IGF-I receptor heterozygous mutations have been described in humans. Subdivision of Endocrinology. The extent of the two deletions was determined with single-nucleotide polymorphism (SNP) array analysis. Oregon Health and Science University. Jr. IGFBP-3 and GHBP levels were normal. Case Description and Methods: The proband was a boy born small for gestational age (SGA). which recognizes and degrades transcripts harboring a premature translation-termination codon (PTC). Erasmus Medical Center Sophia Children’s Hospital.6 SDS) and microcephaly. Primary fibroblast cultures 52 Stefano Cianfarani .and postnatal growth retardation. GH responses to stimulation tests.ester@erasmusmc. thereby preventing the production of faulty proteins. GH therapy did not induce catch-up growth. hearing problems and good response to growth hormone (GH) therapy. Conclusion: IGF1R haploinsufficiency may be suspected in children born SGA with short stature. Unexpectedly. microcephaly and mental retardation. Schwartz ID. Results: Two patients with heterozygous de novo deletions of the insulin-like growth factor 1 receptor (IGF1R) gene were identified. a phenotype closely resembling that of subjects with IGF-I gene defects [6–9]. In this study. and SOCS3) were present in a cohort of 100 children born SGA with persistent short stature. Genetic factors certainly play a role in determining birth size and postnatal growth. Hokken-Koelega AC. Familial short stature caused by haploinsufficiency of the insulin-like growth factor I receptor due to nonsense-mediated messenger ribonucleic acid decay Fang P. GHR. SOCS2. only a few genetic alterations have been associated with intrauterine growth retardation. To ensure the accuracy of gene expression. Losekoot M Department of Pediatrics. Patient A also showed delayed psychomotor development. The Netherlands w. IGF-I. GH1. van Duyvenvoorde HA.New paradigms Multiple forms of IGF-1 receptor haploinsufficiency Two short children born small for gestational age with insulin-like growth factor 1 receptor haploinsufficiency illustrate the heterogeneity of its phenotype Ester WA. NSD1. Govaerts LC. One of the best studied quality control mechanisms is nonsense-mediated mRNA decay (NMD). Roberts CT. Hwa V. Family history revealed severe short stature on the maternal side of the family. STAT5B. Derr MA. No mental retardation was reported. IGF1.. eukaryotes have evolved several surveillance mechanisms. dysmorphic features and developmental delay.

Growth and Growth Factors 53 . Moreover. although in a proportion of children born SGA. found IGF1R haploinsufficiency in 2 of 100 short SGA children and confirms that alterations in IGF1R expression may cause. The second paper by Fang et al. Nutrition. and the increased serum IGF-I levels. Although infectious diseases represent the major cause of death in black South Africans. this study has the merit to provide evidence. IGF1R was sequenced and both mRNA and protein expression was investigated. making the final outcome of GH therapy uncertain.95:2503–2507 Background: The age-related decline of serum IGF-I has been associated with the risk of developing diabetes and cardiovascular disease. The study of Ester et al. School for Physiology. Schutte R Hypertension in Africa Research Team. it has to be pointed out that the study children did not achieve adult height yet.’s paper is to offer an overview of the phenotypes associated with mutations and deletions of IGF1R gene. that the NMD pathway may play a key role in determining IGF1R haploinsufficiency eventually leading to the development of IGF-I resistance and human growth failure. intrauterine growth retardation. eventually.and postnatal growth retardation. which may overcome the reduced peripheral sensitivity. van Rooyen JM. and Consumer Sciences. However. New paradigms Is there a relationship between IGF-I and cardiovascular risk? A significant decline in IGF-I may predispose young Africans to subsequent cardiometabolic vulnerability Schutte AE. The aims of the study were to measure IGF-I concentrations in African and Caucasian subjects. the prevalence of cardiovascular disease is nevertheless high in urban areas. Low serum IGF1 and short-term response to GH therapy remain to be explained. for the first time. peculiar phenotype and developmental delay. that a mechanism involving nonsense-mediated mRNA decay may cause IGFIR haploinsufficiency and. [6] of 2 children with fetal and postnatal growth failure caused by defects in the IGF-IR gene. and the authors speculate that haploinsufficiency may be cell type-dependent. pre. Huisman HW. Malan L. describes a novel heterozygous mutation in the tyrosine kinase domain of the IGF1R in multiple subjects of the same family apparently characterized by ‘familial short stature’. South Africa J Clin Endocrinol Metab 2010. These findings are consistent with the description by Abuzzahab et al. the 2 patients with IGF1R haploinsufficiency described in this paper showed a good response to GH therapy similarly to another child previously reported by the same authors [11]. The expression of the IGF1R was minimally lower in the patient’s cells. for the first time. Conclusions: This study describes a novel heterozygous mutation in the IGF1R and indicates. the severity of short stature together with intrauterine growth retardation in the proband suggested a condition different from a simple normal variant of growth. This unexpected GH effectiveness in promoting growth despite the partial absence of IGF1R was explained by both a direct effect of GH on the epiphyseal chondrocytes independent of the biological actions of IGFs. This duplication comprised nucleotides encoding part of the tyrosine kinase domain located within the -subunit. thus providing clinical indicators to drive the investigator toward the assessment of this gene. Louw R. resulting in haploinsufficiency of the wild-type IGF1R protein. Results: IGF1R sequencing showed a heterozygous duplication in exon 18 in the proband and other family members with growth failure. and to correlate the IGF-I levels with risk parameters for cardiovascular disease.were established from skin biopsies taken from the patient and his siblings and parents. Malan NT. Fourie CM. This 19Dup mutation in the mutant IGF1R allele led to degradation of the mutant mRNA through the NMD pathway. postnatal growth impairment. van der Westhuizen FH. However. with possibly a relatively strong effect in growth plate chondrocytes. The results open many interesting questions. North-West University (Potchefstroom Campus). In addition. Another and probably stronger merit of Ester et al.

In this paper. Lamberts SW. Diabetes and cardiovascular disease are common in African urban areas. circulating concentrations of IGF-I do not 54 Stefano Cianfarani . IGF-I influences blood glucose concentrations directly by stimulating glucose uptake in target cells and indirectly by increasing the sensitivity of tissues to insulin. together with the observed relationship between IGF-I levels and cardiovascular risk factors. Results: In African participants. blood pressure. Results: 697 subjects (69. Hofland LJ. 165 subjects (16.3%) had impaired fasting glucose (IFG). it has to be pointed out that elevated levels of IGF-I have been implicated in the development and maintenance of many different cancers. insulin levels. and pulse wave velocity were assessed. van Duijn CM. with insulin sensitivity and metabolic syndrome in an elderly population-based cohort. the findings in African subjects are strongly consistent with the previous observations. and though correlation does not necessarily mean causation.1%) had diabetes. blood pressure was significantly higher and serum IGF-I concentration significantly lower than in Caucasian counterparts. and exerting anti-inflammatory actions [12–14]. a significant negative correlation of IGF-I with blood pressure. Rotterdam. Janssen JA Department of Internal Medicine. The American Diabetes Association 2003 criteria were used to classify glucose tolerance. an accelerated age-related decline in IGF-I circulating levels in African people. This finding. However. It remains to be established whether the faster decline in IGF-I levels in Africans is due to genetic predisposition or environmental factors (such as alcohol abuse or poor nutrition) or both. Thereafter. This bioassay determines IGF-I bioactivity by measuring intracellular receptor autophosphorylation upon IGF-I binding [15]. show. a prospective large-scale cohort study aimed at investigating incidence and risk factors of cardiovascular diseases in elderly people. regulating nitric oxide production. Although this study presents limitations such as the cross-sectional design and the lack of information on other important factors such as GH and IGF-binding proteins.Methods: This was a cross-sectional study involving 211 African and 316 Caucasian subjects (aged 20–70 years). In non-diabetic subjects. Finally.036 elderly subjects were recruited. IGF-I significantly dropped in the 10th decile. This study provides further indirect evidence on such a protective role of IGF-I against the development of cardiovascular disease. Schutte et al. IGF-I. parameters of glucose homeostasis. IGF-I bioactivity was determined by the IGF-I KIRA. The Netherlands Diabetes 2010. IGF-I bioactivity progressively increased up to and including the 9th decile. a decline of IGF-I bioactivity was observed when five criteria of the metabolic syndrome were present. The age-related decline in IGF-I is associated with the increased incidence of cardiovascular diseases. measured the IGF-I kinase receptor activation assay (KIRA). after stratification according to deciles of HOMA-IR value. and the metabolic syndrome Brugts MP.7%) had normal fasting glucose (NFG). suggests that earlier and greater reduction of IGF-I could be associated with cardiometabolic vulnerability. Erasmus Medical Center. Witteman JC. IGF-I bioactivity resulted positively related to insulin resistance markers. This potential role of IGF-I warrants further research even envisaging a therapeutic implication involving perhaps low-dose IGF-I or GH treatment to prevent the early development of cardiometabolic diseases. The aim of this study to relate the IGF-I bioactivity. and high-density lipoprotein cholesterol was shown in young Africans. There is a complex relationship between the GH-IGF-I axis and glucose metabolism. There is increasing evidence that IGF-I plays a key protective role in endothelial function. Conclusions: IGF-I bioactivity is closely related with insulin resistance up to a maximum threshold being significantly lower in subjects with diabetes than in subjects with NFG and IFG. Finally. Methods: The subjects were selected within the Rotterdam Study population.59:505–508 Background: The GH-IGF-I axis has been implicated in the development of metabolic syndrome. improving insulin sensitivity. IGF-I bioactivity was also directly related to the condition of metabolic syndrome. Conclusions: Africans show an accelerated decline in IGF-I levels around the age of 40 years. for the first time. peaking when three components were present. The decline of IGF-I with age was significantly faster in African subjects than in Caucasians. 1. and 153 subjects (15. IGF-I bioactivity in an elderly population: relation to insulin sensitivity. Unlike insulin. pulse wave velocity.

Legay C. sensorineural deafness and severe mental retardation associated with microcephaly. insulin sensitivity and.fluctuate substantially with time. a potential IGF1 defect was investigated. Insulin is also essential for GH stimulation of hepatic IGF-I production either by regulating GH receptor expression or by modulating GH signaling. ultimately. suggesting the development of hepatic insulin resistance (manifested by a relative increase of IGFBP-1) and hyperinsulinemia-induced GH resistance. Concepts revised Partial primary deficiency of insulin-like growth factor (IGF)-I activity associated with IGF1 mutation demonstrates its critical role in growth and brain development Netchine I. to consanguineous parents. This substitution was shown to affect protein function leading to a partial loss of protein affinity for the receptor and significant reduction of mitogenic activity.netchine@trs. low weight (–5 SDS) and microcephaly (–2. He was given GH therapy at standard dose for children born small for gestational age (SGA) with no significant improvement of his growth curve. this study shows that IGF-I bioactivity declines during progression of the metabolic syndrome.7 SDS). The child had anorexia and scarce adipose tissue. Perin L. with birth weight 2. Ricort JM. GH stimulation test and spontaneous GH secretion assessment revealed normal GH concentrations. birth length 44 cm (–3. No dysmorphic features were present. Hôpital Armand-Trousseau.7 SDS) and head circumference 32 cm (–2. dynamic changes in IGF-I bioactivity are attributed to interactions with IGF-binding proteins (IGFBPs). Daubas C. Le Bouc Y Assistance Publique-Hôpitaux de Paris. predispose to metabolic and cardiovascular disease. IGF-I levels were almost undetectable if measured with a highly specific monoclonal assay but elevated in a polyclonal assay.aphp. Brain MRI scan was normal. all were characterized by severe pre. Godeau F. Case Description: The patient was born at 40 weeks. Furthermore. In contrast. Houang M. postnatal growth impairment and brain alterations. In subjects with more than three components of the metabolic syndrome.4 SDS). Results: Due to the discrepancy between the extremely low IGF-I concentrations and normal/elevated IGFBP-3 and ALS levels. in specific conditions. The response to IGF-I generation test was subnormal. Mild developmental delay was present. Conventional work-up for growth retardation was normal. IGFBP-1 production is inhibited by insulin.350 g (–2. The main finding of this study is that circulating IGF-I bioactivity progressively increases with increasing severity of insulin resistance and hyperinsulinemia. IGFBP-3 and ALS levels were in the upper normal range or above. Paris. This study suggests a close relationship between IGF-I. As subjects with the metabolic syndrome are chronically exposed to high insulin levels. Seurin D.94:3913–3921 Background: Insulin-like growth factors-I and -II (IGF-I and IGF-II) play a key role in fetal growth and development. Instead. Conclusions: Partial loss of IGF-I activity may cause a milder phenotype than complete IGF1 deficiency and allow a partial response to high-dose GH therapy. This study describes a child with IGF1 mutation associated with severe intrauterine growth retardation. Hearing test was normal. Only few specific IGF-I gene (IGF1) defects have been described so far. reaching a plateau. Explorations Fonctionnelles Endocriniennes. cardiovascular risk and stimulates further studies aimed at elucidating whether IGF-I may prevent or. GHBP levels were within the normal range. IGF-I bioactivity significantly declined. partial catchup growth was observed.and postnatal growth retardation.5 SDS). the observed increase in IGF-I bioactivity may be secondary to an insulin-mediated suppression of IGFBP-1 levels. It is plausible that such IGF1 mutations may be not uncommon in children born SGA with microcephaly and poor response to conventional GH therapy. Among the six IGFBPs. Growth and Growth Factors 55 .fr J Clin Endocrinol Metab 2009.5 SDS). At referral. Mester J. Azzi S. However. when a higher dose was used. the child showed severe short stature (–3. France irene. Herich R. A previously unidentified homozygous missense mutation in exon 4 leading to replacement of an arginine in position 36 of the C domain by a glutamine was identified.

B regulates bone growth and chondrogenesis.B DNA-binding activity and cell proliferation in human fibroblasts. Pa. Unlike the previous 3 children. no effect was elicited in the patient’s cells.B is released from the complexes and translocates to the nucleus where it modulates the expression of target genes. The patient unfortunately died shortly after stem cell transplantation performed for the immune disorder. phosphatidylinositol 3-kinase (PI3K) assay. partial GH insensitivity was noted [19] and the effects of GH and IGF-I on NF. GH and IGF-I intracellular signaling takes place through a complex network of factors whose function is finely tuned to allow the proper cell response. thus suggesting that NF. In rodents.B signaling facilitates longitudinal bone growth and growth plate chondrogenesis and that NF.B DNA-binding activity. De Luca F St. This study shows for the first time the key role of NF. The hallmark of the diagnosis is the discrepancy between the reduced IGF-I levels and IGFBP-3 and ALS serum levels in the upper normal range. This paper describes the fourth case with alterations in the IGF-I gene [16–18]. Conclusions: GH and IGF-I do not stimulate cell proliferation and gene expression in fibroblasts isolated from this patient harboring a mutation of I B . 3 patients have been described with an IGF1 molecular defect leading to complete or very severe IGF-I deficiency.B activity secondary to a mutation of I B was complex. Christopher’s Hospital for Children. The results of this study indicate that both GH and IGF-I independently stimulate NF.and postnatal growth failure and mental retardation.To date. GHR and IGF-IR expression was normal in the patient’s cells. Alterations of this intracellular cascade induce the blockade of signal transmission ultimately leading to growth arrest.B represents a family of transcription factors including five members which in resting cells are bound to specific inhibitory proteins. this case showed a milder phenotype and only a partial loss of IGF-I binding and activity. his father and controls were cultured. USA J Clin Endocrinol Metab 2010. reporting a child with severe postnatal growth retardation associated with GH insensitivity. Mutations/deletions of GH and IGF receptors. these children may also benefit from IGF-I treatment. IGF-I failed to stimulate PI3K activity and TDAG51 expression. growth retardation representing only a tiny portion of a constellation of severe symptoms and signs. the I Bs. and STAT5b have been described. Bidlingmaier M. When the cell is stimulated. NF.B DNA-binding activity. Despite the mild IGF-I deficiency. The clinical implication is that these patients are able respond to doses of GH higher than those conventionally used. Growth hormone and insulin-like growth factor I insensitivity of fibroblasts isolated from a patient with an I B mutation Wu S. Moreover. Therefore. Finally.. Methods: Skin fibroblasts from the patient. whereas no effect was elicited in the patient’s fibroblasts.B DNA-binding activity and fibroblast incorporation of 3H-thymidine was observed in the controls and patient’s father. NF.B p65 in rats mediates the growthpromoting effects of IGF-I. It was previously demonstrated in rats that NF. cell proliferation assessed by 3H-thymidine incorporation. Lankester A.B activity is necessary for the growth-promoting actions of both hormones. Walenkamp MJ. In a patient with heterozygous mutation of I B . and target gene expression were investigated. Philadelphia. IGF-I receptor (IGF-IR) and TDAG51. Wit JM. this child showed severe pre. cell proliferation.95:1220–1228 Background: Nuclear factor (NF). the article reports that low IGF-I serum concentrations using a monoclonal antibody assay were found to be normal in a polyclonal antibody assay – an issue worth remembering. that also include I B . immunological defects. STAT5 phosphorylation and expression of specific genes such as GH receptor (GHR). ectodermal dysplasia and delay of psychomotor development. Fibroblasts were tested for NF. a target gene of IGF-I. The phenotype of this patient with impairment of NF. thus confirming the pivotal role of IGF-I in growth and neurodevelopment. this report demonstrates that even partial IGF-I deficiency has marked effects on brain development and cognitive functions. Whilst GH addition to culture medium induced STAT5 phosphorylation and IGF-I mRNA expression in controls’ and father’s fibroblasts. This report demonstrates that any alteration in the steps of the post-receptor signals may affect 56 Stefano Cianfarani . Once again this study shows the heterogeneity of the phenotype and raises the question whether this kind of missense mutations may be commoner than expected in children born SGA. Finally.B activity in signal transduction. Results: GH and IGF-I dose-dependent effect on NF.

pregnancy plasma was able to induce proteolysis of IGF-I-IGFBP-5 complexes. IGFBP proteases are proteolytic enzymes that fragment IGFBPs and reduce their affinity for IGFs. Dissociation of IGFs from IGFBP-containing complexes is thought to be mediated by limited proteolysis of IGFBPs. During pregnancy. thus suggesting that IGFBP-5 proteolysis in pregnancy leads to increased IGF-I bioactivity. these data seem to be consistent with each other. Involvement of pregnancy-associated plasma protein-A2 in insulin-like growth factor (IGF)-binding protein-5 proteolysis during pregnancy: a potential mechanism for increasing IGF bioavailability Yan X. The aim of the study was to characterize the IGFBP-5 proteolytic activity and determine its physiological function.edu. there has been no direct demonstration of its proteolysis. resulting in fragments with reduced IGF-binding affinity. Accordingly. Leonards. St. coincident with an increased demand for bioavailable IGFs.W. The former was present only in pregnancy plasma whereas the latter was present in both pregnant and non-pregnant samples. and the well-being of the mother. GH deficiency and catabolic conditions. the majority of the protein being in either free or IGF-IGFBP-5 binary complexed forms. it was absent in specimens at all stages of pregnancy which showed the presence of proteolyzed fragments in the 18to 25-kDa range. Results: Whilst the intact form of IGFBP-5 was present in non-pregnancy samples. multiple endocrine adaptations occur to guarantee the best growth and development of the fetus. often including dysregulation of other pathways converging on the same cellular junction. This Growth and Growth Factors 57 . ultimately leading to increased free IGF concentrations. The protease inhibitor profile and mass spectrometry analyses showed that the >150-kDa fraction contained PAPP-A2 (pregnancy-associated plasma protein-A) or a PAPP-A2-like protease responsible for the proteolysis of IGFBP-5 during pregnancy. IGFBP-5 undergoes substantial size redistribution. PAPP-A2 was identified to be the specific protease for IGFBP-5 during pregnancy. The level of IGFBP-5 proteolytic activity increased progressively during pregnancy. IGFBP-5 fragments were purified from pregnancy samples and analyzed by mass spectrometry. Conclusions: Circulating IGFBP-5 is fully proteolyzed by PAPP-A2 during pregnancy. Although pregnancy plasma is reported to have proteolytic activity against IGFBP-5.S. Australia sfirth@med. The formation of binary complexes may facilitate the transfer of IGFs from circulation to tissues. Taken together. Methods: Plasma from healthy non-pregnant and pregnant women was fractioned by gel-filtration chromatography. increased proteolysis of IGFBP-5 has been described in pregnant plasma associated with increased capacity of IGF-I to stimulate IGF-I receptor phosphorylation. Such proteolytic activity has been reported in pregnancy and other catabolic conditions. These physiological changes also involve the IGF system.the biological action of both GH and IGF-I. Royal North Shore Hospital. In addition. In this study. eventually increasing local IGF bioactivity. which may play a key role in growth and development of fetus as well as maternal well-being. and to increase IGF-I receptor phosphorylation. Baxter RC. During pregnancy. Such proteolytic activity has been reported to be augmented in pregnancy. particularly in the third trimester. for the first time. resulting in increased proteolysis of IGFBP-3 finalized to augment the fraction of free IGFs. it has recently been reported that PAPP-A2 is increased in the serum of pre-eclamptic patients [20]. This proteolysis leads to increased IGF bioavailability. Firth SM Kolling Institute of Medical Research. one in the >150-kDa fraction and the second one eluting in the approximately 40-kDa fraction. Size exclusion chromatography revealed two major sources of proteolytic activity. N.au J Clin Endocrinol Metab 2010. suggesting a physiological adaptation to the need of a greater IGF bioactivity for fetal and maternal demands during pregnancy. Finally. Plasma proteolytic activity against IGFBP-5 was determined. coincident with an increased demand for bioavailable IGFs. The higher proportion of IGFBP-5 in binary complexes during pregnancy may potentially facilitate the transport of IGFs to tissues and thus play a significant role in regulating IGF bioavailability.95:1412–1420 Background: The majority of IGFs circulate in blood in high molecular mass ternary complexes containing either IGFBP-3 or IGFBP-5 and the acid-labile subunit.usyd. IGFBP-5 circulating forms were identified by immunoblotting.

Riley Hospital for Children. placebo-controlled. have increased efficiency of deep lung delivery and improved systemic absorption This preliminary short-term investigation on inhaled GH demonstrates proof of principle and looks promising in terms of tolerability and efficacy in increasing both GH and IGF-I.5%. Ind. Conclusions: This is the first study in children showing that inhaled GH administered to GHD children for 7 days was effective in inducing a dose-dependent raise in GH and IGF-I levels and was well tolerated. PD and safety of SIP treatment in children were tested. headache and cough were observed in some patients. the bioavailability of GH administered by this route is low relatively to GH administered subcutaneously. Cuttler L.edu J Clin Endocrinol Metab 2009. was 5. double-blind. Silverman B. Clinical trials New treatments Inhaled growth hormone (GH) compared with subcutaneous GH in children with GH deficiency: pharmacokinetics. Park S. Aerosol technology has recently allowed the development of an innovative formulation of GH. This annoying method of administration affects long-term compliance leading to dose missing and therapy discontinuation.. a less invasive method looks desirable to guarantee a better adherence to treatment and better final results. the relatively low bioavailability and biopotency of inhaled GH require further extensive studies to refine this aerosol technology.5%. randomized. pharmacodynamics. long-term GH therapy remains poorly acceptable for parents and children. 22 GH-deficient children were recruited. sometimes even to the refusal of treatment.suggests that PAPP-A2 up-regulation reflects a compensatory mechanism finalized to preserve fetal growth and development under unfavorable conditions such as eclampsia. The mean relative biopotency. based on IGF-I response. Recent advances in aerosol technology. de la Pena A. Drop S. Patients underwent two 7-day treatment phases with either inhaled GH or subcutaneous GH + placebo separated by 6–13 days of washout. The two routes induced similar increases in mean serum GH area under the curve and in IGF-I levels in a dose-dependent fashion. 58 Stefano Cianfarani . Cutler G. Indianapolis. Indiana University School of Medicine. Preliminary pharmacokinetic (PK) and pharmacodynamic (PD) data in primates were promising. USA ewalvoor@iupui. No change in pulmonary function was recorded. termed somatropin inhalation powder (SIP). The search for an alternative way for administering GH in children is certainly worthwhile. This study aimed at determining bioavailability and biopotency of SIP in comparison with GH given subcutaneously. and safety Walvoord EC. Therefore. Methods: The design was a multicenter.94:2052–2059 Background: Since the description of the first patient treated with growth hormone (GH) in 1958. Although this study demonstrates the potential feasibility of this alternative route of administration in children. However. In addition. Chipman JJ Department of Pediatrics. the overall PK profile was similar to that of subcutaneous GH. The short-term administration of SIP resulted in being safe. The mean relative bioavailability for SIP administration compared with subcutaneous GH was 3. Results: Although the absorption of SIP was faster. GH has been administered initially by intramuscular and subsequently by subcutaneous injections. though vomiting. PK. crossover trial. by increasing particle size and lowering their density and tendency to agglomerate. Despite the use of ad-hoc devices to alleviate the burden of daily injections. Rose SR. without any major side effects. The questionnaires provided to patients and parents showed a clear preference for the inhalation route.

28:3477–3486 Background: An oncogenic role of polyoma viruses in human cancers has been repeatedly proposed. differentiation and migration of neural cells during embryo-fetal brain development. Engstrom E. Mount Sinai School of Medicine.Y..New indications of IGF-I therapy A pharmacokinetic and dosing study of intravenous insulin-like growth factor-I and IGF-binding protein-3 complex to preterm infants Lofqvist C. for the first time. The Samuel Bronfman Department of Medicine.86 and 0. IGF-I promotes proliferation. New York. Friberg LE. Moreover. Camacho-Hubner C. Goteborg Sweden Pediatr Res 2009. Vijayakumar A. This Swedish group previously reported that serum IGF-I levels can predict which preterm babies will develop the retinopathy of prematurity [21. IGF-I is a fetal growth factor essential for the development of the central nervous system. 22].65:574–579 Background: Preterm babies show almost undetectable circulating levels of insulin-like growth factor-I (IGF-I) and previous reports from the same authors demonstrated an association between low IGF-I concentrations and risk of developing the retinopathy of prematurity.000 g. New paradigms Cooperation between oncogenic viruses and IGF-I receptors Physical and functional interaction between polyoma virus middle T antigen and insulin and IGF-I receptors is required for oncogene activation and tumor initiation Novosyadlyy R. IGF-I has been demonstrated to have neuroprotective properties both in vivo and in vitro. The individual dose of rhIGF-I ranged from 1 to 12 µg/kg and was infused over 3 h. Finally. The aim of this study was to test tolerability and pharmacokinetics of IGF-I and IGFBP-3 complex administered intravenously to a small group of premature newborns. LeRoith D Division of Endocrinology. maturation.90 h respectively for a child of 1. IGF-I plays a key role in proliferation. Lann D. Smith LE. N. nevertheless it sheds. Conclusions: Infusion of rhIGF-I and rhIGFBP-3 complex is able to increase both circulating peptides in extremely preterm infants and is well tolerated. The estimated half-lives of IGF-I and IGFBP-3 were 0. Methods: Five infants born at gestational age 26–29 weeks with IGF-I levels <25 µg/l at postnatal day 2 were studied. Hellstrom A Department of Ophthalmology. Fierz Y. The study substance was an equimolar preparation of recombinant protein complex of rhIGF-I and rhIGFBP-3 diluted with 10% glucose solution. USA Oncogene 2009. Tumorigenesis seems to be mediated by polyoma virus middle T antigen (PyVmT) oncogene. and differentiation of neural stem cells. All the safety measures were reassuring. This study may thus represent a basis for further investigations on efficacy and safety of IGF-I in severe prematurity to stimulate growth and prevent retinopathy and brain damage. This paper represents the logical step ahead towards the therapeutic use of IGF-I in combination with IGFBP-3 to prevent the development of retinopathy in preterm infants. Ley D. Results: The infusion of rhIGF-I and rhIGFBP-3 complex determined a marked increase of both IGF-I and IGFBP-3 concentrations. and the low IGF-I levels of premature neonates have been associated with brain vulnerability. Kurshan N. Niklasson A. Borg J. some light on the pharmacokinetics and safety of IGF-I administration in extreme premature infants. IGF-I plays an important role in retinal vascular development in both experimental and clinical studies. Moreover. maturation. PyVmT- Growth and Growth Factors 59 . In preterm infants. Diabetes and Bone Diseases. Sahlgrenska Academy at Gothenburg University. The major weakness of the study is the small number of study subjects (only 5). low serum levels of IGF-I have been associated with slow weight gain and slow head (brain) growth as well as with the later development of retinopathy of prematurity.

IGFR and IR provide PyVmT. inhibiting apoptosis. Boston. Howard Hughes Medical Institute. Conclusion: Although PyVmT mimics the action of tyrosine kinase receptors. High circulating IGF-I and insulin levels are associated with increased risk of many cancers. whereas low levels of these hormones are accompanied by delayed tumor development. plays a key role in determining the fate of HSPCs in bone marrow and the authors asked whether systemic and/or local factors may affect HSPC number and function. the mechanisms of PyVmT activation are poorly understood. one of the most powerful viral oncogenes. These results indicate that the interaction between PyVmT and cellular receptor tyrosine kinases such as IR and IGF-IR. Shadrach JL. After 4 weeks the size of Met-1 orthograft tumors was evaluated.. Joslin Diabetes Center. hepatocellular carcinoma. Results: Insulin and IGF-I receptor (IR and IGFIR) are markedly expressed and phosphorylated in Met-1 cells overexpressing PyVmT. Met-1 cells were injected into inguinal mammary fat pads of wild-type FVB/N mice.463:495–500 Background: Aging is associated with progressive decline in cell replacement and repair processes. and alterations of hematopoietic stem and progenitor cells (HSPCs) ultimately leading to defects of immune system and increased risk of malignancy. including Burkitt’s lymphoma. cervical cancer. insulin and IGF-I receptor gene silencing was induced by transfection. This study demonstrates cooperation between IGF system and a viral oncogen such as polyoma virus. However. Treatment of these cells with insulin and IGF-I activates both PI3K and MAPK pathways inducing mitogenesis. it lacks intrinsic tyrosine kinase activity and requires cellular kinases for its activation. These animals were compared with isochronic pairs (young-young or agedaged) joined at identical ages. cancer initiation. This mechanism may represent a novel biological paradigm for oncogene activation in mammalian cells. the tumorigenic action of polyoma virus is mainly determined by PyVmT. A number of human cancers have been shown to be caused by viral infections. New paradigms Blocking IGF-I. PyVnT undergoes tyrosine phosphorylation and activates MAPK and PI3K/Akt pathways. The potential clinical implication is that oncogenesis might be targeted by a double strategy directed to both viral infection and IGF system elements. The IGF system activation is also involved in the development and maintenance of tumors. Wagers AJ Department of Stem Cell and Regenerative Biology. or niche. Methods: Met-1 and DB-7 cells derived from two different lines of mouse mammary tumor virus (MMTV)-PyVmT transgenic mice and human mammary carcinoma MCF-7 and MDA-MB-231 cells were studied. the tyrosine kinase activity necessary to initiate intracellular signaling ultimately leading to cell transformation. T-cell leukemia and Kaposi’s sarcoma. In particular. IR and IGF-IR knockdown abrogates the ability of Met-1 cells to initiate tumor formation in vivo when implanted into the inguinal mammary fat pads of recipient mice. Mass. IR and IGF-IR interact with PyVmT and both insulin and IGF-I enhance this interaction and induce PyVmT tyrosine phosphorylation. the elixir of life? Systemic signals regulate ageing and rejuvenation of blood stem cell niches Mayack SR. Harvard University. in promoting cell transformation via activation of common intracellular pathways including PI3K/Akt and MAPK. consequently. Methods: Heterochronic parabiotic pairs were generated by surgically joining young (2 months) with older (>21 months) mice. nasopharyngeal carcinoma. In Met-1 cells. Stem cell supportive microenvironment. This parabiotic procedure provides a biological model in which the ani- 60 Stefano Cianfarani . Harvard Stem Cell Institute. The aim of this study was to test the role played by the interactions between insulin and IGF-I receptors with PyVnT in oncogene activation and tumor initiation. USA Nature 2010.transforming activity is linked with the downstream signaling after incorporation to the cell membrane. Thereafter. and stimulating migration and invasion. Kim FS. plays a key role in PyVmT activation and.

thus suggesting that IGF-1 impairs the osteoblast niche cell regulation of HSCs thereby contributing to ageassociated hematopoietic dysfunction. Ludwig Maximilians University.mals share a common blood circulation. they would probably commit to differentiation rather than selfrenew. Tissue. New anti-cancer treatments Anti-insulin-like growth factor I receptor immunoliposomes: a single formulation combining two anticancer treatments with enhanced therapeutic efficiency Hantel C. osteoblastic niche cells were isolated using fluorescence-activated cell sorting (FACS) from collagenase-treated bones. Suss R. The study of Mayack et al. Medizinische Klinik-Innenstadt. Schneider S. Local tissue environment regulates the number and function of cells in all tissues. Lewrick F. Beuschlein F Endocrine Research Unit. Such observation has potential major clinical implications envisaging the development of new therapeutic strategies aimed at reversing the age-related immune dysfunction and cancer risk. Munich. bone marrow cells from aged mice exposed to young systemic factors showed recovery of engraftment potential. IGF-1 seems to induce ageing of HSC-regulatory niche cells. The hematopoietic stem cells (HSCs) have the potential to self-renew to maintain the HSC pool. but not systemic. The age-dependent alterations in osteoblastic niche cell number and function were restored to youthful levels when aged animals were exposed to young circulation. the inhibition of IGF-1 signaling in aged osteoblastic niche cells promoted youthful HSC-regulatory function. Reincke M. indicates for the first time that the regulatory role of osteoblast niche cells in hematopoietic stem cell is closely dependent on IGF-1 in mice. They can be reversed by exposure to a young circulation or by inhibition of IGF-1 in the marrow microenvironment. Age-associated blood diseases are thought to arise in part owing to discrete changes in aged hematopoietic stem and progenitor cells. indicating that IGF-1 impairs the osteoblastic niche cells appropriate regulation of HSCs. Conclusions: The results suggest that the age-associated changes in bone marrow niche cells are both systemically and locally regulated. growth and survival of cancer cells. as well as restoration of youthful ratios of B lymphoid to myeloid. particularly targeting the IGF-I receptor (IGFI-R) which mediates the biological action of both IGF-I and IGF-II. thus contributing to the age-associated hematopoietic dysfunction. HSCs need to be localized in a particular location (termed the HSC niche) within the bone marrow to retain their multipotency and if the HSCs are located elsewhere. Germany J Clin Endocrinol Metab 2010. Zwermann O. Locally. particularly in bone marrow. The aim of this Growth and Growth Factors 61 . Studies in genetically modified mice supported roles for cells of the osteoblast lineage in the retention and regulation of HSCs in the bone marrow. In the hematopoietic system. The finding that IGF-1 neutralization restores youthful function to aged osteoblastic niche cells highlights a new and important activity for this growth factor in controlling the fate of stem cells. A number of strategies have been proposed to silence the IGF system in various types of tumor cells.95:943–952 Background: Insulin-like growth factors (IGFs) I and II are overexpressed in the vast majority of tumors and play a pivotal role in transformation. The possible role of niche and systemic factors in HSPC ageing was investigated using direct isolation of hematopoietic stem cell (HSC)-regulatory niche cells. manifested by increased reconstitution of peripheral blood leukocytes. Results: The exposure to young circulation of aged-heterochronic partners showed significant recovery of HSC number and function which approached normal ‘youthful’ levels. specifically targeting IGF-1 in the marrow microenvironment. In particular. Switching off osteoblast IGF-1 signaling restores the cell youthful function. Perren A. Finally. thus enabling to test whether physiological levels of circulating cells or factors can significantly alter tissue function. ageing is associated with deficient immune function and increased incidence of malignancy. and neutralization of IGF-1 signaling in the bone marrow microenvironment reverts age-related changes in osteoblastic niche cells. The interaction of HSC with aged osteoblastic niche cells was sufficient to induce HSPC accumulation similarly to that observed in aged marrow.

breast and prostate cancer cells.. Results: All tumor tissues showed overexpression of IGFI-R. and (6) the use of peptide aptamers. The novelty of this study was the combined approach with a cytostatic molecule such as doxorubicin coupled to anti-IGFI-R antibodies in the same carrier. For in vivo experiments commercially available sterically stabilized liposomes loaded with DXR were used. These include: (1) the use of antisense molecules to reduce IGF-I-R translation. Conclusions: In vitro and in vivo treatment with these novel anti-IGFI-R immunoliposomes resulted effective in reducing cell proliferation. Young JJ. who described the resistance of fibroblasts harboring a null mutation of IGFI-R to transformation induced by various viral and cellular oncogenes [23]. Tumor cell lines were used to test antibody association and internalization in vitro. therapeutic treatments were given intravenously as single bolus. (5) the use of dominant negative gene variants. Female athymic NMRI v/v mice were inoculated with BON (GEP-NET) cells for inducing tumor development and when longest tumor diameters ranged between 0. showing a similar capacity of binding to the cell surface and being internalized. and increasing lifespan in animals bearing GEPNET tumors. USA Mol Endocrinol 2010. Mertens AR. Oregon Health and Science University.5 and 0. (3) the use of peptides mimicking IGF-I to block the ligand/receptor interaction. The anti-IGFI-R Ab was coupled to the liposomal surface via sterol-based postinsertion technique using a succinimide activated sterol-PEG1300-anchor. Preliminary in vitro experiments indicated that this agent could also represent a promising therapeutic tool for different cancer types. (4) the use of specific inhibitors of the receptor catalytic activity. New mechanisms Distinct alterations in chromatin organization of the two IGF-I promoters precede growth hormone-induced activation of IGF-I gene transcription Chia DJ. Oreg. a class of molecules genetically selected for specific binding to the receptor. Quantitative Stat5 chromatin immunoprecipitation assay (ChIP) was 62 Stefano Cianfarani . were internalized and resulted effective in inhibiting proliferation and inducing apoptosis of cancer cells. Rotwein P Department of Pediatrics. Portland. (2) the use of blocking antibodies directed to the extracellular part of the receptor. This role was elegantly discovered by Sell et al. The anti-IGFI-R immunoliposomes were also tested in other human tumor cell lines different from GEP-NET such as neuroblastoma. Anti-IGFI-R immunoliposomes significantly associated to cells. inducing apoptosis. IGF-I gene contains two promoters differently active in the different tissues with the only exception of liver where both promoters are functionally active. The IGFI-R is important for cancer development and progression. Treatment of human neuroendocrine BON cell xenografts increased the survival time of animals. Unfortunately the in vitro promising results obtained with all these methods were not replicable in vivo. Methods: Samples of gastrointestinal NETs from 59 patients and samples from normal tissues were analyzed. As IGFI-R is overexpressed in the majority of tumor cells. The aim of this study was to investigate the effect of GH on IGF-I promoter function. a number of inhibition strategies for IGFI-R signaling have been developed [24]. This report describes the development of DXR-encapsulated immunoliposomes coupled with an IGFI-R blocking Ab to both target IGFI-R-overexpressing tumor tissues and inhibit IGF-dependent pathways. IGF-I mRNA expression was assessed by RT-PCR.24:779–789 Background: Most growth hormone (GH) biological actions are mediated by IGF-I whose expression and secretion is directly stimulated by GH in liver and other tissues. The preliminary in vitro and in vivo results are encouraging but the therapeutic efficacy and safety of such an approach in humans remain to be established.7 cm. The mechanisms by which IGF-I promoters are regulated by GH are still largely unknown. Methods: Liver from hypophysectomized male Sprague-Dawley rats was studied.study was to investigate the antitumor action of a monoclonal anti-IGFI-R antibody coupled to liposomes loaded with doxorubicin (DXR) in neuroendocrine (NETs) tumors of the gastroenteropancreatic (GEP) system.

References 1. Finally. which leads to IGF-I gene transcription. Ledet T. Hebert M: Review of 64 cases of death in children with Prader-Willi syndrome. as well as recruitment of polymerase II. Delafontaine P: IGF-I reduces inflammatory responses. The activation of IGF-I promoters associated with a rise in acetylation of histones H3 and H4 in promoter-associated chromatin. Circulation 2004. Murad MH. Titterington J.284:E1149–E1155. Histone acetylation and methylation were determined. Genes Dev 2007. Boot AM.27:2684–2690. Frystyk J: A highly sensitive and specific assay for determination of IGF-I bioactivity in human serum. Results: Whereas in absence of GH.and antiinflammatory cytokine mRNA expression in the burn wound. Molinas C. 8. et al: A case for clarity.90:4679–4687. N Engl J Med 2003. suppresses oxidative stress.63:33–39. A series of quantitative ChIP experiments were performed.1:58–65. Abuzzahab MJ. 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Yang F. et al: IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. Schunemann HJ.93:2421–2425. 10. Recruitment and modification of transcriptional coregulators may represent fundamental and physiologically relevant dynamic genomic effects of GH. 12. Crea F. L’Allemand D: Fatal outcome of sleep apnoea in PWS during the initial phase of growth hormone treatment. J Clin Endocrinol Metab 2008. Schneider A. A contribution to the debate about the safety of growth hormone treatment in children with PWS. Orskov H. Pereira AM. Diene G. Whereas GH treatment does not influence recruitment of Pol II to promoter 1 which in absence of GH shows Pol II already present in a preinitiation complex. Andreotti F: Insulin-like growth factor-1 as a vascular protective factor.91:3062– 3070. Volpe M. 7. and decreases atherosclerosis progression in ApoE-deficient mice. Song YH. A single GH systemic administration induces instantaneous acetylation and methylation of core histones. Perez-Polo JR. Zuppi C. de Muinck Keizer-Schrama SM. J Clin Endocrinol Metab 2001.92:1542–1548. Conti E. Christiansen JS. 5. Gene Ther 2001. next investigations will be targeted to elucidate the pathways downstream Stat5b activation which eventually orchestrate chromatin structure and function. and helpfulness: state-of-the-art clinical practice guidelines in endocrinology using the grading of recommendations. Kalf ME. Walenkamp MJ. 4.performed to determine whether GH causes recruitment of Stat5b to the IGF-I promoters. Growth and Growth Factors 63 . assessment. and evaluation system. GH treatment was able to induce recruitment of polymerase II (Pol II) to promoter 2. 9. a single systemic GH administration induced a significant increase in transcription from both liver IGF-I promoters. 3.58:24–26.93:666–673.21:1833–1856. Am J Physiol 2003. de Mos M. Am J Med Genet A 2008. et al: Successful long-term growth hormone therapy in a girl with haploinsufficiency of the insulin-like growth factor-I receptor due to a terminal 15q26. Carrozza C. A case report. consistency. GH acutely modified histone lysine methylation at the IGF-I promoters. Nesic O.8:1409–1415. Conclusion: The authors conclude that GH induces rapid and dramatic changes in hepatic chromatin at the IGF-I locus and activates IGF-I gene transcription in the liver by distinct promoter-specific mechanisms. J Clin Endocrinol Metab 2007. van der Kamp HJ. Jessen N. 6. Maquat LE: Quality control of eukaryotic mRNA: safeguarding cells from abnormal mRNA function. Sukhanov S. development. J Clin Endocrinol Metab 2005. et al: A variable degree of intrauterine and postnatal growth retardation in a family with a missense mutation in the insulin-like growth factor I receptor. Tiulpakov A. Lund S. Stat5 ChIP experiments failed to detect a substantial association of Stat5b with either IGF-I promoter. Li Y. Kanzaki S. Rubtsov P. Mohler J. et al: A familial insulin-like growth factor-I receptor mutant leads to short stature: clinical and biochemical characterization. Capoluongo E. Cianfarani S: Insulin sensitivity in children born small for gestational age. Larsen MB. 15. Vaughn C. J Clin Endocrinol Metab 2006.146A:881–887.2-qter deletion detected by multiplex ligation probe amplification. IGF-I gene transcription was negligible. Horm Res 2005. GH facilitates recruitment and then activation of RNA Pol II to initiate transcription. Tauber M. at promoter 2. Arterioscler Thromb Vasc Biol 2007. 11. Goddard A.110:2260–2265. 13. and that GH activates IGF-I gene transcription in the liver via distinct promoter-specific mechanisms. 14. Kawashima Y. Chen JW. Swiglo BA. Higashi Y. Isken O. Horm Res 2002. Eiholzer U: Deaths in children with Prader-Willi syndrome.

20. DeAngelis T et al: Effect of a null mutation of the type I IGF receptor gene on growth and transformation of mouse embryo fibroblasts.14:3604–3612. Sekiya T. Camacho-Hubner C.16. Niklasson A et al: Postnatal serum insulin-like growth factor I deficiency is associated with retinopathy of prematurity and other complications of premature birth. Pryor-Koishi K.112:1016–1020. Karperien M. Engstrom E. 23. J Clin Endocrinol Metab 2005. Engstrom E. J Exp Med 2004. Kogo H. Mol Hum Reprod 2008. Growth Horm IGF Res 2004.90:2855–2864. van Dissel JT. J Med Genet 2003. Udagawa Y: Increased levels of pregnancy associated plasma protein-A2 in the serum of pre-eclamptic patients. van Dongen J. et al: Homozygous and heterozygous expression of a novel insulin-like growth factor-I mutation. Lankester A: The same I B mutation in two related individuals leads to completely different clinical syndromes. Walenkamp MJ. Janssen R. Nishizawa H.200:559–568. N Engl J Med 1996. Mol Cell Biol 1994. 19. Bahr C.40:913–917 18. Bonapace G. ten Dam M. Hard A-L. Perruzzi C. Savage MO. Bredius R. Proc Natl Acad Sci USA 2001. 21. Hoeve MA. Pereira AM. Hellstrom A. Ottenhoff TH. van der Burg M. Liu J-L et al: Low IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: direct correlation with clinical retinopathy of prematurity. Concolino D. 22. Carlsson B. Kurahashi H. 17. van de Vosse E.98:5804–5808. Hellstrom A. Deveaud C. Hard A-L. Dumenil G. Woods KA. Miura M. Groner B: The insulin-like growth factor-1 receptor as a drug target: novel approaches to cancer therapy.335:1363–1367. van Wengen A. van Tol M. Kato T. Sell C. Suzuki M. Weemaes C. Formicola S. 24. 64 Stefano Cianfarani .14:287-295.14:595–602. Coppola D. Meihua J. Strisciuglio P: A novel mutation in a patient with insulin-like growth factor 1 deficiency. Albertsson-Wikland KA. Pediatrics 2003. Clark AJ: Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene.

uk N Engl J Med 2009. University of Turku. Institute of Genetics and Molecular Medicine. OPG immunoprecipitated with patient’s serum. University of Edinburgh.ac. . We selected a few papers identifying new genes linked to to important clinical conditions if mutated. ’growth plate’ and ’mineral metabolism’ where each paper is discussed from a pediatric endocrine point of view.361:1459–1465 Background: Osteoporosis is a recognized complication of celiac disease and it is generally considered to be secondary to malabsorption and calcium and vitamin D deficiencies. A new paradigm is represented by two papers discovering that serotonin regulates bone mass accrual in opposite directions depending on site of synthesis. Poland d Pediatric Endocrinology Unit. Finland Pediatric Endocrinology. Haifa. A clear breakthrough and mechanism of the year is the discovery of RANKL/RANK as key thermoregulators creating a link between bone physiology and central control of body temperature and fever. A paper describing a new mechanism of IGF-1 to modulate thyroid hormone effects in the growth plate is also highligted. Stockholm.Bone. Fraser WD. Determann C. RANK signaling assay demonstrated that NF. These include cyclophilin B – linked to severe osteogenesis imperfecta.ralston@ed. Three samples of 15 patients with celiac disease were positive. while serum specimens from 10 healthy controls. Ralston SH Rheumatic Diseases Unit. Osteoprotegerin (OPG) immunoprecipitation assays and RANK signaling assays were performed. Medical University of Silesia. Western General Hospital. Karolinska Institutet. Department of Women’s and Children’s Health. Edinburgh. and 14 patients with primary hypothyroidism were negative for the autoantibody. Methods: Serum samples were obtained from a 40-year-old male patient with celiac disease and autoimmune hypothyroidism. Rambam Medical Center.B activation was inhibited by the addition of human recombinant OPG in the presence of the immunoglobulin fraction from control serum. Israel c Pediatric Endocrinology and Diabetes. rather than a consequence of an autoimmune process. Department of Pediatrics. We have made a subjective selection of 19 papers and divided the chapter into ’bone’. Katowice. Sweden b a It has been an outstanding year of publications in the field of pediatric endocrinology. and 14 patients with autoimmune hypothyroidism. and ENPP1 – linked to hypophosphatemic rickets. Growth Plate and Mineral Metabolism Terhi Heinoa. as well as from 10 age-matched healthy male controls. Technion – Israel Institute of Technology. 12 patients with celiac disease. Dov Tiosanob. 15 patients with celiac disease. van’t Hof R. but the inhibitory effect of OPG was lost in the presence of immunoglobulins purified from the patient’s serum. though at a lower intensity. McRorie E. As food for thought. who developed high-turnover osteoporosis. UK stuart. Conclusion: A high turnover osteoporosis in a patient with celiac disease was associated with the spontaneous development of autoantibodies against OPG. we included a paper disclosing how hibernating bears prevent bone loss. Results: In Western blotting. Aneta Gawlikc and Lars Sävendahld Department of Cell Biology and Anatomy. Institute of Biomedicine. New paradigms OPG autoantibodies linked to bone loss in celiac disease Osteoporosis associated with neutralizing autoantibodies against osteoprotegerin Riches PL.

Conversely. but prevented its interaction with collagen in vitro. New genes Mutations in osteogenesis imperfecta go beyond collagen type I Severe osteogenesis imperfecta in cyclophilin B-deficient mice Choi JW.bram@mayo. Madden BJ. through an unknown mechanism. knockdown of either P3H1 or CRTAP did not affect cellular levels of CypB. Conclusion: The data presented in this paper provide a significant new mechanistic insight into the pathophysiology of OI and reveal interactions of members of the P3H1/CRTAP/CypB complex in directing proper collagen formation. indicated that elevated bone turnover was the primary cause of this patient’s osteoporosis. The mechanism by which OPG autoantibodies developed remains unclear. his osteoporosis worsened. and fragility fractures are consistent with the phenotype seen both in targeted OPG–/– mice and humans with juvenile Paget’s disease and OPG-inactivating mutations. denosumab. Methods: To study the role of mammalian CypB. 66 Terhi Heino/Dov Tiosano/Aneta Gawlik/Lars Sävendahl . Furthermore. elevated alkaline phosphatase levels. while the role of CypB in this complex has been unknown. celiac disease and high bone turnover osteoporosis. Minn. Results: In early life. The syndrome is characterized by exquisitely fragile bones due to osteoporosis. It is tempting to speculate that in this case. The high-turnover osteoporosis.. Evans GL. RANKL antagonist. Bergen HR.e.edu PLoS Genet 2009. Sutor SL. encoded by the Ppib gene. Lindquist L. USA richard. The authors found that the levels of P3H1 were substantially reduced in Ppib–/– cells. 3rd. knockdown of CRTAP also caused depletion of cellular P3H1 and the post-translational prolyl-3-hydroxylation of type I collagen by P3H1 was essentially absent in CypB-deficient cells and tissues from CypB-knockout mice. endogenous OPG had become the target of an autoimmune response in this patient. calcium and vitamin D supplementation. P3H1 exists in a complex with CRTAP and cyclophilin B (CypB). A new pathophysiological mechanism of rapid bone loss was discovered: neutralizing autoantibodies against osteoprotegerin (OPG). Mutations in CRTAP cause OI in mice and humans. the authors generated mice lacking this protein. However. i. Rochester. a remarkable response to zoledronic acid treatment. but presumably.This case report identifies a young man with autoimmune hypothyroidism. His bone disease was very severe and despite the gluten-free diet. The 3 patients with the autoantibodies had lower bone mineral density values than those without the autoantibodies.5:e1000750 Background: Osteogenesis imperfecta (OI) is an inherited disorder of collagen and majority of cases are caused by point mutations in the type I collagen genes COL1A1 and COL1A2. The morphology of collagen fibrils in Ppib–/– mice was abnormal and in vitro studies revealed that procollagen did not localize properly to the Golgi in CypB-deficient fibroblasts. Mayo Clinic College of Medicine. Ppib–/– mice developed kyphosis and severe osteoporosis. while CRTAP was unaffected. Future studies should determine whether OPG autoantibodies are associated with the development or severity of osteoporosis in other patients with celiac disease or other autoimmune diseases. encoded by the LEPRE1 gene). Yaszemski MJ. would have been an even more specifically targeted therapy. They also demonstrated the presence of autoantibodies against osteoprotegerin in 3 of 15 patients with celiac disease. This strongly suggests that his acquired illness was due to the development of neutralizing autoantibodies against OPG. which is a potent inhibitor of osteoclastic bone resorption. Hefferan TE. Bram RJ Department of Immunology. OI also occurs in humans with homozygous mutations in prolyl-3-hydroxylase-1 (P3H1.

However. Chang W. Shi Z. Leikin S. also show phenotypic features of OI.15:757–765 Background: Bone remodeling is an important biological process that depends on the precise coordination of bone resorption and subsequent bone formation.nih. For example. Growth Plate and Mineral Metabolism 67 . Thus. The proband’s collagen had normal collagen folding and normal prolyl 3-hydroxylation.362:521–528 Background: OI is a heritable disorder causing bone fragility. such as Camurati-Engelmann disease (CED). Results: No mutations in COL1A1. It is now clear that osteogenesis imperfecta (OI) is not caused only by mutations in collagen 1 and 2 chain genes. The current study by Choi et al. Lei W. Conclusions: The data demonstrates that recessive OI can be caused by a homozygous start-codon mutation in the Ppib gene. the role of CypB in the complex and the identity of the major collagen isomerase still need to be resolved. Identifying novel mutations will furthermore improve the molecular diagnosis of OI in the future.. these data are useful in explaining the clinical and phenotypical variety of OI. USA oidoc@helix. University of Alabama at Birmingham. demonstrates that mice lacking cyclophilin B. Makareeva E. Novel mutations associated with this disease have been found in the enzymatic complex which is needed to process collagen into mature fibrils. Bethesda. Barnes et al. Cabral WA. The normal collagen folding and prolyl 3-hydroxylation however indicates that CypB is not the exclusive peptidyl-prolyl cis-trans isomerase that catalyzes the rate-limiting step in collagen folding. Cao X Department of Pathology. Pang L.gov N Engl J Med 2010. which is in contrast to the findings of Choi et al. CRTAP. Feng X. Weis M. Md. a third partner of the collagen hydroxylation enzyme complex. CRTAP or LEPRE1 were identified.. National Institutes of Health. Wan M. Wan C. They however observed a normal collagen folding and prolyl 3-hydroxylation in these patients. Mutations in type I collagen result in autosomal dominant OI. showing that translational prolyl-3-hydroxylation of type I collagen by P3H1 was essentially absent in cells and tissues from CypB-deficient mice. Bone. Peng X. Disturbances in the balance of bone remodeling are associated with skeletal diseases. the third component of the complex. soon after the publication of this paper. Zhao L. Carter EM.1-induced migration of bone mesenchymal stem cells couples bone resorption with formation Tang Y. as is currently thought. Methods: The authors identified two siblings in a consanguinous Senegalese family. Wu X. Interestingly. Birmingham. Van Hul W.in bone remodeling TGF. Ala. USA cao@uab. Hu J. Marini JC National Institute of Child Health and Human Development. Raggio CL. COL1A2. whereas mutations in either of two components of the collagen prolyl 3-hydroxylation complex (CRTAP and P3H1) cause autosomal recessive OI with rhizomelia (shortening of proximal segments of upper and lower limbs) and delayed collagen folding. and LEPRE1 [2] mutations have previously been shown to be linked to OI. The siblings had recessive osteogenesis imperfecta without rhizomelia and their genomic DNA was screened. the fundamental questions concerning the function of the 3-hydroxylase modifications. Eyre DR. reported two OI siblings from a consanguineous family due to a homozygous start codon mutation in the peptidyl-prolyl isomerase B (PPIB) gene which results in a lack of cyclophilin B. but the siblings had a homozygous start-codon mutation in the Ppib gene resulting in a lack of CypB. Rotimi CN. Nagy TR.edu Nat Med 2009.Lack of cyclophilin B in osteogenesis imperfecta with normal collagen folding Barnes AM. New hope A novel role for TGF. reviewed in Yearbook 2007 [1].

(TGF. This intruiguing study provides evidence for the critical role of TGF. Stenbeck G. Bozec A. the authors demonstrate that mice carrying a mutation in the TGF. including in vitro cultures of osteoclasts and bone marrow stromal cells (BMSCs). Keller GM Department of Craniofacial Development and Orthodontics. the molecular mechanisms have not been elucidated so far. but a few important points remain to be investigated. Wagner EF. the potential impact of TGF.1 as a potential therapeutic target for bone diseases. However.Methods: This study used multiple methods.1 functions to couple bone resorption and formation. modulation of TGF.1. UK agi. This recent study by Tang et al. Transforming growth factors. Treatment with a TGF. CD11b.isotype (TGF.1 gene develop Camurati-Engelmann disease.1). Even though this work reveals a novel role for TGF. high levels of active TGF.1 knockout mice and CED transgenic mice. CD18. Second. as well as in vivo studies on transforming growth factor (TGF). King’s College London. demonstrates that TGF. When cultured in the presence of essential osteoclast differentiation factors. recent discoveries in generating induced pluripotent stem (iPS) cells has further enabled understanding of specific emryonic lineages and opened new opportunities for patientspecific stem cells. it should be clarified whether another important human TGF.ac. TGF. which showed the typical progressive diaphyseal dysplasia seen in the human disease. Interestingly.1 in the bone marrow. followed by specification to hematopoiesis and myelopoiesis by vascular endothelial growth factor (VEGF) and hematopoietic cytokines in serum-free media. Human ES and iPS cells were maintained and differentiated towards monocyte-macrophage lineage and finally to functional osteoclasts. New hope Embryonal stem (ES) and induced pluripotent stem (iPS) cells – powerful tools in bone biology Directed differentiation of hematopoietic precursors and functional osteoclasts from human ES and iPS cells Grigoriadis AE. First.1.in the treatment of bone disease. Kennedy M.e.1 activity could be an effective treatment for diseases of bone remodeling. Methods: In this study.115:2769–2776 Background: The differentiation of human embryonic stem (ES) cells into multiple hematopoietic lineages is well established. Guy’s Hospital. which induced the migration of BMSCs to the bone resorptive sites.grigoriadis@kcl. Results: A precursor population enriched for cells expressing the monocyte-macrophage lineage markers CD14. macrophage colony-stimulating factor (M-CSF) and 68 Terhi Heino/Dov Tiosano/Aneta Gawlik/Lars Sävendahl .) play an important role in bone metabolism and it has been hypothesized to function as a coupling factor that links bone resorption to bone formation. Analyzing mice carrying a CED-derived mutant TGFB1 (encoding TGF.receptor inhibition was shown to partially rescue uncoupled bone remodeling.type I receptor inhibitor partially rescued the uncoupled bone remodeling and prevented the fractures. i. In addition. These questions should be answered before considering potential clinical applications of TGF.1 were found in the bone marrow.could be delivered specifically and efficiently to target cells. the stepwise generation of bone-resorbing osteoclasts from ES and iPS cells is reported.1 is the key chemoattractant that tightly couples bone degradation and formation in space and time.1 in bone remodeling and suggests TGF. Park IH. and CD115 was obtained by generation of a primitive streak-like population in embryoid bodies. and express high levels of TGF. Conclusion: Since TGF.uk Blood 2010. a disease characterized by progressive diaphyseal dysplasia. It induced the migration of bone marrow stromal cells to the bone remodeling area. drug discovery and studying disease mechanisms. London. The process was mediated through a SMAD signaling pathway. In addition.inhibitors and stimulators in osteoblast differentiation should be investigated using in vivo systems. Results: Bone resorption released active TGF. we do not know how molecules affecting TGF.in bone metabolism. Brunton F.2) has a similar activity in bone marrow stromal cells as TGF.

edu Cell Metab 2010. New mechanisms Oxidative stress and osteogenesis FoxO1 is a positive regulator of bone formation by favoring protein synthesis and resistance to oxidative stress in osteoblasts Rached MT. whereas osteoclasts are highly specialized. and calcitonin receptor.. Division of Endocrinology. In addition. the authors investigated their potential impact on skeletal integrity. Depinho RA. Results: Among the three FoxO proteins. N. The O subclass of human Fox proteins (FoxO) include FoxO1. Induced pluripotency as a tool for biological discovery was selected as the Method of the Year 2009 by Nature Methods [3]. Although the potential of mouse ES cells to differentiate into osteoclasts has been reported previously. Molecular analyses confirmed the RANKL-dependent expression of the osteoclastic marker genes NFATc1. Oxidative stress enhances the activation of FoxO transcription factors that defend against oxidative stress by activating genes involved in free radical scavenging and apoptosis. Kode A. FoxO4 and FoxO6. Since human osteoclasts are traditionally obtained by a time-consuming process of isolating and differentiating peripheral blood monocytes. This can be done by evaluating how the individual mutations affect osteoclast differentiation and function in vitro. the new method can be utilized to more efficiently identify novel antiresorptive compounds for osteoporosis. FoxO3. FoxO1 regulation of osteoblast proliferation occurred through its interaction with ATF4. the current study by Grigoriadis et al. Growth Plate and Mineral Metabolism 69 . for the first time demonstrates the generation of osteoclasts from human ES and iPS cells. Columbia University. as well as for other conditions of accelerated bone resorption. USA sk2836@columbia. is associated with decreased number of osteoblasts and increased levels of oxidative stress within osteoblasts. the derivation of iPS cells from patients harboring cell-autonomous genetic mutations enables studying disease pathology. Osteoblasts are derived from mesenchymal stem cells. multinucleated osteoclasts that expressed tartrate-resistant acid phosphatase and were capable of resorption. precursor cells formed large. and defined manner. New York. differentiation. Conclusion: This study reports the possibility to generate large numbers of osteoclasts from human ES and iPS cells in a consistent. as well as through its regulation of a stress-dependent pathway influencing p53 signaling.receptor activator of nuclear factorligand (RANKL). Paik JH. Methods: Since transcription factors of the FoxO family confer stress resistance. Yoshikawa Y. In this report. Since the first reports of such a form of cellular reprogramming a few years ago. They employed osteoblast-specific deletion of FoxO proteins in mice (FoxO1ob–/–) and performed a vast range of histological. Conclusion: These results identify FoxO1 as a crucial regulator of osteoblast physiology and provide a direct mechanistic link between oxidative stress and the regulation of bone remodeling. Forkhead box (Fox) proteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth. and longevity. proliferation. This study furthermore establishes a basis for genetic rescue and autologous cell-based therapies for disorders characterized by increased bone loss. multinucleated cells that are derived from hematopoietic stem cells.11:147–160 Background: Osteoporosis. Xu L. cellular. a transcription factor regulating amino acid import. research on iPS cells has progressed on a vast speed. the authors utilized osteo- Bone. reproducible. a disease characterized by low bone mass. Kousteni S Department of Medicine. only FoxO1 was required for proliferation and redox balance in osteoblasts and thereby controlling bone formation.Y. biochemical and molecular analyses. cathepsin K. Bone formation and bone mass in FoxO1ob–/– mice was normalized by decreasing oxidative stress levels or increasing protein intake. College of Physicians and Surgeons.

as well as via influencing p53 signaling. They provide evidence for FoxO-dependent oxidative defense as a mechanism to protect against oxidative stress in osteoblasts.edu Bone 2009. as well as decrease in osteoblast number. They furthermore demonstrated that overexpression of a FoxO3 transgene in mature osteoblasts decreased oxidative stress and osteoblast apoptosis. Food for thought How do hibernating bears prevent bone loss? Grizzly bears (Ursus arctos horribilis) and black bears (Ursus americanus) prevent trabecular bone loss during disuse (hibernation) McGee-Lawrence ME.. bone formation and bone mass. Houghton. In addition. bone formation rate. and vertebral bone mass. bears completely prevent cortical bone loss by balancing intracortical bone remodeling during disuse (hibernation). bones from black bears killed by hunters in the fall or in the spring were collected.and post-hibernation bears in the ilium. however. Mich. The important concept based on the data presented here and in previous reports from the same group is that hibernating bears possess a mechanism by which they do not lose bone (both trabecular and cortical) associated with disuse. Even though indicators of cellular activity (mineral apposition rate. Conclusion: Bears appear to prevent bone loss during disuse by maintaining a balance between bone formation and bone resorption. is more detrimentally affected than cortical bone in other animal models of disuse. bone architectural properties and bone mineral density (BMD) of grizzly bear (Ursus arctos horribilis) and black bear (Ursus americanus) trabecular bone were studied. Despite some inconsistency in the role of individual FoxOs. Condon KW. Michigan Technological University. Trabecular bone. Drummer TD.blast-specific deletion of FoxO proteins. Bones were obtained from hibernating (16–18 weeks after hibernation) and active (at least 14 weeks of physical activity following hibernation) grizzly bears. trabecular bone resorption and formation remained balanced in hibernating grizzly bears. and thereby experience annual periods of bone disuse and remobilization that are approximately equal in length. Barlow LN. Methods: The effects of hibernation on bone remodeling. Further investigation on the mechanisms of preventing disuse-induced bone loss in bears may contribute to development of novel treatments for osteoporosis. in another paper in the very same volume of Cell Metabolism. An increasing amount of evidence has linked oxidative stress with aging and the development of age-related diseases. [4] performed a simultaneous conditional deletion of all three FoxOs in mice and observed an increase in bone oxidative stress and osteoblast apoptosis. osteoid thickness) decreased. Interestingly. with an increase in osteoblast number. Donahue SW Department of Biomedical Engineering. such as Werner syndrome or Hutchinson-Gilford progeria. Black HL. Castillo AB. USA swdonahu@mtu. thereby leading to loss of cortical and trabecular bone. Bone formation in mice lacking FoxO1 in osteoblasts returned to normal by a decrease in oxidative stress or an increase in protein intake. They also demonstrated that FoxO1 regulated osteoblast proliferation via interacting with activating transcription factor 4 (ATF4). In contrast. Kennedy O. Robbins CT. Auger J. However. No increase in cortical 70 Terhi Heino/Dov Tiosano/Aneta Gawlik/Lars Sävendahl .45:1186–1191 Background: Reduced skeletal loading (disuse) causes an imbalance in bone formation and bone resorption. Thereby it is tempting to speculate that impaired function or deletion of FoXO proteins could be involved in bone loss observed in pediatric conditions of early aging. which consequently preserves bone structure and strength. Ambrogini et al. Results: No differences were observed in bone volume fraction or BMD between hibernating and active bears or between pre. Bears hibernate for around 6 months of the year. these papers nevertheless identify FoxO proteins as crucial regulators of bone formation and bone mass homeostasis in mice. and showed that only FoxO1 was required for proliferation and redox balance in osteoblasts. the material and structural properties of black bear (Ursus americanus) and grizzly bear (Ursus arctos) bone are not compromised with age or during hibernation. Nelson OL. Wojda SJ. distal femur. or calcaneus.

and learning disabilities. Hiort O. Hennig BP. Baten E. the gene coding for parathyroid hormone-related protein (PTHrP). Germany stefan. The genetic cause of the great majority of BDE cases is unknown. The primary mediator of PTHRP/PTH receptor signaling in chondrocytes is GNAS. Charité Universitatsmedizin Berlin.porosity and no difference in trabecular bone mass were found after hibernation compared to before. Bone. Gillerot Y. This is a fascinating study on an exceptional material and could lead to an expanded understanding of how to reduce the negative bone balance associated with disuse or age-related bone loss. Growth Plate and Mineral Metabolism 71 . The observation that heterozygous loss-offunction mutations in PTHLH result in a growth defect that is very similar to that observed in GNAS mutations suggests a particular importance for this component of the pathway in the growth of bones of the hands and feet. ranging from moderate shortening of individual metacarpals to a shortening of all bones in the hands and/or feet. Agilent Technologies). Haploinsufficiency of GNAS in mice results in premature differentiation of growth plate chondrocytes. Kruger G. Isolated brachydactyly type E (BDE) is characterized by a general shortening of metacarpals and metatarsals and/or phalanges. In a large pedigree with BDE. Blom E. a nonstop (X178WextX*54). Balanced bone formation and resorption occurs likely to preserve calcium homeostasis during hibernation while the bears recycle (instead of excrete) catabolic waste products. Conclusion: Loss-of-function mutations in PTHLH cause BDE with short stature.mundlos@charite. de Ravel T. via PTH and serotonin. Seemann P. One of the missense mutations was tested in chicken micromass culture with a retroviral expression system and was shown to result in a loss of function. In addition. Mutation analysis performed in these individuals identified two missense (L44P and L60P). The here characterized pedigree with BDE adds another condition to the PTHRP-pathway disease family.de Am J Hum Genet 2010. However. suggesting that the bone remodeling rate was not altered during hibernation.g. trabecular bone showed no differences in eroded surface or osteoid surface. Results: In a large pedigree with BDE.86:434–439 Background: Brachydactyly type E (BDE [MIM 113300]) is characterized by a general shortening of metacarpals and metatarsals and/or phalanges. The possible mechanisms could involve neuroendocrine control of bone remodeling and energy regulation. and a nonsense (K120X) mutation in PTHLH. the authors detected a microdeletion encompassing PTHLH. The phenotype is variable even within families. as well as with mutations in HOXD13 [MIM 142989] [5. BDE has been associated in sporadic cases with microdeletions of 2q37. thus resembling the phenotype described for PTHRP/ PTH receptor as well as for PTHLH-deficient mice [7]. Koll R. short stature. PTHrP is known to regulate the balance between chondrocyte proliferation and the onset of hypertrophic differentiation during endochondral bone development. the authors performed array-based comparative genomic hybridization (array CGH) via a whole-genome oligonucleotide array (244K. Dathe K. the genetic cause of the great majority of BDE cases has remained unexplained. 6]. Weigel JF. Mundlos S Institut fur Medizinische Genetik. the authors detected a microdeletion of approximately 900 kb encompassing PTHLH. Brachydactylies are a family of limb malformations characterized by short hands and/or feet due to aplastic or hypoplastic skeletal elements. e. Methods: As submicroscopic aberrations are a known cause for congenital limb malformations and brachydactylies. including Turner syndrome. the gene coding for parathyroid hormone-related protein (PTHRP). Inactivation of PTHRP in mice results in short-limbed dwarfism due to premature differentiation of chondrocyte. Berlin. Important for clinical practice A new disease gene for brachydactyly Deletion and point mutations of PTHLH cause brachydactyly type E Klopocki E. or Albright hereditary osteodystrophy.

Methods: Chondrocytes were isolated from the resting zone of the distal femoral growth plate of 2-dayold neonatal Sprague-Dawley rats and cultured in monolayer or 3D pellets. The positive effects of IGF-1/IGF1R on chondrocyte proliferation and terminal differentiation was partially inhibited by Wnt antagonists. The Lerner Research Institute. 1.New mechanisms IGF-1 modulates thyroid hormone effects in the growth plate Thyroid hormone-mediated growth and differentiation of growth plate chondrocytes involves IGF-1 modulation of -catenin signaling Wang L. Conclusion: The authors conclude that interactions between thyroid hormone and -catenin signaling in regulating growth plate chondrocyte proliferation and terminal differentiation are modulated by IGF-1/ IGF1R signaling through both the Wnt and PI3K/Akt signaling pathways. and −catenin signaling pathways in regulating cell proliferation and terminal differentiation of growth plate chondrocytes.25:1138–1146 Background: Terminal differentiation of growth plate chondrocytes is in part regulated by thyroid hormone through modulation of the Wnt/ -catenin signaling pathway. T3 activated IGF-1/IGF1R signaling and IGF-1-dependent PI3K/Akt/GSK3 signaling in proliferative and prehypertrophic growth plate chondrocytes. Departments of Orthopaedic Surgery and Biomedical Engineering. Ohio. T3-mediated Wnt-4 expression. Schematic diagram of the proposed interactions between thyroid hormone. The Cleveland Clinic Foundation. USA ballocr@ccf. cell proliferation and terminal differentiation of growth plate chondrocytes were partially prevented by inhibitors of the IGF1R and PI3K/Akt signaling. Thyroid hormone IGF-1/IGF1R Wnt-4 PI3K/Akt GSK3 -catenin Cyclin D1 Runx2/cbfa1 Col10a1 Proliferation Terminal differentiation Fig. Results: The authors show that IGF-1 and IGF1R (adenovirus transfection) stimulate Wnt-4 expression and -catenin activation in growth plate chondrocytes. -catenin activation. 72 Terhi Heino/Dov Tiosano/Aneta Gawlik/Lars Sävendahl . Shao YY. IGF-1/IGF1R.org J Bone Miner Res 2010. Cleveland. Ballock RT Orthopaedic Research Center. Thyroid hormone is a known stimulator of IGF-1 receptor expression and IGF-1 has been described as a stabilizer of -catenin.

Results: In Atf4–/– growth plate. in turn regulating the transcription of -catenin responsive genes and subsequently promoting cell proliferation in the growth plate (fig. suggesting an autonomous function of Atf4 in chondrocytes during endochondral ossification. the typical columnar structure of proliferative chondrocytes was found to be disturbed. Li L. activating the -catenin signaling pathway through either the PI3K/Akt pathway or the Wnt pathway. IGF-1 signals via the type 1 IGF receptor (IGF1R).yang@vanderbilt. whereas the hypertrophic zone transiently expanded. TR 1 deleted mice have impaired Igf1r expression and IGF-1 signaling in the growth plate. At least partly this can now be explained by thyroid hormone interaction with IGF-1/IGF1R signaling in the growth plate. such as type II collagen (Col2a1). which is caused by a failure of Atf4–/– osteoblasts to achieve terminal differentiation and to synthesize type I collagen. The expression of Indian hedgehog (Ihh) was markedly decreased. was found to be normal. Atf4 is expressed in proliferative and prehypertrophic growth plate chondrocytes. Perrien DS. The investigators behind this paper have previously shown that inactivation of the transcription factor Atf4 in mice results in severe osteopenia. PTH/PTHrP receptor (Pth1r) and type X collagen (Col10a1). Thyroid hormone initially may stimulate IGF-1/IGF1R signaling in growth plate chondrocytes. including delayed ossification and low bone mass. They now present data supporting that IGF-1 is actively involved in the crosstalk between the Wnt/ -catenin and PI3K/Akt pathways in the regulation of growth plate chondrocyte proliferation and differentiation by thyroid hormone. Clinicians who initiate thyroxine treatment in hypothyroid children often observe a prominent catch-up growth soon after treatment start.edu Development 2009. New genes A novel activator of Ihh that paces bone growth Atf4 regulates chondrocyte proliferation and differentiation during endochondral ossification by activating Ihh transcription Wang W. reactivation of hedgehog signaling pharmacologically in mouse limb explants corrected the Atf4–/– chondrocyte proliferation and short limb phenotypes. forced expression of Atf4 in chondrocytes induced endogenous Ihh mRNA and Atf4 was found to directly bind to the Ihh promoter and activate its transcription. short stature and short limbs. The proliferative zone was found to be shortened. The authors also established Atf4-overexpressing chondrocytes. USA xiangli. Methods: Wild-type (WT) and Atf4–/– embryos and mice were obtained by crossing Atf4+/– mice. Growth Plate and Mineral Metabolism 73 . Lian N. Nashville. 1).Thyroid hormone is a systemic factor that potently regulates skeletal maturation in the growth plate and thyroid hormone receptor (TR. the main constituent of bone matrix [11]. This study reveals Atf4 as a crucial regulator of chondrogenesis and identifies Ihh as a transcriptional target of Atf4 in chondrocytes. Supporting these findings..136:4143–4153 Background: Ablation of activating transcription factor 4 (Atf4) in mice leads to severe skeletal defects. Tenn. suggesting that the IGF1R is a physiologic target for thyroid hormone action in the growth plate [9]. both are expressed in the proliferating and prehypertrophic zone chondrocytes of the growth plate [8]. Conclusion: The authors conclude that Atf4 acts as a novel transcriptional activator of Ihh in chondrocytes that paces longitudinal bone growth by controlling growth plate chondrocyte proliferation and differentiation. whereas the expression of other chondrocyte marker genes. decreased chondrocyte proliferation and an abnormally Bone. Vanderbilt University Medical Center. Elefteriou F. Yang X Vanderbilt Center for Bone Biology. Moss HE. The investigators behind this report reported previously that thyroid hormone interacts with Wnt/ -catenin signaling pathway in the terminal differentiation of growth plate chondrocytes [10]. Mice lacking Atf4 exhibit dwarfism and are characterized by markedly reduced growth plates.) and is essential for regulating the process of endochondrial ossification. Furthermore.

which. The features to look for are short stature associated with middle phalanges of all the digits that are rudimentary or fused with the terminal phalanges. and reduced bone growth in the presence of the NKCC inhibitor bumetanide. These phenotypic abnormalities are similar to those of Ihh–/– mice [12]. However. signified by a dramatic increase in volume. but not all patients. 74 Terhi Heino/Dov Tiosano/Aneta Gawlik/Lars Sävendahl . The Na-K-Cl co-transporter (NKCC) is well known to be activated in many cell types leading to cell volume increase. Damron TA. Conclusion: The authors conclude that NKCC contributes to the volume increase normally occuring in hypertrophic growth plate chondrocytes. The authors hypothesised that NKCC may be responsible for the volume expansion normally occuring in hypertrophic growth plate chondrocytes. BMP. This study reveals a novel mechanism by which Atf4 regulates chondrocyte proliferation and differentiation via upregulating Ihh expression.uk J Bone Miner Res 2010. Loqman MY. its cellular localisation. the mechanisms which drive growth plate HZ chondrocyte volume expansion are unknown.47 Background: The underlaying mechanisms of growth plate chondrocyte volume increase and bone lengthening are poorly understood. Edinburgh. with a ’reserve’ zone preceding proliferative zone (PZ) chondrocytes. It is also of great interest to study whether the same mechanisms are responsible for the bone defects seen in Atf4–/– mice. DOI 10. are reported to regulate chondrocyte proliferation and differentiation. Histological analysis showed that this was linked to a reduction in hypertrophic zone height. Methods: Metatarsals/metscarpals from 7-day-old rat pups (P7) were incubated in the presence/absence of the specific NKCC inhibitor bumetanide and whole bone lengths and histological analysis of growth plate measured after 24 h. P53. a mutated Aft4 should be considered when you see a patient with features of brachydactyly A1 (MIM #112500).ac. however. Hall AC Centre for Integrative Physiology. what upstream signals regulate Atf4 expression and activity and what downstream effector molecules of hedgehog signaling are controlling chondrocyte proliferation and differentiation. It remains unclear. UK p.g. Fluorescent NKCC was visualised by immunohistochemistry applying confocal laser scanning microscopy on rat (P7) tibial growth plates. and P58 rats. Igf1. Microarray analysis was performed on mRNA isolated from proliferative and hypertrophic zone cells of tibial growth plates from P49. University of Edinburgh. No human disease has so far been identified linked to a mutated Aft4. After a regulated period of time a marked differentiation occurs. Wnt and PTHrP families. in press. New concerns Loop diuretics may affect growth plate chondrocytes and bone growth A key role for membrane transporter NKCC1 in mediating chondrocyte volume increase in the mammalian growth plate Bush PG. microarray analysis showed an increase in NKCC1 mRNA between proliferative and hypertrophic cells. In addition.bush@brighton. The growth plate is highly organized. Based on the phenotypic similarities between Aft4 and Ihh mice. School of Biomedical Sciences. including members of the FGF. This statement was supported by data showing an increase of NKCC1 mRNA in hypertrophic zone cells. Whether they act on chondrocytes by modifying Atf4 activity remains to be determined. indicate that Atf4 and Ihh lie in the same genetic pathway regulating chondrogenesis during skeletal development. a disorder where a mutated ihh is found in some.1002/jbmr. The volume of a typical cell increases 15-fold in the HZ and it has been postulated that this cell volume increase occurs through a combination of classical hypertrophy and regulated volume expansion [13].expanded hypertrophic zone. Many extracellular regulators. Quantification of fluorescence immunohistochemistry demonstrated a significant transition of NKCC from the intracellular space of proliferative cells to the cytosolic membrane of hypertrophic cells. resulting in the formation of hypertrophic zone (HZ) chondrocytes. Results: Bumetanide resulted in a dose-dependent suppression of bone growth. Pritchard M. together with the dramatic decrease in Ihh expression observed in Atf4–/– growth plates.

which inhibited bone elongation by approximately 35%. However this is achieved at the expense of osteopenia and polycystic ovaries. Whole metatarsal/metacarpal rudiments were incubated with the loop diuretic bumetanide. De Schutter T. In addition. hitherto known to act in neuronal tissues. Indeed. in which sexually immature female rats were treated with the steroidal. Growth Plate and Mineral Metabolism 75 . It is important to point out that there are limited reports of skeletal growth retardation in children exposed to loop diuretics. furosemide). NKCC mediates electro-neutral ion transport. the Na-K-2Cl co-transporter (NKCC). the authors tested the hypothesis that NKCC1 is involved with HZ chondrocyte volume increase and longitudinal bone growth. GarciaSegura LM. irreversible aromatase inhibitor exemestane. a specific NKCC inhibitor. and is characterized by its sensitivity to loop diuretics (e. organ weights. Kremer Hovinga S. A control group was ovariectomized (OVX).73:49–60 Background: As a potential approach for growth enhancement in children with short stature aromatase inhibition has been proposed. The authors aimed to assess the effect and potential adverse effects of aromatase inhibition on growth in female rats. Postnov AA. it would be expected to be under the same hormonal control that regulates bone growth. Wit JM. the authors report the results of a study. Importantly. Further investigation is warranted to determine the regulatory control of NKCC in the mammalian growth plate and to the possible detrimental effect on bone growth with chronic exposure to loop diuretics in children. De Clerck N. but also resulted in multiple ovarian cysts and changes in bone archi- Bone. In the femur. Reduced growth might however go unreported due to the conditions which required prescription of loop diuretics. growth plate width. trabecular number and thickness were decreased in the metaphysis and epiphysis in both E100 and OVX rats. at least in female rats Marginal growth increase. the histology of ovaries. The main conclusion is that exemestane partially inhibits aromatase activity.van_gool@lumc.The intracellular sodium concentration ([Na+]i) plays a key role in determining cell volume. van Doorn J. is an obvious candidate for HZ chondrocyte expansion due to its ability to increase cell volume in other cell types [14]. the near ubiquitous NKCC1 and KCC2. No significant effects were found on IGF-I levels and brain morphology. uterus and brain were analyzed and X-ray microtomography was applied to the femur. Leiden. exemestane marginally increases growth in female rats. bumetanide. Results: At 100 mg/kg/week (E100). Methods: Prepubertal Wistar rats were given intramuscular injections with placebo or the aromatase inhibitor exemestane (10. In the present study. Karperien M Department of Pediatrics. but less prominently than OVX. and insulinlike growth factor I (IGF-I) levels were measured.g. and Na+ is moved across the cytoplasmic membrane through a range of transport proteins. Weight and length gain. where it demonstrates increased expression from the PZ to HZ [15]. altered bone quality and polycystic ovaries in female prepubertal rats after treatment with the aromatase inhibitor exemestane van Gool SA.nl Horm Res Paediatr 2010. The Netherlands s. Two NKCC isoforms are known. One of these. Conclusion: The authors conclude that at a high dose. Leiden University Medical Center. If NKCC plays a major role in HZ chondrocyte volume increase. NKCC has been shown to be regulated by cortisol in other tissue [16] but if this is the case also in the growth plate remains to be elucidated. In the present article. E100 significantly decreased ovarian weight and multiple cysts were seen upon histological evaluation. Although considered to be present in all tissues only mRNA for NKCC1 has been reported in growth plates. exemestane significantly increased weight gain and growth plate width. New concerns Aromatase inhibition may cause osteoporosis and polycystic ovaries. tibia and femur length. 30 or 100 mg/kg/week) for 3 weeks. Veiga SJ. which caused only a marginal length gain and appendicular growth.

pronounced adverse effects were found in ovarian histology and bone architecture. Division of Nutrition. BMI before pregnancy. 42. The objective of this paper was to determine the association of mothers’ vitamin D status with bone variables of their newborns. was used as cutoff to define two equal-sized groups (below or above median). Hytinantti T. However. and it remains unclear whether these would have long-term permanent consequences for reproduction and fracture risk. bone mineral content (BMC). and bone remodeling markers. respectively. low maternal 25-OHD may be responsible for prematurity and in late pregnancy is associated with reduced intrauterine long bone growth and slightly shorter gestation [19]. Surcel H.01). Miettinen M. promote adequate calcium supplementation to the fetus. Results: The median value of the individual means for first trimester and 2-day postpartum 25-OHD level. Methods: 125 pregnant women participated in a longitudinal follow-up. However. treatment with aromatase inhibitors in girls in clinical practice should not be advised.95:1749–1757 Background: Maternal vitamin D status may program neonatal skeletal development.3 mm2 larger (p = 0. tibia BMC was 0.6 nmol/l. 23.tecture consistent with early-stage osteopenia. Blood was collected from mothers during the first trimester and 2 days postpartum. Follow-up on a YB 2009 paper Time for new nutritional recommendations for pregnant women? Maternal vitamin D status determines bone variables in the newborn Viljakainen HT. Moreover.6 nmol/l had higher tibial bone mineral content and higher cross-sectional area but not bone mineral density (BMD). It confirmed that newborns whose mothers had mean 25-OHD levels above 42.3 µg. Although aromatase inhibition was probably incomplete. considering the potential side effects on bone physiology and morphology of the ovaries.viljakainen@helsinki. and 60% were boys.3 µg. and from umbilical cords at birth for analysis of 25-hydroxyvitamin D (25-OHD).05). Moreover. most of the mothers were vitamin D deficient throughout pregnancy.5 kg/m2. the results suggest that maternal vitamin D status affects bone mineral accrual during the intrauterine period and influences bone size. Maternal vitamin D status during pregnancy may program skeletal development [17] and body composition in the offspring [18]. Saarnio E. such as PTHrP. The fact that BMD was not affected by maternal vitamin D status implies that in utero other hormones. and CSA was 12. and cross-sectional area (CSA). It is obvious that these recommendations need to be updated and adapted to modern lifestyle (indoors) and desired serum levels.02). Species differences in dependency on estrogen signaling probably underlie the discrepancies found in growth phenotype between these aromatase inhibitor treated rats and estrogen-deficient patients described in the literature. Laitinen K. It is important to emphasize that the average maternal intake of vitamin D in the study group was 14.fi J Clin Endocrinol Metab 2010. and 14. Andersson S. pregnancy weight gain. Lamberg-Allardt C Department of Applied Chemistry and Microbiology. but no difference in BMD was observed above median compared with below median group. respectively. Helsinki. 76 Terhi Heino/Dov Tiosano/Aneta Gawlik/Lars Sävendahl . Conclusions: The data showed that although the mean total intake of vitamin D among mothers met current Nordic recommendations. Bone variables were measured by pQCT on average 10 days postpartum. Makitie O. including effects on bone health throughout life. Vitamin D regulates 3% of the human genome. Finland heli.047 g/cm higher (p = 0. University of Helsinki. However. despite this. The mean values for age. 71% of women and 15% of newborns were vitamin D deficient during the pregnancy. and total daily vitamin D intake in mothers were 31 years. 13. PTH. by influencing the interaction between osteoblasts and adipocytes. Newborns of mothers with levels below median were heavier (p = 0. which meets current Nordic recommendations for pregnant women (10 µg or 400 IU).1 kg. Bone contour was analyzed for the detection of total bone mineral density (BMD). which is secreted from the mammary glands and the placenta. This study examined the effect of maternal vitamin D status on skeletal variables of newborns.

Conclusion: ENPP1 was identified as the fourth gene. Now we learn that mutations in the ENPP1 gene can cause either of two diseases – generalized arterial calcification of infancy (GACI) or hypophosphatemic rickets. Chalifa-Caspi V. Interestingly. and DMP1. the authors identified a candidate region on chromosome 6q23. FGF23 and DMP1 mutations. Using homozygosity mapping. Methods: An extended Bedouin family with hypophosphatemic rickets and 236 Bedouin control individuals of the same geographic region were investigated by homozygous mapping. In some cases. Pyrophosphate is the major hydroxyapatite inhibitor. Buriakovsky S. the same mutation seems responsible for these two entities. Manor E. Results: A loss-of-function mutation in the ENPP1 gene was found in members of four families affected with hypophosphatemic rickets. among them the ENPP1 gene. and autosomal-recessive patterns. In children with GACI who survived. Last year we discussed hypophosphatemia as the common denominator of all rickets [20]. Avizov L. Bercovich D. reductions in phosphorous levels and in Tmp/GFR were observed during the second year of life. Methods: The cohort comprised 60 index cases with hypophosphatemia who were found negative for PHEX. Germany timstrom@helmholtz-muenchen. Strom TM Institute of Human Genetics. Goding J. and possible additional functions for ENPP1. while evoking unresolved questions.ac. The three main causes for hypophosphatemia are high PTH. Leventhal N. following PHEX. Growth Plate and Mineral Metabolism 77 . Results: The authors identified an inactivating mutation in the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene causing autosomal-recessive hypophosphatemic rickets (ARHR). Ben Gurion University of the Negev. and is accompanied by excessive secretion of collagen type I to produce the primary bone elements. hypophosphatemic rickets resulting from elevated FGF23 levels. Conclusion: These results suggest a different pathway involved in the generation of ARHR. FGF23 was ele- Bone. Neuherberg. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene Levy-Litan V. In the absence of pyrophosphate.de Am J Hum Genet 2010. Schnabel D. hydroxyapatite production is accelerated. comprising approximately 35 genes. Tiosano D. since it has been reported to occur in some patients with generalized arterial calcification of infancy (GACI). autosomal-dominant. German Research Center for Environmental Health. FGF23. Israel ruthi@bgu. FGF23.New genes New gene involved in hypophosphatemic rickets Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets Lorenz-Depiereux B. Hausler G. Hadad Y.86:267–272 Background: The analysis of rare genetic disorders affecting phosphate homeostasis has led to the identification of several proteins essential for the renal regulation of phosphate homeostasis as FGF23. Faculty of Health Sciences. respectively. Beer Sheva. as discussed in the article by Lorentz-Depiereux et al. ENPP1 encodes the NPPI enzyme that generates pyrophosphate from ATP in the external cellular matrix. to cause.il Am J Hum Genet 2010. presenting as X-linked recessive. The authors considered ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1) as a causal factor of hypophosphatemia. These two papers extend our knowledge of hypophosphatemic rickets. if mutated. elevation in FGF23 and renal P loss. and DMP1.86:273–278 Background: Human disorders of phosphate handling and hypophosphatemic rickets have been shown to result from mutations in PHEX. Hershkovitz E. Parvari R Department of Developmental Genetics and Virology. Helmholtz Zentrum Munchen.

Takahashi N. Furuyashiki T. lymph node organogenesis and formation of a lactating mammary gland. Pifl C. OPGL. Two patients with autosomal-recessive osteopetrosis were also included in the study. The function of RANK in the fever response was genetically mapped to astrocytes. Hanada T. In male mice loss of RANK in neurons had no significant effect on basal circadian body temperatures while genetic inactivation of RANK in female mice brain resulted in altered physiological thermoregulation that is regulated also by ovarian sex hormones. suggesting that RANKL and RANK control thermoregulation during normal female physiology. Surprisingly. Narumiya S. Mechanism of the year RANKL/RANK as key thermoregulators – link between bone physiology and central control of body temperature and fever Central control of fever and female body temperature by RANKL/RANK Hanada R. Ueta Y. Background: In the last years we have learned that RANKL and RANK play a major role in the activation of osteoclasts.oeaw. Vienna. Nestin-Cre and GFAP-Cre rank(floxed) deleter mice were resistant to lipopolysaccharide-induced fever as well as to fever in response to the key inflammatory cytokines IL-1 and TNF. However. central RANKL injections triggered severe fever. exhibiting an impaired fever response to pneumonia.at Nature 2009. in the absence of RANK activity. Trichereau J. Paolino M. as well as to fever in inflammation. Kilic SS. It is still not clear why in some patients the main phenotype is GACI. Bader M. Qadri F.. female NestinCre and GFAP-Cre rank(floxed) mice exhibited increased basal body temperatures. In this elegant study the authors have shown that RANK is a critical mediator of fever in response to inflammation in mice. Komnenovic V.462:505–509 Receptor-activator of NFligand (TNFSF11. Penninger JM IMBA.ac. In addition. von Haeseler A.vated. Fujihara H. Yoshimatsu H. also known as RANKL. and in others hypophosphatemic rickets. Results: In both mice and rats. Now we learn that RANK protein is also specifically expressed in the preoptic area (POA) and the medial septal nucleus (MSn). suggests that RANKL/RANK regulates fever also in humans. 2 patients with RANK mutations were found to exhibit impaired fever response during pneumonia. osteopetrosis develops. Austria josef. Kitaoka S. it was shown that the RANKL/RANK regulate formation of lactating mammary gland during pregnancy [21]. RANKL activated brain regions involved in thermoregulation and induced fever via the COX2-PGE2/EP3R pathway. Leibbrandt A. Moreover. Mimata H.penninger@imba. 78 Terhi Heino/Dov Tiosano/Aneta Gawlik/Lars Sävendahl . Institute of Molecular Biotechnology of the Austrian Academy of Sciences. It directly connects bone physiology to the central control of female body temperature. Klaere S. Conclusion: The data identify a novel function for the important osteoclast differentiation factors RANKL/ RANK in female thermoregulation. RANKL and RANK are also expressed in the central nervous system. Importantly. Methods: In this study tissue-specific Nestin-Cre and GFAP-Cre rank(floxed) deleter mice were used. the clinical observation in 2 siblings with homozygous RANK mutation and severe osteopetrosis. TRANCE and ODF) and its tumor necrosis factor (TNF)-family receptor RANK are essential regulators of bone remodeling. Plehm R.

Methods: They synthesized an inhibitor of tryptophan hydroxylase-1. whereas the osteoclast surface per bone surface was unaffected. and thereafter were intercrossed. Gershon MD. Liu ZW. USA gk2172@columbia. axonal tracing. Liu XS. Tecott LH. Gao XB. immunohistochemistry. The same is true for its regulation of appetite and energy expenditure. Results: Oral administration of this small molecule once daily for up to 6 weeks acted as a bone metabolic agent fully rescuing gonadectomy-induced bone loss. Conclusion: The authors concluded that these results provide a proof of principle that inhibiting gutderived serotonin biosynthesis could become a new bone anabolic treatment for osteoporosis. and this small molecule was orally administered once daily for up to 6 weeks in ovariectomized rodents. and appetite via Htr1a and 2b receptors on arcuate neurons.Y. Leptin inhibits these functions and increases energy expenditure because it reduces serotonin synthesis and firing of serotonergic neurons. Serotonin is probably the first example of a molecule whose influence on bone mass accrual depends on the site of synthesis: Gut-derived serotonin inhibits bone mass while brainstem-derived serotonin (BDS) favors bone density. Vidal M. Medhamurthy R. Li Z.. Guo XE. Columbia University Medical Center. Oury F.138:976–989 Background: Leptin inhibition of bone mass requires the integrity of specific hypothalamic neurons but not expression of its receptor on these neurons. Lu X. Results: The authors showed that brainstem-derived serotonin (BDS) favors bone mass accrual following its binding to Htr2c receptors on ventromedial hypothalamic neurons. in situ hybridization. Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis Yadav VK. Growth Plate and Mineral Metabolism 79 . Karsenty G. acting as a neurotransmitter. appetite. USA pd2193@columbia. N. deoxypyridinoline in the serum and urinary elimination of catecholamines were performed. demonstrated that leptin inhibits serotonin synthesis in Thp2 (tryptophan Bone. accounts for only about 5% of the total pool of serotonin in the body. Conclusion: The authors conclude that their study modifies the map of leptin signaling in the brain and identifies a molecular basis for the common regulation of bone and energy metabolism. The rescue was due to an increase in osteoblasts number and bone formation rate. Balapure AK. BDS decreases sympathetic activity.New paradigms Serotonin regulates bone mass accrual in opposite directions depending on the site of synthesis A serotonin-dependent mechanism explains the leptin regulation of bone mass.. Just the opposite. New York. For further analyses. Hen R. and energy expenditure Yadav VK. Suresh PS. Mann JJ. the initial enzyme in GDS biosynthesis. Methods: In this study.edu Cell 2009. Ducy P Department of Genetics and Development. This suggests that leptin acts elsewhere in the brain to achieve these three functions. its influence on bone remodeling is dominant over gut-derived serotonin (GDS).Y.16:308–312 Background: As gut-derived serotonin (GDS) inhibits bone formation. mice were generated by embryonic stem cell manipulation to obtain Tph2+/– (tryptophan hydroxylase-1). Columbia University. the authors asked whether hampering its biosynthesis could treat osteoporosis through an anabolic mechanism. We emphasize that although BDS. Tanaka KF. Balaji S. Gingrich JA. Guo XE. Confavreux C. New York. Mann JJ. Suda N. Klemenhagen KC. In this paper Yadav et al. It has been shown in the past that leptin inhibits bone mass accrual by the activation of the sympathetic activity. These two papers demonstrate the complexity of bone mass regulation by serotonin. Horvath TL.edu Nat Med 2010. Karsenty G Department of Genetics and Development. and microcomputed tomography as well as measurement of serotonin levels in the brain. N.

Sävendahl L: Growth Plate. pp 53–69.Brainstem Hypothalamus Serotonin Htr2c Leptin Htr1a Htr2b Adipocytes Appetite Bone mass Htr1b Osteoblast Serotonin Creb Enterochromaffin cell Tph1 Bone Decreased osteoblast proliferation Duodenum Fig. Bertin TK. 2. Hum Mutat 2008. hydroxylase 2) expression neurons. 80 Terhi Heino/Dov Tiosano/Aneta Gawlik/Lars Sävendahl . Bone and Calcium. Heino T.29:1435–1442. Schwarze U. et al: CRTAP and LEPRE1 mutations in recessive osteogenesis imperfecta. as well as the lack of haversian remodeling in the former. Morello R. 2). 2. Pace JM. Basel. Depending on site of synthesis. This biology is now harnessed with an orally available inhibitor of gut serotonin synthesis that promotes bone formation in rodents without altering brain serotonin [22] which highlights the significance of serotonin as a modulator of bone metabolism (fig. Lennington J. Rodents grow throughout their lives and do not remodel their cortical bone. Chrysis D. these results need be confirmed in humans. References 1. 2007. serotonin regulates bone mass in opposite directions: duodenum-derived serotonin acts on osteoblasts through the Htr1b receptor and Creb (cAMP response element binding. in Carel J-C. In the second paper. transcription factor) response to inhibit their proliferation while brainstem-derived serotonin favors bone mass accrual following its binding to Htr2c receptors on ventromedial hypothalamic neurons and appetite via Htr1a and 2b receptors on arcuate neurons [23]. Considering the lower rate of bone remodeling in rodents. and can fully rescue gonadectomy-induced bone loss. the authors show that an inhibitor of GDS synthesis acts as a bone anabolic agent. The net effect is activation of the sympathetic system to reduce bone mineral density. as compared to humans. Karger. Hochberg Z (eds): Yearbook of Pediatric Endocrinology 2007. Baldridge D.

Kawaguchi H. 8. Ambrogini E. Morley R. 9. 5.94:765–771. Morley R: Maternal vitamin D in pregnancy may influence not only offspring bone mass but other aspects of musculoskeletal health and adiposity. Kiilerich P. 22. J Cell Physiol 2008.22:1988–1995. Bialek P. Damron TA: Microarray analysis of proliferative and hypertrophic growth plate zones identifies differentiation markers and signal pathways. Gingrich JA. Moorehead RA. 13.194:31–40. 14. Weinstein LS. 23. Horton JA. Russell JM: Sodium-potassium-chloride cotransport. Irie-Sasaki J. Almeida M. Cell 2008. Wang L. McMahon AP: Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Physiol Rev 2000. Wang Y. Johnson D. Shao YY. Kong YY. Barnes KM. Hall AC: The osmotic sensitivity of rat growth plate chondrocytes in situ. 7.91:906–912.56:400–407. J Endocrinol 2007. Oude Luttikhuis ME. et al: Missense mutations in the homeodomain of HOXD13 are associated with brachydactyly types D and E. Ying H.11:136–146. Whitson HE. J Bone Miner Metab 2009. implication for Coffin-Lowry syndrome. Cell Metab 2010. Madsen SS: Cortisol regulation of ion transporter mRNA in Atlantic salmon gill and the effect of salinity on the signaling pathway. J Clin Endocrinol Metab 2006. Ponsonby AL. Pasco JA. et al: Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. 21. Flint J. Bastepe M. 19. Bone 2004. et al: The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Papaioannou A. Parker EA. Kristiansen K. Kan SH.13:2072–2086. et al: ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology. 20.27:392– 401. Paik JH. Wolstenholme J. J Bone Miner Res 2007. et al: Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo. Kronenberg HM. Wark JD. Hammerschmidt M. Proc Natl Acad Sci USA 2004. Wilson LC. Oley CA. Cheng SY.194:417–427. Med Hypotheses 2008. Adachi JD. Richards JB.214:621–629. Editorial: Method of the Year 2009. Fata JE. Bone. Schinke T. Masuoka HC. Cell 2004. Ryu JH. Matsuda K. Sayers A. Trembath RC.3.80:211–276. 17. clarifying the mechanisms of hypertrophy. Esnouf RM. Suda N. St-Jacques B. Arch Intern Med 2007. Li J.72:984–997. Hegde A. et al: FoxO-mediated defense against oxidative stress in osteoblasts is indispensable for skeletal homeostasis in mice.117:387–398. Bassett JH.167:188–194. Ogata N.71:266– 269.101:14794– 14799. 11. Cell 2000. Farnum CE. Juppner H. Hochberg Z: Hypophosphatemia: the common denominator of all rickets. Roche P. Oldridge M. Nat Methods 2010. 4. Carlin JB. 12. J Endocrinol 2007. Am J Hum Genet 2003. et al: Brachydactyly and mental retardation: an Albright hereditary osteodystrophy-like syndrome localized to 2q37. Ballock RT: Thyroid hormone interacts with the Wnt/ -catenin signaling pathway in the terminal differentiation of growth plate chondrocytes. Sasaki T. Parisinos CA.19:3045–3059. J Clin Endocrinol Metab 2009. O’Shea PJ. Yang X. Vuillermin PJ. Baron J.135:825–837.35:1273–1293. 16. Joseph L. Bush PG. Reichel L. Han L. Yadav VK.7:1. Prior JC. Tiosano D. Genes Dev 1999. 18. 6. 10. Jacquot S. Pasco JA. Growth Plate and Mineral Metabolism 81 . Wark JD: Maternal 25-hydroxyvitamin D and parathyroid hormone concentrations and offspring birth size. Tanaka KF. Am J Hum Genet 1995. Tobias JH: Estimated maternal ultraviolet B exposure levels in pregnancy influence skeletal development of the child. Schutz G. et al: Effect of selective serotonin reuptake inhibitors on the risk of fracture. Buckley M. Middleton F.103:41–50. Carlin JB. Martin-Millan M. Williams GR: Contrasting skeletal phenotypes in mice with an identical mutation targeted to thyroid hormone receptor 1 or . Sriskantharajah S. Depinho RA. Leverton K. Nilsson O: Spatial and temporal regulation of GH-IGF-related gene expression in growth plate cartilage. 15. Mol Endocrinol 2005.

we hope you will find them enjoyable to read and some provocative and helpful for your activity in the pediatric endocrinology arena.. endocrine pharmacology. possible adverse effect caused by use of aromatase inhibitors for short stature. inflammation. some which we might have missed in our search of the area and yet others which were not possible to include due to space limitation. as well as reduced numbers of muscle fiber and/or diameter. Important for clinical practice/new concerns in obesity Maternal obesity. (2) inflammation inhibits AMP-activated protein kinase. Although the present selection of papers obviously represents our own bias. persistent effects on offspring. reproductive behavior. This years’ chapter includes references to recent papers on reproductive concerns of parental obesity. Department of Women’s and Children’s Health. including predisposition to obesity and type 2 diabetes. Stockholm. Its development involves myogenesis. and the commitment of fetal mesenchymal stem cells. all of which have lasting negative effects on offspring muscle function and properties. which promotes adipogenesis. Tong JF. adipogenesis. leading to harmful. which attenuates myogenesis. Wyo. Zhao J. Laramie.edu Biol Reprod 2010. Shifting commitment of mesenchymal stem cells from myogenesis to adipogenesis and fibrogenesis will result in increased intramuscular fat and connective tissue. USA mindu@uwyo. Conclusion: More studies are needed to further explore the underlying mechanisms associated with maternal obesity. Yan X. which are all derived from mesenchymal stem cells. Results: Maternal obesity leads to low-grade inflammation. puberty. assisted reproduction technologies. Zhu MJ Department of Animal Science. therefore the fetal stage is crucial for skeletal muscle development. and many more. and (3) inflammation may induce epigenetic modification through polycomb group proteins. and fibrogenesis. gonadal physiology. Karolinska Institutet and Karolinska University Hospital. changes in the properties of offspring skeletal muscle and its mass resulting from maternal obesity may be responsible for the increase in type 2 diabetes and obesity. Methods: Since skeletal muscle is the principal site for glucose and fatty acid utilization and composes 40–50% of total body mass. . There were of course several other excellent papers published in these areas during the past year. Sweden Reproductive endocrinology is a wide field encompassing areas such as germ stem cell biology. and fetal skeletal muscle development Du M. There is no net increase in the muscle fiber number after birth. guidelines on endocrine treatment of transsexual adolescents. Astrid Lindgren Children’s Hospital.Reproductive Endocrinology Olle Söder and Lena Sahlin Paediatric Endocrinology Unit. inflammation.82:4–12 Background: Maternal obesity coupled with Western-style and high-energy diets represents a special problem that can result in poor fetal development. changing the commitment of mesenchymal stem cells in fetal muscles through several possible mechanisms: (1) inflammation down-regulates wingless and int (WNT) signaling. University of Wyoming. and many other topics of great interest for pediatric endocrinologists.

Maternal metabolism and obesity: modifiable determinants of pregnancy outcome
Nelson SM, Matthews P, Poston L Division of Developmental Medicine, Reproductive and Maternal Medicine, Faculty of Medicine, University of Glasgow, Glasgow, UK s.nelson@clinmed.gla.ac.uk Hum Reprod Update 2010;16:255–275
Background: Obesity among pregnant women is highly prevalent worldwide and is associated in a linear manner with markedly increased risk of adverse outcome for mother and infant. The role of maternal metabolism in determining these outcomes and the potential for lifestyle modification are largely unknown. Methods: Studies were identified by searching PubMed, the metaRegister of clinical trials and Google Scholar without limitations. Sensitive search strategies were combined with relevant medical subject headings and text words. Results: Maternal obesity and gestational weight gain have a significant impact on maternal metabolism and offspring development. Insulin resistance, glucose homeostasis, fat oxidation and amino acid synthesis are all disrupted by maternal obesity and contribute to adverse outcomes. Modification of lifestyle is an effective intervention strategy for improvement of maternal metabolism and the prevention of type 2 diabetes and, potentially, gestational diabetes. Conclusion: Maternal obesity requires the development of effective interventions to improve pregnancy outcome. Strategies that incorporate a detailed understanding of the maternal metabolic environment and its consequences for the health of the mother and the growth of the child are likely to identify the best approach.

Maternal and paternal obesity has a known negative impact on fertility and pregnancy outcome. The two selected papers show a need of pre-maternity advice on lifestyle factors, since a reduction in weight will reduce the risk of negative effects on the child, but also increase the likelihood of becoming pregnant [1]. The impact of obesity and the low-grade inflammation on mesenchymal stem cells with potentially negative effects on offspring muscle function and metabolism need further investigation. A meta-analysis aimed at determining if paternal factors like semen parameters and reproductive hormones are affected by obesity [2]. The authors found no relation between increased BMI and semen parameters, but strong evidence of a negative relationship for testosterone, SHBG and free testosterone with increased BMI. A significantly higher number of embryos with a normal karyotype were found in miscarriages of overweight and obese women as compared to normal weight women. The results indicate that the excess risk of miscarriages in the overweight and obese population is independent of embryonic aneuploidy [3]. A recent comment in Biology of Reproduction [4] stated that the high incidence of obesity may aggravate adverse effects of environmental pollutants. Many of these environmental toxicants are lipophilic and thus stored and accumulated in fat tissue. An increased fat mass will therefore increase the toxic dose in obese individuals. Paradoxically, such toxic effects may increase during weight loss when compounds stored in fat are released to the systemic circulation. Combined interaction of reproductive toxicants and obesity is indicated to be additive [5], which predicts an increased need for assisted reproductive technologies (ART) in the future. Of great concern with such development is that more children may be at risk to be born with birth defects and possibly imprinting disorders [6]. A likely explanation for the abnormalities in children born after ART is the link to an altered embryonic epigenome [7]. Preventive measures at the population level and with focus on risk groups, like education in the importance of lifestyle factors, are of great importance for future reproductive health and favorable pregnancy outcome.

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Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline
Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, Gooren LJ, Meyer WJ, 3rd, Spack NP, Tangpricha V, Montori VM The Endocrine Society, Chevy Chase, Md., USA J Clin Endocrinol Metab 2009;94:3132–3154
Background: The aim was to formulate practice guidelines for endocrine care and treatment of transsexual persons including children. Methods: An evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and the quality of evidence, which was low or very low. Results: Committees and members of The Endocrine Society, European Society of Endocrinology, European Society for Paediatric Endocrinology, Lawson Wilkins Pediatric Endocrine Society, and World Professional Association for Transgender Health commented on preliminary drafts of these guidelines. Conclusions: Transsexual persons seeking to develop the physical characteristics of the desired gender require a safe, effective hormone regimen that will (1) suppress endogenous hormone secretion determined by the person’s genetic/biologic sex and (2) maintain sex hormone levels within the normal range for the person’s desired gender. A mental health professional must recommend endocrine treatment and participate in ongoing care throughout the endocrine transition and decision for surgical sex reassignment. Because a diagnosis of transsexualism in a prepubertal child cannot be made with certainty, the authors do not recommend endocrine treatment of prepubertal children. They recommend treating transsexual adolescents (Tanner stage 2 or later) by suppressing puberty with GnRH analogues until age 16 years, after which cross-sex hormones may be given under strict criteria. They suggest suppressing endogenous sex hormones, maintaining physiologic levels of gender-appropriate sex hormones and monitoring for known risks in adult transsexual persons.

Psychosexual identity is probably the most important part of the individual’s sex and gender complex. Still, we know very little about its underlying biology and disorders, and the diagnostic criteria of gender identity disorders (GID) are based on a weak evidence base. This guidelines paper is therefore an important tool for pediatric endocrinologists caring for children with GID. An increasingly high number of adolescents with GID are referred to many centers, probably due to greater awareness of the condition and changes in healthcare-seeking behavior. Although the diagnostic work-up of GID is mainly psychiatric, the pediatric endocrinologist has an important role as a team member not only in the pharmacological treatment but also in the initial phase to exclude a cryptic DSD. GID patients and particularly adolescents create many challenges for the physician and it is therefore especially important to have evidence- and experience-based guidelines to consult for the daily routine.

Food for fertility...

Childhood nutrition and later fertility: pathways through education and pre-pregnant nutritional status
Graff M, Yount KM, Ramakrishnan U, Martorell R, Stein AD Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, N.C., USA migraff@email.unc.edu Demography 2010;47:125–144
Background: Better childhood nutrition is associated with earlier physical maturation during adolescence and increased schooling attainment. However, as earlier onset of puberty and increased schooling can have opposing effects on fertility, the net effect of improvements in childhood nutrition on a woman’s fertility are uncertain.

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Methods: Using path analysis, the strength of the pathways was estimated between childhood growth and subsequent fertility outcomes in Guatemalan women followed prospectively since birth. Results: Height for age z score at 24 months was positively related to body mass index (BMI) and height in adolescence and to schooling attainment. BMI was negatively associated and schooling was positively associated with age at first birth. Total associations with the number of children born were positive with BMI and negative with schooling. Height was not related to age at first birth or the number of children born. Conclusions: In summary, childhood nutrition, as reflected by height at 2 years, was positively associated with delayed age at first birth and fewer children born. If schooling is available for girls, increased growth during childhood will most likely result in a net decrease in fertility.

This investigation links early childhood nutritional aspects with later fertility parameters in an underprivileged society. The paper shows that a well-nourished girl (as determined by height at 2 years) spends more time at school, postpones the birth of her first child and also that she will have fewer children. If the girl has an increased BMI (is overnourished) she will give birth earlier and also have more children, and spend less time at school. Although there are obvious questions as to who is the hen and who is the egg for several associations described, the long-term prospective nature of this paper makes it quite valuable.

An old concern maintained – bisphenol-A

Neonatal bisphenol-A exposure alters rat reproductive development and ovarian morphology without impairing activation of gonadotropinreleasing hormone neurons
Adewale HB, Jefferson WN, Newbold RR, Patisaul HB Department of Biology, North Carolina State University, Raleigh, N.C., USA Biol Reprod 2009;81:690–699
Background: Developmental exposure to endocrine-disrupting compounds (EDCs) is hypothesized to adversely affect female reproductive physiology by interfering with the organization of the hypothalamic-pituitary-gonadal axis. Methods: The effects of neonatal exposure to two environmentally relevant doses of bisphenol-A (BPA) was compared with the ER -selective agonist PPT on the development of the female rat hypothalamus and ovary. Oil vehicle and estradiol benzoate (E2) were used as negative and positive controls, respectively. Results: Exposure to E2, PPT, or the low dose of BPA advanced pubertal onset. A total of 67% of females exposed to the high BPA dose were acyclic by 15 weeks after vaginal opening compared with 14% of those exposed to the low BPA dose, all of the E2- and PPT-treated females, and none of the control animals. Ovaries from the E2-treated females were undersized and showed no evidence of folliculogenesis, whereas ovaries from the PPT-treated females were characterized by large antral-like follicles, which did not appear to support ovulation. Severity of deficits within the BPA-treated groups increased with dose and included large antral-like follicles and lower numbers of corpora lutea. Fos induction in hypothalamic gonadotropic (GnRH) neurons after hormone priming was impaired in the E2- and PPT-treated groups but neither of the BPA-treated groups. Conclusion: These data suggest that BPA disrupts ovarian development but not the ability of GnRH neurons to respond to steroid-positive feedback.

The research field of endocrine-disrupting compounds is controversial and the risks of exposure to bisphenol-A have been particularly debated. This paper adds novel hard data to the field. Previously, bisphenol-A has been shown to affect the regulation of vascular endothelial growth factor in rat uterine endothelial cells thus affecting fertility. In addition, the severity of reproductive tract deficits within neonatally bisphenol-A-treated animals increased with the dose of bisphenol-A and included large antral-like follicles and lower numbers of corpora lutea. The present results demonstrate that

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bisphenol-A disrupted ovarian development but not the ability of GnRH neurons to respond to steroid-positive feedback. Thus, this endocrine-disrupting compounds is primarily affecting fertility at the gonadal level. A recent review by Hunt et al. [8] discusses, in light of the ‘bisphenol-A saga’, the importance to analyze environmental factors to determine their potential effects on reproduction in mammals – in order to preserve reproductive health.

Food for thought Sex without reproduction – reproduction without sex

Sex and reproduction: an evolving relationship
Benagiano G, Carrara S, Filippi V Department of Obstetrics and Gynaecology, Sapienza University, Rome, Italy giuseppe.benagiano@uniroma1.it Hum Reprod Update 2010;16:96–107
Background: Technological advances now allow for both sex without reproduction and reproduction without sex. This review summarizes social and ethical commentaries on the new relationship between sex and reproduction. Methods: This is a literature study where a systematic search was made using PubMed, Medline, ScienceDirect, classic books, Google and/or religious websites. The search focused on publications between 1975 and 2009, but some older materials were also utilized. Results: The classic picture of sex for reproduction and bonding between mating partners is increasingly being replaced by reproduction separate from sexual activity. Although not every advance in assisted reproduction resulted in a further separation from sexual intercourse, these two fundamental human activities are today increasingly carried out independently. Thus, reproduction is possible, not only without sex, but even through the intervention of more than two partners. The possibility of reproduction with only one or even no gametes, although highly controversial and not yet feasible, is nonetheless being investigated. Conclusion: Technological advances in the field of reproductive biology have enabled couples considered infertile to conceive and have healthy babies, causing a revolution in culture and customs. The independence of sex and reproduction is now established and in the future human reproduction may move even further away from the sexual act, an option definitely unacceptable to some ethicists.

Since more and more children are conceived in a laboratory setting rather than during parental intercourse, a need for increasing awareness is needed in examination of these children for adverse effects from advanced ART. The effect on the genome, transferred though generations, is a risk that should not be ignored [6, 7]. As fantastic as the prospect to give infertile couples the possibility of parenthood, the awareness of potentially adverse, maybe subtle, effects in their children must be brought to attention and any deviations reported. As a consequence of obesity as discussed above, an increased need for ART is evolving in parallel with the increased incidence of obesity in a large part of the world. The accumulation of endocrine disrupting compounds (EDCs) in fat and their potentially detrimental effect on fertility point to the risk of the combination of obesity, EDCs and ART to set the scene for a dim scenario for future generations.

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Concepts revised – a female (hormone) behind the man

The androgen receptor governs the execution, but not programming, of male sexual and territorial behaviors
Juntti SA, Tollkuhn J, Wu MV, Fraser EJ, Soderborg T, Tan S, Honda S, Harada N, Shah NM Graduate Program in Neuroscience, University of California, San Francisco, Calif., USA Neuron 2010;66:260–272
Background: Testosterone and estrogen are essential for male behaviors in vertebrates. How these two sex steroid and their signaling pathways interact to control masculinization of the brain and behavior is not known. Circulating testosterone activates the androgen receptor (AR) and also serves as a substrate for local production of estrogen in the brain. Methods: AR was specifically deleted in the mouse nervous system. This approach permitted determination of the function of AR in sexually dimorphic behaviors in males while maintaining circulating testosterone levels within the normal range. Results: The AR mutant males were found to exhibit masculine sexual and territorial displays, but to have striking deficits in specific components of these behaviors. The mutant mice were for example less likely to initiate mating and spent less time fighting to protect their home cage, as compared to the wildtype mice. Conclusions: Taken together with the very limited expression of AR in the developing brain, these results indicate that testosterone most probably acts as a precursor to estrogen to masculinize the brain and behavior. The AR mutant mice exhibited striking deficits in the pattern and extent of male sexual and territorial behaviors. AR is not essential for the masculinization of mating, aggression and urine marking, but rather serves to amplify the display of this behavioral repertoire in males.

For decades the dominating concept has been that the male fetus is masculinized by a prenatal androgen surge [9]. This new evidence using genetically modified mice shows that animals lacking AR in the brain do develop male sexual and territorial behaviors. Thus, there is always an imposing female (factor) behind every man! On the same theme, see the paper by Wu et al. analyzed page 2 in the neuroendocrinology chapter.

Stem cells are here to stay

A signaling principle for the specification of the germ cell lineage in mice
Ohinata Y, Ohta H, Shigeta M, Yamanaka K, Wakayama T, Saitou M Center for Developmental Biology, RIKEN Kobe Institute, Minatojima-Minamimachi, Chuo-ku, Japan Cell 2009;137:571–584
Background: Specification of the germ cell lineage is vital to development and heredity. In mice, the germ cell fate is induced in pluripotent epiblast cells by signaling molecules, yet the underlying mechanism remains unknown. Methods and Results: The authors demonstrate that germ cell fate in the epiblast is a direct consequence of BMP4 signaling from the extraembryonic ectoderm (ExE), which is antagonized by the anterior visceral endoderm (AVE). BMP8b from the ExE restricts AVE development, thereby contributing to BMP4 signaling. In addition, Wnt3 in the epiblast ensures its responsiveness to BMP4. Serum-free, defined cultures revealed that, in response to BMP4, competent epiblasts uniformly expressed key transcriptional regulators Blimp1 and Prdm14 and acquire germ-cell properties, including genome-wide epigenetic reprogramming, in an orderly fashion. Conclusions: Induced cells contributed to both spermatogenesis and fertility of offspring. By identifying a signaling principle in germ cell specification, this study presents a strategy for reconstituting the mammalian germ cell lineage in vitro.

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results in the rapid emergence of cells that are comparable to migratory PGCs. A number of recent studies have shown that gametes can be derived from murine embryonic stem cells (mESCs) but simple approaches to for derivation of such cells in humans are yet to be demonstrated. The methodology does not require genetic manipulation or complex three-dimensional culture. Afrikanova I. Importantly. this process is accompanied by the development of Sertoli-like cells. the relatively simple and straightforward approaches used will facilitate their clinical implementation. to preserve fertility in children receiving gonadotoxic chemotherapy for cancer..5 (E11. University of California. USA Stem Cells 2009. Hudson QJ. Methods: Using human ESCs. the authors describe a novel method for rapid derivation and enrichment of primordial germ cells (PGCs) and Sertoli cells.82:380–389 Background: Mammalian gonadal sex-determining (GSD) genes are expressed in a unique population of somatic cells that differentiate into granulosa cells in XX gonads or Sertoli cells in XY gonads.27:68–77 Background: In vitro gametogenesis established from stem cells without use of viral vectors and genetic manipulation is highly warranted for regenerative medicine purposes in humans. Importantly.edu Biol Reprod 2010. Methods: A unique mouse model was developed. Under more stringent differentiating conditions. The above two studies cited are examples of the continuous contribution and impact of the stem cell field to our understanding of the early steps of sexual differentiation and germ cell development. Yebra M. Conclusions: The putative Sertoli-germ cell co-cultures generated in this study may ultimately be developed to establish autologous human gametogenesis as a mean to rescue male fertility in selected cases with gonadal damage.g. known to provide trophic support and immunoprotection to developing germ cells. Washburn LL. these cells can be monitored and purified on the basis of the expression of the chemokine receptor CXCR4. Calif.5) and allow SSCs to be isolated from undifferen- Reproductive Endocrinology 89 . e. Results: The authors determined that simply reducing the size of cultured ESC colonies and manipulating the number of feeding cycles. Eicher EM The Jackson Laboratory. Bar Harbor. This also keeps open and widens the roads to future exploitation in human reproductive medicine. San Diego. carrying two transgenes that allow XX and XY mice to be distinguished as early as embryonic day 11. Cirulli V. Results first obtained in mouse models are now being increasingly translated into human systems. USA Gerrit.. Although it is still a long journey before the efficacy and safety of these novel cell therapy methods will be ascertained for clinical use in human medicine. Department of Pediatrics. New genes – sex determination New candidate genes identified for controlling mouse gonadal sex determination and the early stages of granulosa and Sertoli cell differentiation Bouma GJ. La Jolla. Montgomery AM Whittier Institute.A novel approach for the derivation of putative primordial germ cells and Sertoli cells from human embryonic stem cells Bucay N.Bouma@colostate. with success in most cases so far. Kaido T. Hayek A. The ability to efficiently isolate these somatic support cells (SSCs) during the earliest stages of gonad development would facilitate identifying (1) new candidate GSD genes that may be involved in cases of unexplained abnormal gonad development and (2) genes involved in the earliest stages of granulosa and Sertoli cell differentiation. these cells mature and upregulate the expression of specific germ cell markers. Me. It is therefore important for the clinical pediatric endocrinologist to be well informed and updated on these continuous developments.

In the absence of functional Sry the same precursor cells develop into granulosa cells determining the ovary. the authors detected more than 50 genes that were expressed in early development in fetal gonadal tissue in a sexually dimorphic fashion. The Mouse Genome 430v2. there are still other molecular events and genes involved in sex determination yet to be discovered. and Fbln2. USA joanner@bcm. Kress J. testis differentiation can occur in its absence.. Klasen C. Riethmacher D. More recent studies in mice and humans indicate that many other intra-ovarian signaling cascades affect follicular development and gonadotropin action in a stage.0 GeneChip (Affymetrix) was used to identify transcripts exhibiting a sexual dimorphic expression pattern in XX and XY isolated SSCs. Methods: Review paper with update on current status of our understating of ovarian function and folliculogenesis and their translational implications. Most DSD cases with gonadal dysgenesis not caused by numerical chromosome aberrations have still an unknown origin. including humans. and whole-mount in situ hybridization analysis verified 4930563E18Rik. Baylor College of Medicine. and Sprr2d are expressed in XX gonads. is normally responsible for triggering the indifferent gonads to develop as testes rather than ovaries. Tex. 90 Olle Söder/Lena Sahlin . Germany Cell 2009. and RAS/ERK1/2 signaling pathways and the FOXO/FOXL2 transcription factors. a gene not identified in other microarray studies. New mechanisms The ovary Basic biology and clinical implications Richards JS.5) fetal gonads. Eisenberger T. Some of these identified genes can be studied for a role in the pathogenesis of human DSDs. Treier AC.tiated (E11./SMAD. European Molecular Biology Laboratory. Sekido R. Jakob S. Lovell-Badge R.edu J Clin Invest 2010. in which gonadotropin-releasing hormone (GnRH) controls the release of the gonadotropic hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Holter NI. Ppargc1a. Schutz G. and that ovarian steroids exert both negative and positive regulatory effects on GnRH secretion. Pld1. Conclusion: The data provide a comprehensive resource for the spatial-temporal expression pattern of genes that are part of the genetic network underlying the early stages of mammalian fetal gonadal development.139:1130–1142 Background: In mammals. In XY mammalian embryos. the transcription factor SRY. Anlag K. including the development of granulosa and Sertoli cells. Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation Uhlenhaut NH. However. Heidelberg.tmc. which thereafter develop into testes. including low-level expressed genes such as Sry. Klugmann C.and context-specific manner. Pangas SA Department of Molecular and Cellular Biology. In this study employing an elegantly created mouse model. Treier M Developmental Biology Unit. Results: The analysis revealed previously unidentified sexually dimorphic transcripts. and Scrn1 are expressed in XY gonads. initial expression of Sry occurs in Sertoli cell precursors in the gonadal anlagen. Multi-gene real-time PCR analysis of 57 genes verified that 53 were expressed in fetal gonads in a sexually dimorphic pattern. encoded by the Y chromosome.5) and early differentiated (E12. Results and Conclusions: Evidence from mutant mouse models and clinical observations indicate that some of the most powerful intra-ovarian regulators of follicular development include the TGF. Cooney AJ. However. Methods: Inducible deletion of Foxl2 in adult ovarian follicles.120:963–972 Background: The classical view of ovarian follicle development is that it is regulated by the hypothalamicpituitary-ovarian axis. Houston. WNT/ FZD/ -catenin.

Results: The forkhead transcriptional regulator FOXL2. Andersson AM.6 pmol/l. whereas levels in prepubertal girls were significantly higher (median 9. This paper was also commented on in Nature Medicine [11].47 nmol/l. 48 pubertal children were studied. this does not exclude that sex steroids have important biological roles in prepubertal children. that females continue to fight against their inner males throughout life [10]. Antignac JP. Unité Sous Contrat 2013.7 pmol/l). Conclusions: Using an accurate and sensitive method. as in PCOS. 5 -dihydrotestosterone. p < 0. girls had significantly higher androsterone (4.45 vs.95 nmol/l. significantly higher levels of estrogens as well as androgen metabolites were found in prepubertal girls compared with age-matched boys.95:82–92 Background: Estrogens and androgens play key roles for pubertal onset and sexual maturation. produce primarily androgens rather than estrogens. Most currently used immunoassays are not sensitive enough to accurately measure the low circulating levels of sex steroids in children without any signs of puberty. <0. Thus. a single gene deletion could induce male transformation – the old dogma that the testis and ovary are terminally differentiated tissues is not any longer valid.69 vs.45 nmol/l.001). 0. estradiol.e. France J Clin Endocrinol Metab 2010. Among the older prepubertal children (>8 years). p < 0. Deletion of Foxl2 leads to immediate upregulation of testis-specific genes including the critical SRY target gene Sox9.07 vs.01). reprogramming of granulosa and theca cell lineages into Sertoli-like and Leydig-like cell lineages occurs with testosterone levels comparable to those of normal XY male littermates. was shown to be required to prevent transdifferentiation of an adult ovary to a testis. 5 -dihydrotestosterone (0.05) compared with similarly aged prepubertal boys. Institut National de la Recherche Agronomique. Conclusions: Maintenance of the ovarian phenotype is an active process throughout life. Sorensen K. Aksglaede L. However. 1.10 nmol/l. Ecole Nationale Vétérinaire de Nantes. The original paper on FOXL2 published in Cell presents seminal work demonstrating that the ovarian-specific gene FOXL2 has a role to suppress testis transdifferentiation in the adult ovary. The transient knockout of FOXL2 expression results in ovaries that. etiocholanolone (5. 1. and estrone measured by an ultrasensitive method based on gas chromatography-tandem mass spectrometry in samples from 81 healthy school children (42 boys) without any signs of puberty.11 vs. p < 0. Juul A. They might also have important medical implications for the understanding and treatment of some disorders of sexual development in children and premature menopause in women. The higher prepubertal sex steroid levels in girls may contribute to their earlier onset of puberty including pubic hair development. Skakkebaek NE. New methodology – can you be too sensitive? Assessment of circulating sex steroid levels in prepubertal and pubertal boys and girls by a novel ultrasensitive gas chromatography-tandem mass spectrometry method Courant F. Concordantly. etiocholanolone. The authors used ultrasensitive methodology with high accuracy to determine circulating sex steroid levels in prepubertal and pubertal children of both sexes and found subtle sexual dimorphisms for Reproductive Endocrinology 91 . Methods: Total (unconjugated plus conjugated) serum levels of 17 -testosterone.05). 17 -testosterone. 5 -dihydrotestosterone. androsterone. Monteau F. Bizec BL Laboratoire d’Etude des Residus et Contaminants dans les Aliments. i.0001). as a single factor. where Foxl2’s possible impact on the polycystic ovary syndrome (PCOS) is discussed. The aim of the study was to accurately determine levels of sex steroid hormones and their metabolites in serum of healthy children before any physical signs of puberty and to evaluate possible sex differences. and 17 -testosterone concentrations (0. p < 0. p < 0. Results: 17 -Estradiol levels in prepubertal boys were undetectable or extremely low (median <3. Nantes. These two papers on the ovary are excellent updates on important basic mechanisms and clinical implications of ovarian development and function. For comparison.

polybrominated biphenyls) or delayed (e.500–3. lead) puberty.g. However.edu Paediatr Perinat Epidemiol 2010.324:339–344 Background: Secular trends in timing of puberty appear to continue although undernutrition has not been any longer a limiting factor for pubertal development. Division of Cancer Prevention. Maternal-reported birth weight. it is not surprising that the observed environmental effects are rather modest when individual exposures are assessed. Bethesda. Results: Since genetic background explains 50–80% of variability in the timing of puberty. Md. Turku. This paper may serve as an important source of normative data for several sex steroids in children. USA solivo-marston@cph. Now obesity and other environmental reasons have been suspected to cause this trend. OR = 3. age. Gender-specific differences in birth weight and the odds of puberty: NHANES III. Conclusions: The authors review the available data on recent trends in timing of puberty and the possible role of endocrine disrupters. 92 Olle Söder/Lena Sahlin . 8. Finland Mol Cell Endocrinol 2010. race. Concerns – earlier start of puberty Trends in puberty timing in humans and environmental modifiers Toppari Ja.999 g) were more likely to be Tanner stage 2+ than 1.the levels of estrogens at the low picomolar level for the levels of androgens at the subnanomolar level. and endocrine disrupting chemicals have become into focus as possible contributors. Graubard BI. 1988–1994 Olivo-Marston S. Forman MR The Laboratory of Human Carcinogenesis. Results: Birth weight was not associated with the OR of Tanner stage 2+ among girls.g.osu.000 g) were more likely to have breast development 3+ than girls of normal birth weight. girls born at high birth weight (>4. The National Cancer Institute. smoking in pregnancy and other information were provided in a home interview. Multiple logistic regression models were computed for the endpoints of the OR of being Tanner stage 2+ vs.18 (95% CI 1.. University of Turku. Childhood BMI was associated with the OR of having entered puberty among girls. some exposures have been reported to be associated with early (e. The findings need replication in prospective longitudinal studies and research to understand the mechanisms underlying the relation of early life exposures to cancer risk. 1 or being 2+ vs.25). but not boys.500 g) and boys born higher than average birth weight (3.39. Girls (n = 956) and boys (n = 1. Visvanathan K. these sex steroids exert any biological function and whether the differences observed have any phenotypic relevance..199) who had data on birth weight and Tanner staging were included. Conclusions: The birth weight-puberty association varies by gender and by pubertal pathway. Despite that. Methods: Epidemiological studies on endocrine disrupters are still scarce and show only weak associations between exposures and timing of puberty. height and body mass index (BMI).. 1 in an asynchronous pubertal pathway after adjustment for the complex sampling design of NHANES. it remains to be determined whether at these very low levels. however boys who were low birth weight (<2. Juul Ab Departments of aPhysiology and bPaediatrics. while Tanner staging to assess pubertal status was part of a medical examination.24:222–231 Background and Methods: The association between birth weight and the odds ratio (OR) of pubertal status in girls aged between 8 and 11 and in boys aged between 8 and 12 was examined using the 1988-94 Third National Health and Nutrition Examination Survey (NHANES III). The National Institutes of Health. In an analysis of asynchronous maturation.

was reported to be associated with timing of puberty in humans. Raivio Ta. It is clear that there is still limited data to associate specific endocrine disrupting chemicals with an earlier onset of puberty although ongoing prospective studies may add more insights into this issue. bChildren’s Hospital. Finland J Clin Endocrinol Metab 2010. a human ortholog of the gene-regulating processing of microRNAs (miRNAs) controlling the timing of major developmental events in the nematode Caenorhabtidis elegans. Kuopio University Hospital and University of Kuopio.b. a gain-offunction allele of lin-28 causes a retarded phenotype. particularly in girls. Alternatively. The role of body weight. [12]) LIN28B in constitutional delay of growth and puberty Tommiska Ja. In C. and this variant was present in 100 controls with the same frequency. 115 males and 30 females with CDGP were included. as well as the fragment of 3' untranslated region containing miRNA recognition elements A and B. Lack of any variation in the coding region of the gene suggests that LIN28B in developmental timing is so crucial that any changes in the conserved protein would probably be lethal.c. and dDepartment of Pediatrics. elegans.b. continues to provoke discussions and scientific debate. Reproductive Endocrinology 93 . Tommiska et al. Still. Vaaralahti Ka. The four coding exons (exons 1–4) and exon-intron boundaries. These two studies report on and discuss the possible association of earlier onset of puberty with environmental factors and with birth weight.b. Kuopio. a transmitted condition with so far no mechanistic basis. reports from several continents now seem to agree that there is a recent trend to start puberty earlier. This year. The data presented here clearly indicate that variations in LIN28B are not a common cause of CDGP but leave open several possibilities. Given the sample size. It should be remembered that the common variant of LIN28B detected by several groups [12] only modulated the age at menarche by a few weeks. Wehkalampi Kb. These patients did not differ in phenotypic features as compared with non-carriers. which is difficult to explain as a consequence of a continuing secular trend or genetic alterations. 16 of 145 subjects carried a 2-nucleotide deletion immediately 5' from miRNA recognition element A. and as one example of LIN28B. Longitudinal studies with prospective cohorts employing more accurate methods to determine puberty onset will add to this.95:3063–3066 Background: Recently. in the timing of puberty [12]. Laitinen EMa. BMI and the obesity epidemic as triggers of the onset of puberty has been convincingly demonstrated for certain ethnic groups but whether such mechanisms operate at the wider population level needs further attention. there is urgent need to look more closely into possible environmental factors behind this phenomenon. Dunkel Ld Department of Physiology. The objective of the study was to evaluate the variation in the LIN28B gene in 145 subjects with constitutional delay of growth and puberty (CDGP). Helsinki. variation in LIN28B. However. of LIN28B were PCR amplified from genomic DNA obtained from peripheral blood leukocytes of the subjects and bidirectionally sequenced. Institute of Biomedicine. Conclusions: These results show that mutations in the coding region or 3’ untranslated region miRNA recognition elements A and B of LIN28B do not underlie CDGP. Results: No variation in the coding region of LIN28B in the 145 subjects with CDGP was found. Helsinki University Central Hospital. Follow-up on a Yearbook 2009 paper (Ong et al. tried to find variation in the LIN28B gene in individuals with constitutional delay in growth and puberty (CDGP). CDGP was defined by Tanner genital or breast stage II and pubertal growth spurt taking place 2 SD later than average. Last year we reported on the importance of microRNAs. Thus. Methods: For this study. University of Helsinki. cNational Institute for Health and Welfare. No variation in the coding region of the gene was found in CDGP subject.The concept of an earlier start of puberty at the population level during the past few decades. The last severe alterations of LIN28B might be lethal or lead to different phenotypes than the one analyzed here. other genes in the LIN28B pathway could be involved in CDGP. it remains possible that variations in LIN28B are rare causes of CDGP not detected in the sample studied here.

Monte Alegre. Arlt Wi. Massachusetts General Hospital. and (3) 5 remained azoospermic despite achieving adult testicular volumes and normal hormonal profiles. Tusset Cb. Gulhane School of Medicine. University of Washington Medical Center. UK. most IHH patients respond to physiological pulsatile GnRH replacement by normalizing serum LH. São Paulo. Ribeirão Preto. IHH men can have primary pituitary and/or testicular defects. Pitteloud N Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine. which are unmasked by GnRH replacement. Universidade de São Paulo. A retrospective study of response to GnRH at a Clinical Research Center was conducted. FSH.95:2857–2867 Background: Mutations in TAC3 and TACR3 (encoding neurokinin B and its receptor) have been identified in Turkish patients with idiopathic hypogonadotropic hypogonadism (IHH). Jr. Birmingham. Hoang XH. Massachusetts General Hospital. cDepartamento de Clinica Medica. University of Brasilia. Department of Medicine. Dwyer AAa. Faculdade de Medicina de Ribeirão Preto. Crowley WF. Boston. Lofrano Ac. FSH.95:3019–3027 Background: Idiopathic hypogonadotropic hypogonadism (IHH) with normal smell (normosmic IHH) or anosmia (Kallmann syndrome) is associated with defects in the production or action of GnRH.. Carroll Jc. Crowley WFa. LH. de Mendonca BBb. pituitary. Au M. suggesting primary defects in spermatogenesis. USA. show atypical responses. Noel SDc. Diabetes. Hughes VAa. Kaiser UBc. School of Clinical and Experimental Medicine. Interestingly. cSection of Endocrinology.. USA J Clin Endocrinol Metab 2010. Newcastle-upon-Tyne. bLaboratorio de Hormonios e Genetica Molecular. and sequence of IHH-associated genes was measured. Brazil. Faculty of Health Sciences. Ankara. Ozata Mf. de Castro Mc. Plummer L. iClinical Genetics Unit. A broad 94 Olle Söder/Lena Sahlin .. Cole TRi. Brasilia. Physiological regimens of pulsatile sc GnRH were administered for at least 12 months. Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo. Quinton Rg. Turkey. Birmingham Women’s Hospital National Health Service Foundation Trust. University of Birmingham. Boston. Diabetes. or genetic characteristics of IHH men with atypical responses to GnRH indicate alternative or additional defects in the hypothalamic-pituitary-gonadal axis. Brigham and Women’s Hospital and Harvard Medical School. biochemical. Seattle. Mass. Au MGa. USA. Dose-response studies using iv GnRH pulses assessed the pituitary LH response. (2) 8 achieved spermatogenesis and normal T but only with hypergonadotropism. Institute for Human Genetics. Brazil. USA. University of Newcastle-upon-Tyne. hDivision of General Internal Medicine. Accordingly. however. sperm in ejaculate. Stewart SEi. and Metabolism. Serum T. some patients. University Hospital of Brasilia and Molecular Pharmacology Laboratory. Mass. and Hypertension. Mutations were identified only in KAL1 across groups. Hall JEa. and testosterone (T) levels and achieving gametogenesis. and Centre for Endocrinology. UK J Clin Endocrinol Metab 2010. but broader populations have not yet been tested and genotype-phenotype correlations have not been established. Methods: 90 IHH men undergoing long-term pulsatile GnRH treatment over 30 years were studied. Bolu Ef. Results: 26% of subjects displayed atypical responses to GnRH: (1) 10 remained hypogonadotropic and hypogonadal.. and testes Sykiotis GP. Amory JKh. TAC3/TACR3 mutations reveal preferential activation of gonadotropinreleasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood Gianetti Ea. Dwyer A. Seminara SBa a Harvard Center for Reproductive Sciences and Reproductive Endocrine Unit. Costa EMb. Edgbaston. Trarbach Eb. Conclusions: In addition to hypothalamic GnRH deficiency. Mass. São Paulo. gEndocrinology Research Group. demonstrating pituitary and testicular defects. cHarvard Center for Reproductive Sciences and Division of Endocrinology.Important for clinical practice Congenital idiopathic hypogonadotropic hypogonadism: evidence of defects in the hypothalamus. indicating impaired testicular responsiveness to gonadotropins. Hayes FJ. fDepartment of Endocrinology. Boston. Wash. Thambundit A. The aim of the study was to investigate whether the clinical. and inhibin B levels. several IHH-associated genes are expressed in multiple compartments of the hypothalamic-pituitary-gonadal axis. Silveira LFb. Servico de Endocrinologia – Divisão de Clinica Medica I. Avbelj M. Abreu APc. Latronico ACb.

So far. Although the neurokinin B pathway appears essential during early sexual development. at 12 months. 6 of the 7 males and 4 of the 5 females demonstrated evidence for reversibility of their hypogonadotropism. 18 family members. A selection of cognitive tests. Maury S. and 292 controls were studied. 6 non-synonymous. During the treatment. In this study.163:149–155 Background: Aromatase inhibitors.5 years. General conclusions from these studies are that it is worth looking more closely into the molecular defects when working up these cases.5 mg/ day). 345 probands. with idiopathic short stature were treated with the aromatase inhibitor letrozole (2. Results: In TACR3.0– 14. was administered to the participants at entry. the data on patients with TAC3/TACR3 mutations suggest that these are the patients with the reversible phenotype suggesting that molecular analysis could help predict the course of the disease. Helsinki. Luotoniemi E. have emerged as a new potential treatment modality for boys with short stature. 4 synonymous (1 predicted to affect splicing)). placebo-controlled clinical study. Dunkel L Department of Pediatric Endocrinology. Of the 16 males. one homozygous single base pair deletion was identified. In TAC3. for 2 years. Rare sequence variants in TAC3/TACR3 were detected. Methods: Prospective. 19 probands harbored 13 distinct coding sequence rare nucleotide variants (3 nonsense mutations. we explored the effects of aromatase inhibition on cognitive performance in peripubertal boys.cohort of normosmic IHH probands was screened for mutations in TAC3/TACR3 to evaluate the prevalence of such mutations and define the genotype/phenotype relationships. its importance in sustaining the integrity of the hypothalamic-pituitary-gonadal axis appears attenuated over time. Conclusions: Mutations in the neurokinin B pathway are relatively common as causes of hypogonadism. Service E. Phenotypic information was available on 16 males and 7 females with coding sequence variants in TACR3/TAC3. as indicated by high serum testosterone and low serum estradiol concentrations in letrozole-treated boys who progressed into Reproductive Endocrinology 95 . The cognitive effects of such therapy are unknown. randomized. the progression of physical signs of puberty and the concentrations of sex hormones were followed up. Seven of the 16 males and 5 of the 7 females were assessed after discontinuation of therapy. blockers of estrogen biosynthesis. focusing on memory function. without any clue on the factors involved in this reversible phenotype. in vitro functional assays. New Concerns – safety of endocrine treatment Cognitive effects of aromatase inhibitor therapy in peripubertal boys Hero M. 15 had microphallus. These two papers represent a large body of work to better understand the etiology and pathophysiology as well as the clinical phenotypes in central hypogonadotropic hypogonadism. Hospital for Children and Adolescents. One important practical implication is the recognition that some of the patients recognized in adolescence as having hypogonadism actually have reversible phenotypes and later in life have normal gonadotropic function and can reproduce without medical assistance [13]. and that it is not uncommon that these patients suffer from several gene defects that may result in poor functional outcome with respect to fertility despite state-of-the-art endocrine treatment. Finland Eur J Endocrinol. resulting in complete loss of the neurokinin B decapeptide. This is a relatively common diagnosis in the pediatric endocrinology clinic thus adding a substantial number of patients to the records. Methods: The study consisted of sequencing of TAC3/TACR3. 28 boys. Reproductive phenotypes throughout reproductive life and before and after therapy were examined. double-blind. Although not definitive. or placebo. aged 9. a small proportion of such patients has been identified among the vast number of patients with hypogonadism. and neuroendocrine phenotyping conducted in tertiary care centers worldwide. 2010. none of the females had spontaneous thelarche. Results: Letrozole effectively inhibited the conversion of androgen to estrogen. Helsinki University Hospital. and at 24 months after the start of the treatment.

96 Olle Söder/Lena Sahlin . we evaluated in this cross-sectional post-treatment study vertebral body morphology. Hospital for Children and Adolescents. However. It is reassuring to learn that there were no observable negative effects on the cognitive performance of the treated teenager boys. These data re-emphasize the need for formal and comprehensive evaluation of new medications in the context of clinical trials before physicians even consider using them in their daily practice. In both groups there was a gain in performance during the follow-up period in tests of verbal performance. The group of Leo Dunkel should be commended for this long-term commitment to evaluate several aspects of anti-aromatase therapy and not only the primary outcomes. delay bone maturation and are therefore increasingly used to promote growth in children and adolescents with growth disorders. Methods: As estrogen deficiency is associated with various detrimental skeletal effects. or placebo. and intervertebral discs by the use of magnetic resonance imaging (MRI) in two cohorts of males previously treated with the AI letrozole. If AIs are used in growth indications. blockers of estrogen biosynthesis. Epub ahead of print Background: Aromatase inhibitors (AIs). These two papers deal with important safety issues in boys treated with aromatase inhibitors in order to stimulate pubertal growth. Makitie O. Finland J Bone Miner Res 2010. Males with idiopathic short stature received treatment with letrozole or placebo for 2 years during pre-puberty or early puberty. males with constitutional delay of puberty received letrozole or placebo in combination with low-dose testosterone for 1 year during early or mid-puberty. Given the common diagnosis of boys with short stature at the pediatric endocrinology clinic and the poor arsenal of tools available to stimulate their growth and increase final height. No significant differences between the letrozole and placebo-treated boys in development of cognitive performance were found in any of the tests during the follow-up period. Results: In males with idiopathic short stature. which probably reflect impaired vertebral body growth rather than impaired bone quality and compression fractures. dimensions and endplates. Vertebral morphology in aromatase inhibitor-treated males with idiopathic short stature or constitutional delay of puberty Hero M. aromatase inhibitors have been increasingly tried for such purposes. Helsinki. Dunkel L Pediatric Endocrinology and Metabolic Bone Diseases. Wickman S. when it comes to bone health there were clear indications that the spinal skeleton could be adversely affected by the treatment. University of Helsinki. mild vertebral body deformities were found in 5 of 11 (45%) letrozole-treated subjects while in the placebo group no deformities were detected (p = 0. It is unfortunate that this is not the case for the use of aromatase inhibitors [14]. Conclusions: These results suggest that blockade of estrogen biosynthesis with an aromatase inhibitor does not influence cognitive performance in peripubertal males. In the cohort of males with constitutional delay of puberty a high prevalence of endplate and intervertebral disc abnormalities was observed in both letrozole and placebo-treated males. in most of the tests of visuospatial performance. Conclusions: The authors conclude that AI therapy during pre-puberty or early puberty may predispose to vertebral deformities. It is therefore important to address the safety concerns. The effects of treatment on skeletal health are largely unknown. follow-up of vertebral morphology is indicated. Toiviainen-Salo S.01).puberty. and in some tests of verbal memory.

Finland Proc Natl Acad Sci USA. but with a still functional signaling capability. This paper demonstrates that a G-protein coupled receptor (GPCR) made deficient in its hormonebinding capacity. N Engl J Med 2003. Lawson Wilkins Pediatric Endocrine Society Drug and Therapeutics Committee: Use of aromatase inhibitors in children and adolescents with disorders of growth and adolescent development. Chou YY. Hanyaloglu AC. MacDonald AA.82:1–3. Shagoury JK. Söder O. The old dogma is that a one-ligand/one-receptor complex constitutes the functional unit of GPCR signaling. 8. Methods: This evidence has been obtained exclusively from cell culture experiments. using the mouse luteinizing hormone receptor (LHR) as a model GPCR. Dixon J. Cell 2009. 13. can cooperate successfully with a GPCR moiety with a reciprocal deficiency.25:1123– 1126. Sahlin L: Reproductive endocrinology. Shulman DI. Slaugenhaupt SA. Young WC: Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig. Farquhar CM: The impact of body mass index on semen parameters and reproductive hormones in human males: a systematic review with meta-analysis. Goy RW. Schwinof KM. 9.139:1051–1053. Ji TH. Turku. and epigenetic disease.107:2319–2324 Background: G-protein-coupled receptors (GPCRs) are ubiquitous mediators of signaling of hormones. Seminara SB. Wilkins-Haug L: Assisted reproductive technology. Ghanayem BI. neurotransmitters. Conclusions: These results provide compelling in vivo evidence for the physiological relevance of intermolecular cooperation in GPCR signaling. Nat Med 2010. 10. This is compelling evidence for the existence of interaction and functional cooperation between protein receptors at the molecular level within the cell membrane. Carlton MB. Reproductive Endocrinology 97 . Hendrick AG. Endocrinology 1959.16:527–529. 2009. Murdoch A: Obesity and female fertility: a primary care perspective. Gerall AA. Jr. Acierno JS. Karger. Kissling GE. Jr. Gusella JF. 12. Milki AA.21:260–264. Palmert MR. Bukulmez O: Does assisted reproductive technology cause birth defects? Curr Opin Obstet Gynecol 2009. inactivation. teamwork restores the signal Rescue of defective G-protein-coupled receptor function in vivo by intermolecular cooperation Rivero-Muller A. lacking signaling activity but retaining hormone binding. Biol Reprod 2009. Murphy BD: Revisiting reproduction: what a difference a gene makes. O’Rahilly S. Jonas K.35:181–185. and proof for the physiological significance of GPCR di/oligomerization in vivo is still missing. However. Chatzidaki EE. pp 79–92.51:96–105. Kimmins S: Expanding waistlines heighten the risk for reproductive toxicity. Wilkes S. Aparicio SA. These findings have important implications for better understanding of hormone actions and clinical phenotypes in endocrine disorders. Rahman N.16:293– 311.121:e975–e983. Thresher RR. Kuohung W. 6. Huhtaniemi I Department of Physiology.81:807–813. Sinclair A. 14. Smith C: Females battle to suppress their inner male.82:96–104. Hoffler U: Diet-induced obesity in male mice is associated with reduced fertility and potentiation of acrylamide-induced reproductive toxicity. there is mounting evidence that some GPCRs form dimers or oligomers during their biosynthesis. Francis GL. Hum Reprod 2010. 4. in Carel JC. Herbison GP. Landres IV. Travlos G. Pediatrics 2008. 3. Biol Reprod 2010. activation. Phoenix CH. Hunt PA.349:1614–1627. Ji I. Basel.65:369–382. Rubio C. Bai R. Kaiser UB. Clin Obstet Gynecol 2008. Lajic S. In the present study a transgenic mouse model was used. Hochberg Z (eds): Yearbook of Pediatric Endocrinology. Showell M. Biol Reprod 2010. Zahn D. and sensing. Lathi RB: Karyotype of miscarriages in relation to maternal weight. 5. Hum Reprod Update 2010. Susiarjo M. Colledge WH: The GPR54 gene as a regulator of puberty. References 1.New mechanisms – healing by cooperation. Bo-Abbas Y. 2. to exert a normal receptor action. J Fam Plann Reprod Health Care 2009. Eugster EA. 7. Hassold TJ: The bisphenol-A experience: a primer for the analysis of environmental effects on mammalian reproduction. Crowley WF. that transgenic mice co-expressing binding-deficient and signaling-deficient forms of LHR can re-establish normal LH actions through intermolecular functional complementation of the mutant receptors in the absence of functional wild-type receptors. and/or internalization. 11. University of Turku. congenital malformations. Messager S. Results: The authors demonstrate.

and recent advances in the diagnosis and treatment of congenital adrenal hyperplasia. Emerging themes for this year’s chapter include the effect of circadian transcription factors on glucocorticoid receptor action. we have avoided topics that have been discussed in the Yearbook 2009. Chrousos GP. ‘Aghia Sophia’ Children’s Hospital. . Biomedical Research Foundation of the Academy of Athens. we have searched the PubMed for articles on ‘adrenal’ and ‘steroidogenesis’ published in English between June 1. Metabolism and Diabetes.23:1572–1583 Background: Glucocorticoids exert their diverse actions through the glucocorticoid receptor (GR). the role of neuropeptide hormone receptors and microRNAs in the diagnosis and treatment of adrenal cancer. through modulation of glucocorticoid action. 2010. Kino T Section on Pediatric Endocrinology. The Netherlands Division of Endocrinology.gov FASEB J 2009. CLOCK and GR interacted with each other physically.. the implications of ultradian glucocorticoid pulsatility on the expression of target genes. Rotterdam. National Institutes of Health. USA kinot@mail. and Department of Endocrinology. In serum-shock-synchronized cells. Erasmus Medical Center. Whenever possible. Metabolism and Diabetes. University of Athens Medical School.500 citations. and CLOCK suppressed the binding of GR to its DNA recognition sequences by acetylating multiple lysine residues located in its hinge region. We have examined all citations individually and selected the following collection of basic research and clinical articles.Adrenals Erica L. In addition. Our search yielded more than 5.nih. Mechanism of the year CLOCK/BMAL1 is a reverse-phase negative regulator of glucocorticoid action Circadian rhythm transcription factor CLOCK regulates the transcriptional activity of the glucocorticoid receptor by acetylating its hinge region lysine cluster: potential physiological implications Nader N. Conclusions: CLOCK/BMAL1 functions as a reverse-phase negative regulator of glucocorticoid action in target tissues. Circulating concentrations of glucocorticoids fluctuate naturally in a circadian fashion and regulate the transcriptional activity of the GR in target tissues. the transactivational activity of GR fluctuated spontaneously in a circadian fashion in reverse phase with CLOCK/BMAL1 mRNA expression. van den Akkera and Evangelia Charmandarib a b Department of Pediatric Endocrinology. Methods and Results: CLOCK/BMAL1 repressed the GR-induced transcriptional activity in a histone acetyltransferase (HAT) activity-dependent fashion. Bethesda. unless progress in the field has been incremental. The basic helix-loop-helix protein CLOCK and its heterodimer partner BMAL1 are self-oscillating transcription factors that generate circadian rhythms in both the central nervous system and periphery. possibly by antagonizing the biological actions of diurnally fluctuating circulating glucocorticoids.T. Eunice Kennedy Shriver National Institute of Child Health and Human Development. Greece For this year’s chapter on ‘Adrenals’. Athens. Program in Reproductive and Adult Endocrinology. 2009 and May 31. Md. Clinical Research Center. a peripheral target tissue circadian rhythm influences the functions of every organ and tissue indirectly.

as well as to stressful stimuli. the circadian CLOCK and stress systems. Md. Similarly. the transactivational activity of glucocorticoids is correlated with the side effects of these steroids. administration of these steroids at a specific period of the circadian cycle might increase their pharmacological efficacy. Circadian rhythms of both the central nervous system and peripheral tissues and organs are generated by the coordinated activation/inactivation of self-oscillating transcription factors. These systems communicate with each other at different signaling levels. This review summarizes the bidirectional interaction between the circadian CLOCK system and the HPA axis. The circadian CLOCK system and the HPA axis regulate the activity of one another through multilevel interactions to ultimately coordinate homeostasis against the day/night change and various unforeseen random internal and external stressors (fig. These circadian and stress-related responses are achieved by two highly conserved and interrelated regulatory networks. as a result of enhanced input of higher centers upon the hypothalamic paraventricular nucleus secretion of CRH and AVP (fig. Chrousos GP. disrupted coupling of cortisol secretion and target tissue sensitivity to glucocorticoids could explain the increased cardiometabolic risk of subjects exposed to frequent jetlag because of traveling across time zones. van den Akker/Evangelia Charmandari . 1). Eunice Kennedy Shriver National Institute of Child Health and Human Development. circulating cortisol concentrations are tightly regulated by the central components of the HPA axis and fluctuate naturally in a circadian fashion. the CLOCK/BMAL1 transcription factors.21:277–286 Organisms have developed concurrent behavioral and physiological adaptations to the strong influence of day/night cycles. including those responsible for intermediary metabolism and immunity. Program in Reproductive and Adult Endocrinology.gov Trends Endocrinol Metab 2010. National Institutes of Health. Kino T Unit on Molecular Hormone Action. reaching their zenith in the early morning and their nadir in the late evening [1]. Kino and colleagues demonstrated that CLOCK/BMAL1 is a reverse-phase negative regulator of glucocorticoid action in target tissues. The circadian activity of the HPA axis is generated by the hypothalamic suprachiasmatic nucleus (SCN). Central among them are the circadian locomotor output cycle kaput (CLOCK) and its heterodimer partner brain-muscle-arnt-like protein 1 (BMAL1). and the hypothalamic-pituitary-adrenal (HPA) axis and its end-effector. which belong to the basic helix-loop-helix (bHLH)-PERARNT-SIM (PAS) superfamily of transcription factors [2]. In this study.. while their transrepressive activity is associated mostly with their beneficial anti-inflammatory activity. antagonizing the biological actions of diurnally fluctuating circulating glucocorticoids and providing a local target tissue counter-regulatory feedback loop to the central CLOCK on the HPA axis. 1). Since CLOCK may differentially regulate these two major class actions of glucocorticoids. whose HPA axis circadian rhythm is characterized by blunting of the evening decreases of circulating glucocorticoids. In humans. Uncoupling of or impaired function in either system may result in the development of pathologic conditions. which respectively consist of oscillating molecular pacemakers. Uncoupling of or dysfunction in either system alters internal homeostasis and causes pathologic changes virtually in all organs and tissues. Disrupted coupling of cortisol secretion and target tissue sensitivity to glucocorticoids may explain the development of central obesity and the metabolic syndrome in chronically stressed individuals. the master oscillator and generator of the circadian rhythm of the body. the glucocorticoid receptor. At pharmacologic concentrations.Interactions of the circadian CLOCK system and the HPA axis Nader N. Bethesda.nih. while at the same time reducing their unwanted side effects.T. 100 Erica L. and discusses their clinical implications. USA kinot@mail.

(b) the corresponding circadian changes of target tissue sensitivity to glucocorticoids and (c) mean target tissue sensitivity to glucocorticoids in the human population. 1. Adrenals 101 . HS = hypersensitivity. N = normal sensitivity. NS = non-stressed individuals.24 h sampling 24 h cortisol Overnight dexamethasone test Plasma cortisol NS –D NS SS +D NS SS –D +D SS a 8 am 8 pm Dark 8 am Circadian tissue glucocorticoid action Target tissue glucocorticoid action b 8 am 8 pm Dark 8 am Mean target tissue sensitivity Target tissue response HS N R Threshold for harmfulness c Cortisol concentration Fig. D = midnight dexamethasone administration. SS = Chronically stressed individuals. will exert disproportionately increased glucocorticoid effects because of the natural circadian target tissue sensitivity increase at this time of the day. Even mild evening cortisol elevations. A heuristic scheme of (a) circadian secretion of cortisol in non-stressed and chronically stressed humans (left panel) and their responses to midnight dexamethasone administration (right panel). as those seen in chronically stressed individuals. R = resistance.

circadian cycle as a result of the activity of the highly dynamic HPA axis. which in turn have a direct impact on GR-regulated transcriptional programs. even low doses of synthetic glucocorticoids. Md. Due to its plasticity. fluctuate together with the changes in extracellular hormone concentration. McKenna MA. Furthermore. The pattern of glucocorticoid secretion is highly pulsatile (ultradian). demonstrating a profound difference between the transcriptional programs induced by ultradian and constant stimulation. Hager and colleagues evaluated the implications of these complex aspects of glucocorticoid action (the rapid fluctuation of serum glucocorticoid concentrations and the fast dynamics of GR interactions with chromatin) on the GR-mediated transcriptional program. The GR has been shown to exchange rapidly with response elements in living cells and its residence time on regulatory elements is measured in seconds. Johnson TA. Glucocorticoids are released from the adrenal glands in a daily. USA Nat Cell Biol 2009. As a result. superimposed on the ultradian and circadian rhythm. with a periodicity of approximately 1 h. Physical and psychological stressors induce a rise in plasma glucocorticoid concentrations. Hager GL Laboratory of Receptor Biology and Gene Expression. Conclusions: The GR signaling pathway has been optimized for a prompt and timely response to fluctuations in glucocorticoid concentrations.. These data provide a basis for a more complex view of gene regulation by GR and open new approaches for the development of synthetic glucocorticoids. nascent RNA transcripts from a number of GR-regulated genes are released in distinct quanta during ultradian treatment. In this article. such treatments may not provide an accurate assessment of physiological hormone action. However. National Cancer Institute. Methods and Results: Ultradian hormone stimulation induces cyclic GR-mediated transcriptional regulation. or gene pulsing. such as dexamethasone. Nascent RNA transcripts from GR-regulated genes are released in distinct quanta.New paradigms Implications of ultradian hormone pulsatility and receptor cross-talk Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription Stavreva DA. both in cultured cells and in animal models. Pooley JR. van den Akker/Evangelia Charmandari . which promotes GR activation and reactivation in response to the ultradian hormone release. They demonstrated that. a common and debilitating manifestation often reported by patients with adrenal insufficiency. are expected to alter the transcription program set by ultradian hormone release significantly. Lightman SL. the ultradian mode of hormone secretion induces cyclic GR-mediated transcriptional regulation. Center for Cancer Research. John S. Voss TC. Wiench M. Bethesda. These findings suggest that gene pulsing in the GR system is necessary for correct transcriptional programming. Temporal HPA axis activity drives a pattern of GR action that leads to gene stimulation that is reflective of the HPA axis profile. or gene pulsing. demonstrating profound differences in the transcriptional program induced by pulsatile ligand stimulation compared with that induced by constant stimulation. Gene pulsing is driven by rapid GR exchange with response elements and by GR recycling through the chaperone machinery. despite optimal glucocorticoid substitution therapy. the inability to simulate ultradian hormone pulsatility may account for the fatigue. 102 Erica L. The dynamics of GR-template interaction. in contrast to treatment with long-acting glucocorticoid formulations.11:1093–1102 Background: Studies on glucocorticoid receptor (GR) action typically assess gene responses by long-term stimulation with synthetic hormones. Conway-Campbell BL. NIH. These findings indicate that biologically accurate regulation of gene targets by GR requires an ultradian mode of hormone stimulation. As a result. the HPA axis integrates many internal and external stimuli. as well as RNA Pol II loading and exchange. given that glucocorticoids are secreted in a circadian and high-frequency (ultradian) mode.T.

Genomic and non-genomic cross talk between the gonadotropin-releasing hormone receptor and glucocorticoid receptor signaling pathways
Kotitschke A, Sadie-Van Gijsen H, Avenant C, Fernandes S, Hapgood JP Department of Molecular and Cell Biology, University of Cape Town, Rondebosch, South Africa Mol Endocrinol 2009;23:1726–1745
Background: The GnRH receptor (GnRHR) is a central regulator of reproductive function in all vertebrates. GnRH exerts its effects by binding to the GnRHR in pituitary gonadotropes. This study investigated the mechanisms of regulation of transcription of the mGnRHR gene. Methods and Results: Reporter assays with transfected mGnRHR promoter showed that both dexamethasone and GnRH increased the transcription of the mGnRHR gene via an activating protein-1 (AP-1) site. Small interfering RNA experiments revealed a requirement for the glucocorticoid receptor (GR) for both the dexamethasone and GnRH response. Chromatin immunoprecipitation (ChIP) and immunofluorescence assays showed that both GnRH and dexamethasone up-regulate the GnRHR gene via nuclear translocation and interaction of the GR with the AP-1 region on the mGnRHR promoter. GnRH activated the unliganded GR by rapid phosphorylation of the GR at Ser-234 in a GnRHRdependent fashion. Also, a direct link between GnRH-induced protein kinase C and MAPK activation was established, leading to unliganded GR phosphorylation at Ser-234 and transactivation of the glucocorticoid response element. Finally, GnRH and dexamethasone synergistically activated the endogenous GnRHR promoter via a mechanism involving steroid receptor coactivator-1 recruitment to the GnRHR AP-1 region. Conclusions: These findings demonstrate a novel mechanism of rapid non-genomic cross-talk between the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes via GnRHRdependent phosphorylation and activation of the unliganded GR in response to GnRH.

Ligand-independent activation of steroid receptors by phosphorylation is a common mechanism of receptor activation in several different cells via several different pathways. This article provides the first evidence for a novel mechanism of rapid non-genomic cross-talk between the HPG and HPA axes via GnRHR-dependent phosphorylation and activation of the unliganded GR in response to GnRH. Given that GnRH regulates several genes in pituitary gonadotropes, this non-genomic cross-talk represents a mechanism whereby the GnRHR-activated, unliganded GR may modulate the expression of several GnRH and GR target genes [3]. Furthermore, this GnRHR-GR cross-talk may have important physiologic implications, since it participates in the interplay between reproductive, stress and immune responses. It is well established that the neuroendocrine, immune, inflammatory and stressresponse systems are integrated functionally and regulated bidirectionally [4]. For example, stress or chronic activation of the HPA axis suppresses reproduction via the elevated glucocorticoid concentrations that exert their effects at all levels of the HPG axis [5]. This study shows a direct transcriptional effect of glucocorticoids on GnRHR gene expression mediated by the GR, which represents another mechanism whereby the HPA axis could modulate the HPG axis.

New hope A big role for small molecules

Expression of neuropeptide hormone receptors in human adrenal tumors and cell lines: antiproliferative effects of peptide analogues
Ziegler CG, Brown JW, Schally AV, Erler A, Gebauer L, Treszl A, Young L, Fishman LM, Engel JB, Willenberg HS, Petersenn S, Eisenhofer G, Ehrhart-Bornstein M, Bornstein SR University Hospital Carl Gustav Carus, Department of Medicine III, Dresden, Germany Proc Natl Acad Sci USA 2009;106:15879–15884
Background: Peptide analogues targeting neuropeptide receptors have been used effectively in cancer therapy. Adrenocortical tumor formation is characterized by the aberrant expression of peptide receptors relating to uncontrolled cell proliferation and excess hormone secretion.

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Methods: A comprehensive analysis of relevant receptors in human adrenomedullary and adrenocortical tumors was performed and the antiproliferative effects of peptide analogues targeting these receptors were tested. Specifically, the receptor expression of somatostatin-type-2 (sst2) receptor, growth hormone-releasing hormone (GHRH) receptor or GHRH receptor splice variant-1 (SV-1) and luteinizing hormone-releasing hormone (LHRH) receptor were examined at the mRNA and protein levels in normal human adrenal tissues, adrenocortical and adrenomedullary tumors, and cell lines. Results: The cytotoxic derivatives of somatostatin AN-238 and AN-162 reduced the cell numbers of adrenomedullary pheochromocytoma cells and adrenocortical cancer cells. Both the SV-1 and the LHRH receptor were expressed in adrenocortical cancer but not in pheochromocytoma cell lines. The GHRH receptor antagonist MZ-4-71 and LHRH antagonist Cetrorelix significantly reduced cell growth in the adrenocortical cancer cell lines. Conclusions: The expression of receptors for somatostatin, GHRH and LHRH in the normal human adrenal and in adrenal tumors, in association with the growth-inhibitory effects of antitumor peptide analogues, may improve current treatment of adrenal tumors.

The overexpression or aberrant expression of G-protein-coupled receptors for neuropeptides in human adrenal tissue has been associated with adrenal tumor formation and excessive hormone production [6, 7]. In addition, peptide hormone receptors have been detected in adrenocortical cancers, as well as in malignant pheochromocytomas. The identification of these receptors may allow the development of pharmacologic interventions as an alternative approach to current therapy. The present study evaluated specific receptor-targeted chemotherapeutic peptide antagonists and agonists for their potential future use in the antineoplastic therapy of adrenal tumors. It demonstrated that both adrenal tumor tissue and two adrenal tumor cell lines expressed receptors for somatostatin, GHRH or the SV-1 splice variant, as well as for LHRH. The immunohistochemical staining of adrenal tissue showed strong staining for sst2 in normal adrenal cortex, adrenocortical adenoma and carcinoma, as well as benign and malignant pheochromocytomas. The cytotoxic derivatives of somatostatin AN-238 and AN-162 reduced cell numbers of adrenomedullary pheochromocytoma cells and adrenocortical cancer cells, while the GHRH receptor antagonist MZ-4-71 and LHRH antagonist Cetrorelix significantly reduced cell growth in the adrenocortical cancer cell line. These results demonstrate a promising approach for delivering therapeutic compounds selectively to tumor cells, and raise hope for improved targeted treatment strategies for adrenal diseases.

MicroRNA signature of primary pigmented nodular adrenocortical disease: clinical correlations and regulation of Wnt signaling
Iliopoulos D, Bimpaki EI, Nesterova M, Stratakis CA Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Mass., USA Cancer Res 2009;69:3278–3282
Background: MicroRNAs comprise a novel group of gene regulators implicated in the development of different types of cancer. However, their role in primary pigmented nodular adrenocortical disease (PPNAD), a rare form of bilateral adrenal hyperplasia caused by protein kinase A (PKA) regulatory subunit type 1A (PRKARIA)-inactivating mutations, has not been investigated. Methods and Results: A 44-microRNA gene signature of PPNAD was identified following comparison of PPNAD with normal adrenal samples: 33 microRNAs were up-regulated and 11 were down-regulated in PPNAD compared with normal adrenal tissues. Comparison of microRNA microarray data with hormonal measurements showed a negative correlation between let-7b expression and cortisol concentrations in patients with PPNAD. Also, nine microRNA-gene target pairs were identified as playing a potential role in adrenal pathogenesis. MiR-449 was up-regulated and WNT1-inducible signaling pathway protein 2 (WISP2) was identified as its direct target. Finally, pharmacologic inhibition of PKA resulted in the up-regulation of miR-449 leading to the suppression of WISP2. Conclusions: The microRNA profile and its clinical significance in PPNAD were investigated for the first time. The above findings suggest that PKA, via microRNA regulation, affects the Wnt signaling pathway, which is thought to be a primary mediator of PRKAR1A-related tumorigenesis.

An aberrant expression signature of microRNAs (miRNAs), small non-coding RNAs, is a hallmark of several diseases, including cancer. MicroRNA expression profiling by microarray techniques has pro-

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vided a powerful tool to reveal the involvement of these molecules in tumor development and progression, showing that they are differentially expressed in tumors compared with normal tissues. Moreover, specific miRNA signatures have been associated with histopathological and clinical features, suggesting a potential role of these molecules as prognostic and predictive markers [8, 9]. Focusing then on their biological effects and role in cancer, it has been shown that miRNAs can function as potential oncogenes or oncosuppressor genes, depending on the cellular context and on the target genes they regulate. This is the first study of miRNAs in PPNAD, and indeed, in any form of adrenal hyperplasia. In this study, the authors identified a miRNA gene signature for PPNAD [10] and demonstrated that let-7b expression is highly associated with midnight cortisol concentrations, an index of clinical severity of the Cushing syndrome caused by PPNAD tumors. The let-7 miRNA family appears to play a tumor suppressor role in cancer. In addition, using a PPNAD cell line, the authors identified the inhibition of miR-449 and up-regulation of its target gene WISP2. These results suggest that PKA, through miRNA regulation, affects the Wnt signaling pathway, which is important in the regulation of PRKAR1A-related tumorigenesis and in adrenocortical oncogenesis in general. The possibility to modulate miRNA expression either in vitro or in vivo by developing synthetic pre-miRNA molecules or antisense oligonucleotides provides a powerful tool towards a better understanding of the molecular mechanisms regulated by these molecules, and suggests the intriguing and promising perspective of their possible use in therapy.

New concerns Long-term effects of early-life stress

Childhood maltreatment and telomere shortening: preliminary support for an effect of early stress on cellular aging
Tyrka AR, Price LH, Kao HT, Porton B, Marsella SA, Carpenter LL Mood Disorders Research Program, Butler Hospital, Providence, R.I., USA Audrey_Tyrka@Brown.edu Biol Psychiatry 2010;676:531–534
Background: Advanced cellular aging has been proposed as a potential mechanism for the association between psychological stress and several medical and psychiatric illnesses. Previous studies linked chronic psychosocial stress and activation of the hypothalamus-pituitary-adrenal axis to shorter telomere length. Telomeres are DNA repeats that cap the ends of chromosomes and promote stability. They shorten progressively with each cell division and their length is a marker of biological aging. This study was designed to investigate the effect of childhood adversity on telomere length. Methods: 31 adults with no current or past major axis I psychiatric disorder were recruited to participate in this cross-sectional study. Subjects reported on their history of childhood maltreatment with a retrospective self-report questionnaire (CTQ). Telomere length was measured following DNA extraction from whole blood. Results: Participants reporting a history of childhood maltreatment had significantly shorter telomeres than those who did not report a history of maltreatment. This finding was not due to the effects of age, sex, smoking, body mass index or other demographic factors. Both physical neglect and emotional neglect were significantly linked to telomere length. Conclusions: Childhood maltreatment could influence cellular aging.

Stressful life experiences have been associated with an increased risk for psychiatric disorders, as well as cardiovascular and immune diseases [11]. The results of the present study extend previous reports linking shortened leukocyte telomere length and caregiver stress to more remote stressful experiences in childhood. In this study, reported maltreatment was moderate to severe, and a variety of types of abuse and neglect were represented. Analysis of subtypes of maltreatment suggested that both emotional and physical neglect may have the most robust effects. Therefore, in addition to the psychological effects of stress, it is possible that physical stressors might have contributed to these findings. Although the mechanism underlying the above association remains to be elucidated, gluco-

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corticoid-associated oxidative stress damage is likely to play an important role. Glucocorticoids increase neuronal oxidative stress damage [12] and oxidative stress reduces telomere length in vitro [13]. Limitations of this study that should be taken into consideration are the modest sample size, the cross-sectional nature of the study, and the fact that the CTQ is a brief, retrospective self-report questionnaire that may be subject to recall and other biases. Longitudinal, prospective, larger studies are needed to elucidate the effect of psychosocial stress on telomere length over time.

Quality of life in children and adolescents one year after cure of Cushing syndrome: a prospective study
Keil MF, Merke DP, Gandhi R, Wiggs EA, Obunse K, Stratakis CA Program on Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, Bethesda, Md., USA keilm@mail.nih.gov Clin Endocrinol (Oxf) 2009;71:326–333
Background: Cushing syndrome (CS) in children is associated with symptoms that may impair healthrelated quality of life (HRQL). Prospective studies investigating the HRQL in children with CS are lacking. Methods: 40 children (age range 5–18 years) with CS were studied prospectively prior to and 1 year posttreatment for CS. The Child Health Questionnaire (CHQ) was used to assess HRQL, the Wechsler Intelligence Scale for Children (WASI) was used to assess cognitive function, and a CS symptom checklist was used to assess patient-reported symptoms. Results: Active CS was associated with low physical and psychosocial summary scores compared to US population data. Although these scores improved 1 year post-cure, residual impairment remained in physical summary and function. Incomplete recovery of adrenal function at 1 year post-treatment was associated with impaired scores. WASI IQ scores declined and a correlation was noted between age at first evaluation and IQ score changes. Most self-reported CS symptoms improved following treatment, with the exception of forgetfulness, unclear thinking and decreased attention span. Conclusions: CS in children and adolescents is associated with impaired HRQL, with residual impairment 1 year after cure.

Chronic exposure to excess endogenous glucocorticoids in adults, children and adolescents with CS is associated with detrimental health effects including truncal obesity, hypertension, insulin resistance, hyperglycemia, impaired wound healing, hypercoagulability, osteoporosis and gonadal dysfunction. Adult studies have also demonstrated that glucocorticoid excess is associated with impaired cognition. This study showed that children and adolescents with active CS had low physical and psychosocial summary scores compared to their peers in the US population. One year after successful cure of CS, children and adolescents showed residual impairments in HRQL scores for physical summary scores, physical function, global health perception, role-physical and emotional impact on parent. These findings are consistent with previous studies demonstrating that children with CS experienced a decline in cognitive function after cure of CS, despite reversal of cerebral atrophy [14]. This is in contrast to studies of adults with CS, which reported that cognitive impairment and loss of brain volume is partially reversible after successful treatment [15]. In addition, younger children were more likely to experience negative changes in cognitive function from pre- to post-treatment, although all post-treatment IQ scores remained within a normal range. Long-term follow-up of children and adolescents with CS, with particular reference to HRQL, is essential.

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Concepts revised A new role for dehydroepiandrosterone sulfate

Dehydroepiandrosterone sulfate directly activates protein kinase C- to increase human neutrophil superoxide generation
Radford DJ, Wang K, McNelis JC, Taylor AE, Hechenberger G, Hofmann J, Chahal H, Arlt W, Lord JM Medical Research Council Centre for Immune Regulation, School of Immunity & Infection, University of Birmingham, Birmingham, UK J.M.Lord@bham.ac.uk Mol Endocrinol 2010;24;813–821
Background: Dehydroepiandrosterone (DHEA) sulfate (DHEAS) is the most abundant steroid in human circulation, and is secreted in an age-dependent fashion. DHEAS is considered an inactive metabolite that can be activated following cleavage of the sulfate group, thus generating DHEA, an important sex steroid precursor. Methods: Human neutrophils were isolated from healthy male donors. Neutrophil superoxide production, OATP, STS and SULT2A1 mRNA expression analysis, DHEAS uptake assays, protein kinase C (PKC) activation assays and phosphorylation of p47phox were studied. Results: DHEAS, but not DHEA, increased superoxide generation in primed human neutrophils in a dose-dependent fashion. This effect was not prevented by coincubation with androgen and estrogen receptor antagonists but was reversed by inhibition of PKC activity. Neutrophils were found to be unique among leukocytes in expressing an organic anion-transporting polypeptide D, able to mediate active DHEAS influx transport whereas they did not express steroid sulfatase that activates DHEAS to DHEA. DHEAS directly activated recombinant PKC- in a cell-free assay. Enhanced PKC- activation by DHEAS resulted in increased phosphorylation of p47phox, a crucial component of the active reduced nicotinamide adenine dinucleotide phosphate complex responsible for neutrophil superoxide generation. Conclusions: PKC- acts as an intracellular receptor for DHEAS in human neutrophils, a signaling mechanism entirely distinct from the role of DHEA as sex steroid precursor and with important implications for immune senescence, which includes reduced neutrophil superoxide generation in response to pathogens, thereby impacting on a key bactericidal mechanism.

DHEA and its sulfate ester, DHEAS, are the most abundant steroids in human circulation, representing the major products of the adrenal zona reticularis. In humans and higher primates, DHEAS secretion shows a characteristic, age-associated pattern with very high concentrations in the neonatal period, a decline to very low concentrations during the first few months of life, and a continuous increase starting between the sixth and tenth year of age, also termed ‘adrenarche’ [16]. Peak DHEAS concentrations are achieved during the third decade of life followed by a steady decline starting in the fifth decade (adrenopause) with concentrations decreasing to 10–20% of maximal levels around 70 years of age [16]. This age-related decline in DHEAS does not reflect a general loss of adrenocortical output because cortisol concentrations are maintained and are even slightly raised with age [17]. This study challenges the previously held views that DHEAS is an inactive metabolite, and provides evidence for a novel signaling mechanism of DHEAS, which is distinct from its role as a precursor to DHEA and downstream sex steroid synthesis. In human neutrophils, PKC- acts as an intracellular receptor for DHEAS, mediating its stimulatory effects on neutrophil superoxide generation via activation of the NADPH oxidase complex. This is the first report of the direct activation of a major serine/ threonine protein kinase by DHEAS. These effects of DHEAS may have important clinical implications, with particular reference to immunologic conditions and/or old age.

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An ACT is scored from 0 to 9. Morris M Centro Studi sull’Invecchiamento. Calton L. St Leonards. the authors recommend the addition of IHC with IGF2 and a marker of proliferation (Ki-67 because of its wide availability and easy interpretation). MAD2L1. Microarray gene expression profiling is a powerful tool that is able to characterize the transcription profile of a large number of genes in a tumor sample. with a higher score correlating with increased malignancy. is presently the most widely used system for classifying adrenocortical tumors (ACTs) as benign or malignant [18]. The Weiss score.. adrenal tumors have been detected with increasing frequency.16:573–583 Background: The Weiss score is the most widely used system for the diagnosis of adrenocortical tumors (ACTs). University of Sydney. Distinguishing between adrenocortical adenomas (ACAs) and adrenocortical carcinomas (ACCs) can be difficult.Important for clinical practice Immunohistochemistry and liquid chromatography-mass spectrometry in the diagnosis of adrenal disorders Microarray gene expression and immunohistochemistry analyses of adrenocortical tumors identify IGF2 and Ki-67 as useful in differentiating carcinomas from adenomas Soon PS. Hammond G. Brown HA. Genes with high-discriminatory power were identified by univariate and multivariate analyses and confirmed by quantitative real-time reverse transcription PCR and immunohistochemistry (IHC). ACCs demonstrated significantly higher expression of IGF2. Sidhu SB Cancer Genetics.411:222–228 Background: The diagnosis of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is based on the quantification of 17-hydroxyprogesterone (17-OHP) by an immunoassay. leading to high false-positive rates.T.W. However. With the advent of improved imaging techniques. Serum steroid profiling for congenital adrenal hyperplasia using liquid chromatography-tandem mass spectrometry Rossi C. SEPT4 and RPRM. Immunohistochemistry (IHC) using IGF2 and a marker of proliferation can also distinguish ACCs from ACAs. ACTs with a score of 3 can be phenotypically benign or malignant. in an attempt to classify and predict the biological behavior of these tumors accurately. Given that microarray gene expression profiling is expensive and its use in the clinical setting is limited.usyd. Gill AJ. whilst the Weiss score reliably classifies ACTs with a score of 0–2 as ACAs and those with a score of 4–9 as ACCs. Sydney. Kolling Institute of Medical Research. However. 108 Erica L. Fondazione Universitaria G. Australia patsysoon@med. including IGF2. Conclusions: Microarray gene expression profiling accurately differentiates ACCs from ACAs. However. This study has demonstrated that microarray gene expression profiling can accurately categorize ACTs into ACCs and ACAs. This would lead to expeditious treatment for patients with ‘true’ ACCs. during the neonatal period the specificity of screening for CAH is low.edu. Benn DE. and ultimately lead to better prognosis and improved quality of life. Sacchetta P. MAD2L1 and CCNB1 but lower expression of ABLIM1. The combination of IGF2 and Ki-67 IHC is highly accurate in distinguishing between the two groups and is particularly helpful in ACTs with a Weiss score of 3. a 9-point histopathological scoring system. CCNB1 and Ki-67 had high-diagnostic accuracy in differentiating ACCs from ACAs. for the group of ACTs with a Weiss score of 3. McDonald KL. N. Results: Compared with ACAs. Several proteins. A combination of IGF2 and Ki-67 diagnosed ACCs with 96% sensitivity and 100% specificity. the biological behavior of ACTs with a score of 3 can be difficult to predict accurately. van den Akker/Evangelia Charmandari . Italy Clin Chim Acta 2010.S. Chieti.au Endocr Relat Cancer 2009. NAV3. d’Annunzio. Robinson BG. Methods: Microarray profiling of a cohort of adrenocortical carcinomas (ACCs) and adrenocortical adenomas (ACAs) was used to identify discriminatory genes that could be used as an adjunct to the Weiss score. Wallace AM. Clarkson A. Royal North Shore Hospital.

Transient elevations of 17-OHP concentrations are often seen in premature or severely ill newborns in the screening period and contribute to a high false-positive rate [20]. Sinaii N. Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency accounts for 95% of all cases of CAH [19]. This study investigated whether a new modified-release hydrocortisone (MR-HC) formulation (ChronocortTM) is able to simulate physiologic cortisol secretion more closely compared with the conventional hydrocortisone (HC) formulation (CortefTM) in patients with CAH. while MR-HC resulted in a single cortisol peak at approximately 06:00 h. Treatment with MR-HC resulted in significantly lower afternoon (12:00–20:00 h) and night-time (20:00–04:00 h). Vanryzin C. Methods: The steroids were extracted from 50 µl of serum using methyl-tert-butyl-ether and the analysis was performed on a UPLC tandem quadrupole mass spectrometer system. It is fast. sensitivity and precision. 17-hydroxyprogesterone (17-OHP). androstenedione and ACTH concentrations were determined over a 24-hour period. specific and selective method using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS) has been developed for the measurement of serum concentrations of cortisol.and extended-release formulation of hydrocortisone for the treatment of congenital adrenal hyperplasia A pharmacokinetic and pharmacodynamic study of delayed. The application of steroid profiling by LC/MS/ MS to the newborn screening for CAH is expected to reduce the false-positive results through its high analytical specificity and the potential to quantify several compounds in the same analytical run. Ross RJ. Conclusions: A second-tier test for the diagnosis of CAH has been developed. However. Ravindran S. Analytical methods based on mass spectrometry present the most specific quantitative methods for determination of steroid concentrations [21–23]. Eunice Kennedy Shriver National Institute of Child Health and Human Development. Md. and demonstrates excellent resolution between 21-deoxycortisol and 11-deoxycortisol.. 5 and 15 mg) was followed by 1 month of once-daily MR-HC (30 mg at 22:00 h). open-label. Nieman LK. but higher morning (04:00–12:00 h) cortisol concen- Adrenals 109 . conventional hydrocortisone (CortefTM) in the treatment of congenital adrenal hyperplasia Verma S. Clinical trials – new treatments A delayed.72:441–447 Background: Current glucocorticoid therapy for congenital adrenal hyperplasia (CAH) is suboptimal and non-physiologic. crossover pharmacokinetic and pharmacodynamic study was conducted in 14 patients (age range 17–55 years) with classic 21-hydroxylase deficiency. The introduction of an immunoassay for 17-hydroxyprogesterone (17-OHP) in the late 1970s has contributed substantially to the uptake of CAH newborn screening programs. USA Clin Endocrinol (Oxf) 2010. robust and reproducible. Bethesda. Simultaneous measurement of the full range of steroids in the pathway of cortisol biosynthesis allowed confirmation of the affected steroidogenic enzyme. The method allows for detection and quantification of 5 steroids with good linearity. This method is based on LC/MS/ MS. Inter. allows quantification of 5 steroids related to CAH in 5 min. Methods: A phase 2. Kim MS.and extendedrelease hydrocortisone (ChronocortTM) vs. Calis KA. A new method for diagnosing CAH accurately has been developed. 21-deoxycortisol. 4-androstene-3. and newborn screening has been advocated in many countries. Early diagnosis and treatment is associated with a significant reduction in morbidity and mortality. Results: The assay was linear over each analyte concentration range. Cortisol. Merke DP Reproductive Biology and Medicine Branch.A robust. Results: Hydrocortisone therapy resulted in three cortisol peaks.17-dione (A4) and 17-OHP. Arlt W. thereby indicating the enzymatic defect in the vast majority of cases. its diagnostic value is often limited. One week of thrice-daily HC (10.and intra-assay CVs were ≤10% across the analytical range. 11-deoxycortisol. despite the wide availability and usage of this test. owing to low analytical antibody specificity and the limited diagnostic specificity of an isolated raised 17-OHP concentration.

van den Akker/Evangelia Charmandari . but rose in the afternoon with once-daily dosing. ChronocortTM achieved good overnight and early morning (but not afternoon or evening) control of ACTH and adrenal androgen secretion. Ross RJ Academic Unit of Diabetes. Patients on MR-HC had significantly higher afternoon (12:00–20:00 h) 17-OHP. Delayed. the currently available formulations of hydrocortisone are not able to simulate the normal cortisol circadian rhythm.and sustained-release oral formulations of hydrocortisone are being developed. UK Best Pract Res Clin Endocrinol Metab 2009. School of Medicine. Overnight adrenal androgens were well controlled. In patients with classic CAH. Physiologic cortisol replacement in patients with CAH or adrenal insufficiency is expected to offer improved biochemical control and quality of life. In a proof-of-principle study. 110 Erica L. Current treatment aims to provide adequate glucocorticoid and. Conclusions: Modified-release hydrocortisone represents a promising new treatment for CAH. Novel strategies for hydrocortisone replacement Debono M. However. However. Proof-of-concept studies using hydrocortisone infusions predict an improvement in both the biochemical control and the quality of life in treated patients. The use of a delayed. ChronocortTM was shown to mimic the circadian rhythm of serum cortisol secretion in healthy volunteers [26]. suggesting that a morning dose of glucocorticoid is needed. and to suppress the excess secretion of androgens and steroid precursors from the adrenal cortex. Therefore.or under-replacement.trations compared with HC.and extendedrelease formulation of hydrocortisone represents a new treatment approach to CAH that offers the prospect of a more physiologic cortisol replacement. and adrenal hyperandrogenism [19]. when necessary.23:221–232 Current therapy with immediate-release hydrocortisone is the most commonly used regimen for replacement in patients with primary and secondary adrenal insufficiency.T. Recent studies have investigated circadian hydrocortisone therapy imitating the physiologic circadian cortisol rhythm. and patients are often at risk for developing in tandem iatrogenic Cushing’s syndrome and hyperandrogenism [24. which are expected to offer a more practical and effective solution for patients with adrenal insufficiency and congenital adrenal hyperplasia. 25]. patients with adrenal insufficiency have a poor quality of life and an increased mortality despite optimal doses and adherence to treatment. but significantly lower 08:00 h 17-OHP concentrations. ChronocortTM is a novel modified-release formulation of hydrocortisone designed to approximate physiologic cortisol secretion. Sheffield.and/or over-treatment with glucocorticoids in these patients. as well as to decrease the risk for the development of co-morbidities owing to under. impaired development and function of the adrenal medulla. No serious adverse events occurred. Royal Hallamshire Hospital. Price JN. Twice. Further studies are needed to determine the optimal dosing regimen and long-term clinical outcome. Endocrinology and Metabolism. androstenedione and ACTH. conventional hydrocortisone treatment cannot simulate physiologic cortisol production.or thrice-daily doses of hydrocortisone substitution inevitably result in temporary over. mineralocorticoid substitution to prevent adrenal crises. Classic CAH is characterized by a defect in cortisol and aldosterone secretion.

fr PLoS One 2009. Sahut-Barnola I. another ubiquitous molecule with major functions in behavioral. Gas5 is expressed in growth-arrested cells as a result of nutrient deprivation or growth factor withdrawal. PGF2 secretion appeared constitutive and correlated to continuous Background: Adrenals 111 . Ichijo T. thereby influencing cell survival and metabolic activities during starvation. metabolic and immune homeostasis. Pointud JC. Ragazzon B. More specifically. The present study has demonstrated that Gas5 is a strong interactant of the DNA-binding domain (DBD) of the GR.and starvation-associated repressor of the glucocorticoid receptor Kino T. Clermont University. the nuclear translocation of proteins. the most efficient mammalian PGFS belong to aldo-keto reductase 1B (AKR1B) family. which is abundant in cells whose growth has been arrested because of lack of nutrients or growth factors. while increased glucocorticoid secretion or activity is associated with an unfavorable metabolic profile and decreased life expectancy.New mechanisms Non-coding RNA gas5 is a growth arrest. Aldo-keto reductase 1B7 and prostaglandin F2 are regulators of adrenal endocrine functions Lambert-Langlais S. Prostaglandin biosynthesis depends on the sequential action of upstream cyclooxygenases (COX) and terminal synthases but no PGF2 synthases (PGFS) were functionally identified in mammalian cells. Lefebvre H. Val P. energy expenditure and survival.or growth arrest-linked riborepressor of the GR and possibly other steroid hormone receptors. Given that relative starvation produces a favorable metabolic profile and prolongs life in several organisms. In vitro. Md. Eunice Kennedy Shriver National Institute of Child Health and Human Development. Nader N. induced apoptosis by suppressing glucocorticoid-mediated induction of several responsive genes. In chromaffin cells. These findings indicate that Gas5 ncRNA functions as a starvation. Martinez A CNRS. Gas5 ncRNA interacts with the DBD of the ligand-activated GR through a decoy RNA ‘GRE’ and suppresses the GR-induced transcriptional activity of endogenous glucocorticoidresponsive genes by inhibiting binding of the GRs to target genes’ GREs.4:e7309 Prostaglandin F2 (PGF2 ) represses ovarian steroidogenesis and initiates parturition in mammals but its impact on adrenal gland is not known. Manin M.3:ra8 Background: The availability of nutrients influences cellular growth and survival by affecting gene transcription.gov Sci Signal 2010. Methods and Results: The growth arrest-specific 5 (Gas5) non-coding RNA.. Glucocorticoids also influence gene transcription and have diverse activities on cell growth. Volat F. France antoine. the observed Gas5-GR interaction might be of physiologic and/or pathologic importance. Gas5 bound to the DNA-binding domain of the glucocorticoid receptor (GR) and competed with DNA glucocorticoid-response elements for binding to the GR. Hurt DE. Bethesda. Conclusions: Gas5 modulates the transcriptional activity of the GR by acting as a ‘riborepressor’. Chrousos GP Unit on Molecular Hormone Action. The adrenal gland is a major site of AKR1B expression in both human (AKR1B1) and mouse (AKR1B3. Louiset E. National Institutes of Health. Both cortical and medullary compartments were shown to produce PGF2 but expressed different biosynthetic isozymes. Aubière. Program in Reproductive and Adult Endocrinology. cardiovascular. Non-coding RNAs (ncRNAs) have diverse regulatory functions and may affect every aspect of organismal biology by influencing messenger RNA (mRNA) transcription.martinez@univ-bpclermont. degradation and translation. including the cellular inhibitor of apoptosis 2. Methods and Results: This study examined the PGF2 biosynthetic pathway and its functional impact on both cortical and medullary zones using in vivo approaches and murine cell culture models. Urade Y. UMR6247-Genetic. USA kinot@mail. Coudoré F. Lefrançois-Martinez AM. AKR1B7). Delarue C. or both protein abundance and localization [27]. Reproduction and Development. One such singlestrand ncRNA is the growth arrest-specific 5 (Gas5) [28].nih.

genetic deletion of subunits of K+-selective leak-channels (KCNK). TASK1 plays an important role in the regulation of human aldosterone production through regulation of intracellular Ca2+ and CaMK signaling pathways. In steroidogenic cells. However. Conclusions: Human adrenal cortex displays predominant expression of TASK1 over other KCNK family genes. leading to activation of CaMK and increased expression of CYP11B2. NA and H295R cells the expression of TASK1 was predominant when compared to other KCNK family members. These events stimulate the early and the late regulatory steps in aldosterone production.T. In mice. StAR protein and CYP11B2 respectively. PGF2 is an essential autocrine/paracrine regulator of ovarian and testicular steroidogenesis. in APA. little was known about its possible impact on the adrenal gland. Augusta. K+ and ACTH. Methods: TASK1 expression was investigated by comparative microarray analysis of aldosterone-producing adenomas (APA) and normal adrenals (NA). making medulla the primary target of PGF2 action. USA Clin Endocrinol (Oxf) 2009. AKR1B3) could play a pivotal role in the generation of this signal.. a loss-of-function TASK3 mutation has been described in patients with Birk Barel syndrome [31]. Recent studies have demonstrated that deletion of TASK1 and TASK3 in animal models leads to PA [29. Ga. Knockdown of TASK1 induced the expression of steroidogenic acute regulatory (StAR) protein and aldosterone synthase (CYP11B2). culminating with elevated aldosterone production. Primary hyperaldosteronism (PA) is the most common cause of secondary hypertension.and down-expression in cell lines. Binding of Ang II to its type 1 receptor (AT1R) stimulates a variety of signaling cascades. a characteristic that is associated with the expression of high levels of KCNK channels. Furthermore. Adrenal glomerulosa cells are sensitive to small increases in extracellular K+. leads to hyperaldosteronism and histological changes in the adrenal cortex. The present study provides a new insight in the understanding of PGF2 biosynthesis and its role in the function of the adrenal gland. PGF2 receptor was only detected in chromaffin cells. Fluo-4 fluorescent measurements of intracellular Ca2+ and pharmacological inhibition of Ca2+-dependent calmodulin kinases (CaMK) were performed to better define the effects of TASK1 on Ca2+ signaling pathways.expression of COX1 and AKR1B3. The effects of TASK1 knockdown by siRNA transfection were investigated in H295R cells. as well as its potential role in PA. Aldosterone biosynthesis in the zona glomerulosa of the adrenal cortex is physiologically regulated by angiotensin II (Ang II). The role of TASK1 in aldosterone production and its expression in normal adrenal and aldosterone-producing adenomas Nogueira EF. AKR1B1. and that the coordinate cell-specific regulation of both cyclooxygenases (COX1 and COX2) and aldo-keto reductases of the AKR1B subfamily (AKR1B7. van den Akker/Evangelia Charmandari . Results: The expression of TASK1 did not differ between APA and NA. PGF2 secretion was stimulated by ACTH and correlated to ACTH responsiveness of both COX2 and AKR1B7/B1. Mariniello B. and stimulated pregnenolone and aldosterone production. Epub ahead of print Background: Aldosterone production in the adrenal glomerulosa is mainly regulated by angiotensin II and K+. The authors demonstrated for the first time that 112 Erica L. This study investigated the expression of TASK1 in human adrenocortical cells and its role in aldosterone production in H295R cells. The pivotal role of AKR1B7 in ACTH-induced PGF2 release and functional coupling with COX2 was demonstrated using over. 30]. including the TWIK-related acid sensitive K+ 1 and 3 (TASK1 and TASK3). Conclusions: PGF2 repressed glucocorticoid secretion by a decrease in catecholamine release. The present study sought to define the role of TASK1 in adrenal cell aldosterone production. In addition. leading to the release of Ca2+ from the endoplasmic reticulum and subsequent cell membrane depolarization with additional flow of extracellular Ca2+ into the cytoplasm. Mantero F. which in turn decreased adrenal steroidogenesis. Martinez and colleagues established for the first time that PGF2 acts as a negative regulator of both adrenocortical and adrenomedullary functions. Medical College of Georgia. TASK1 and/or TASK3. Cells transfected with siTASK1 had increased intracellular Ca2+. PGF2 may be regarded as a negative autocrine/paracrine regulator within a novel intra-adrenal feedback loop. Rainey WE Department of Physiology. However. Gerry D.

Toledo SP. San Antonio. In a cohort of 103 samples. Opocher G. Toledo RA. New genes Germline mutations in TMEM127 confer susceptibility to pheochromocytoma Qin Y. which is similar to the mean age at diagnosis of sporadic pheochromocytomas. Sass M. Buddavarapu K. Aguiar RC. Chocron ES. All tumors arose from the adrenal medulla and were bilateral in approximately half of the cases. The present study identified TMEM127 as a new gene conferring susceptibility to pheochromocytoma. and that TASK1 knockdown stimulated aldosterone production through augmentation of Ca2+ flux and activation of CaMK in human adrenocortical cells. Clinically. These intracellular signaling events culminated with the activation of early (StAR) and late (CYP11B2) rate-limiting steps in aldosterone production.42:229–233 Background: Pheochromocytomas are catecholamine-secreting tumors of neural crest origin that are often hereditary. truncating germline TMEM127 mutations were detected in approximately 30% of familial tumors and 3% of sporadic pheochromocytomas without a known genetic cause. The molecular basis of the majority of these tumors is not known. The results of this study support the notion that disruptions of TMEM127 function might underlie tumors with an aberrant mTOR pathway and validate the relevance of hereditary tumor models to shed light on cell growth-related signals. Methods and Results: The transmembrane-encoding gene TMEM127 was identified on chromosome 2q11 as a new pheochromocytoma susceptibility gene. indicating a classic mechanism of tumor suppressor gene inactivation. Aronin N. Conclusions: This study identified TMEM127 as a tumor suppressor gene and validated the power of hereditary tumors to elucidate cancer pathogenesis. In tumor DNA. but notably older than the mean age at diagnosis of syndromic cases. Schiavi F. No malignancies or recurrences were detected during follow-up of the affected subjects. with variable transcription levels that may reflect tissue of origin. Adrenals 113 . Lenci RE. Dahia PL Department of Medicine. King EE. Stiles C. Boaretto F. TMEM127 is predicted to encode a protein with three transmembrane regions and no clearly recognizable functional domains. Tex. from mammals to fish. A TASK1-related clinical syndrome has not been described yet.. subjects with TMEM127 mutations developed pheochromocytomas in the fourth decade of life. in vitro gain-of-function and loss-of-function analyses indicated that TMEM127 is a negative regulator of mTOR. Accordingly. Lechleiter JD. Pheochromocytomas with mutations in TMEM127 showed hyperphosphorylation of mammalian target of rapamycin (mTOR) effector proteins. Human TMEM127 is broadly expressed both in normal tissue and in a diverse group of cancer cell lines. Yao L. Its sequence is highly conserved throughout evolution and putative orthologs can be identified in many species. USA Nat Genet 2010.TASK1 is the predominant KCNK family member expressed in the human adrenal cortex. Further studies are necessary to evaluate functional changes in TASK1 that could potentially contribute to conditions associated with increased aldosterone production. the wild-type allele was consistently deleted. TMEM127 has features of a classic tumor suppressor gene and TMEM127 mutations are associated with predisposition to pheochromocytoma development.

CytB5 mutations can result in 17.XY DSD patient with 17. probably by acting as an allosteric factor.Isolated 17. and are involved in the pathogenesis of diseases characterized by dyshomeostasis or cacostasis. but not absent. penoscrotal hypospadias. homeostasis is re-established by various physiologic and behavioral adaptive responses. but rather acts as an allosteric factor that fosters the interactions of POR with P450c17. The stress response is mediated by the stress system.20-lyase deficiency due to the cytochrome b5 mutation W27X Kok RC.20-lyase deficiency.20-lyase deficiency. Steroid hormone concentrations were determined and sequencing the CYB5 gene was performed. Stress occurs when homeostasis is threatened or perceived to be so.20-lyase deficiency was studied. The parents of the index case were heterozygous carriers of this mutation. Cytochrome b5 (CytB5) is an important factor in 17. A case of CytB5 deficiency has been reported previously in a patient with ambiguous genitalia and methemoglobinemia.20-lyase activity. Neuroendocrine hormones have major roles in the regulation of both basal homeostasis and responses to threats. however no steroid hormone concentrations were determined [34]. This mutation results in the absence of residues E48 and E49 of CytB5. POR mutations have been discussed at length in previous Yearbooks. The Netherlands f. Isolated 17. endocrine evaluation and increased methemoglobin concentrations indicated impaired CytB5 function.95:994–999 Background: Cytochrome P450c17 (P450c17) is a bifunctional enzyme necessary for the production of glucocorticoids (17-hydroxylase activity) and sex steroids (17. Department of Internal Medicine.20-lyase reactions required for the production of glucocorticoids and sex steroids.20-lyase activity without influencing 17-hydroxylase activity [32]. This protein has electron-donating capacity. The cofactor cytochrome b5 (CytB5) is also required for optimal 17. Methods: A 46.gov Nat Rev Endocrinol 2009.5:374–381 All living organisms maintain a complex dynamic equilibrium. Erasmus Medical Centre.XY disorders of sex development (DSD). Conclusion: In addition to CYP17A1 gene mutations. can accept electrons from POR and appears to participate in electron transfer for some cytochrome P450 reactions. leading to 46. enhancing 17. No mutation in the CYP17A1 gene had been detected in the patient and his parents. Drop SL. screening for mutations in the CytB5 gene.20-lyase activity). CytB5 is not an effective electron donor to P450c17. Wolffenbuttel KP.nl J Clin Endocrinol Metab 2010.T. Greece chrousog@mail.20-lyase deficiency.20-lyase deficiency is a rare condition characterized by deficient production of androgens.20-lyase activity. or homeostasis. Reviews Stress and disorders of the stress system Chrousos GP Aghia Sophia Children’s Hospital. de Jong FH Endocrine Laboratory. This study investigated the role of CytB5 in a patient with 17.dejong@erasmusmc. University of Athens. as well as for mutations in CYP17A1 and POR genes.h. Results: A homozygous W27X mutation was detected. should be considered. Cytochrome P450c17 (P450c17) catalyzes the 17-hydroxylase and 17. The absence of CytB5 results in low. Sequencing of the CytB5 gene revealed a mutation that led to a premature stop codon and a truncated protein lacking the E48 and E49 residues that are necessary for intact 17. which are necessary for an intact 17.20-lyase activity [33]. the clinical manifestations (bifid scrotum. Rotterdam.20-lyase activity. bilaterally palpable gonads). In patients with 46XY DSD and evidence of 17. leading to the formation of a premature stop codon. P450c17 requires electron donation from reduced nicotinamide adenine dinucleotide phosphate through its redox partner protein cytochrome P450 oxidoreductase (POR). Timmerman MA. van den Akker/Evangelia Charmandari . which is constantly challenged by internal or external adverse forces termed stressors.nih.20-lyase activity. In the patient described in this article. while the production of glucocorticoids is intact. partly located in the central nervous system 114 Erica L. To exert its activities. 17.

Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension Sowers JR. Prenatal development. 2). as well as cardiovascular disease and chronic kidney disease. Obesity. Mo. The homeostatic mechanisms exert their effects in an inverted U-shaped dose-response curve. Emerging evidence suggests that excess circulating aldosterone concentrations impair insulin metabolic signaling and endothelial function. Stress occurs when homeostasis is threatened or perceived to be threatened. Basal. insulin resistance and hypertension commonly cluster with other risk factors for cardiovascular and chronic kidney disease to form the metabolic syndrome. U-type dose response. ‘cacostasis’. optimal range of the curve. Columbia. healthy homeostasis (eustasis) is achieved in the central. and endothelium-dependent vasorelaxation. Eustasis is in the middle. growth and body composition. excessive or inadequate basal activity and responsiveness of this system might impair development. Optimal basal activity and responsiveness of the stress system is essential for a sense of well-being. the cardiovascular and renal abnormalities associated with insulin resistance are mediated in part by aldosterone acting on the mineralocorticoid receptor. hypertension. and partly in peripheral organs. Mineralocorticoid receptor blockade improves pancreatic insulin release. which can be emotional or physical. Epstein M University of Missouri.150:776–783 The prevalence of obesity. more correctly. childhood and adolescence are times of increased vulnerability to stressors. Aldosterone excess has detrimental metabolic effects that contribute to the metabolic syndrome and endothelial dysfunction. which in turn leads to insulin resistance and cardiovascular and renal structural and functional abnormalities. and appropriate social interactions. Both the magnitude and the chronicity of stressors are important. cardiovascular and chronic kidney disease is increasing in developed countries.Homeostatic effect Allostasis (Cacostasis) Eustasis Allostasis (Cacostasis) Deficiency Optimum Excess Homeostatic system activity Fig. The stressors are potentially adverse forces. and might account for many acute or chronic disorders. insulin-mediated glucose utilization. 2009. and lead to a host of behavioral and somatic pathologic conditions. USA Ann Intern Med. Suboptimal effects may be on either side of the curve and can lead to suboptimal adaptation. Adrenals 115 . successful performance of tasks. termed ‘allostasis’ or. The latter might be harmful for the organism. diabetes.. 2. which in turn lead to the development of resistant hypertension. whereas suboptimal effects may occur on either side of the curve and can lead to insufficient adaptation (allostasis or cacostasis) (fig. which may be harmful for the organism in the short or long term. Whaley-Connell A. infancy. Homeostatic systems exert their effects in an inverse. By contrast. optimal range of the curve. When any stressor exceeds a certain severity or temporal threshold. the adaptive homeostatic mechanisms of the organism activate compensatory responses that functionally correspond to the stressor. Furthermore.

Cortisol and ACTH concentrations were determined following a combined dexamethasone/CRH test. University of Zurich. Hoefels S. Conclusions: With increasing OC scores. In this study. and hypertension commonly cluster with other risk factors for cardiovascular or chronic kidney disease to form the metabolic syndrome. insulin resistance. Many of these adverse effects are mediated through rapid.Obesity. depressive symptoms (Beck Depression Inventory. which is associated with increased cardiovascular morbidity and mortality [35]. resistant hypertension. A new paradigm indicates that elevated concentrations of plasma aldosterone mediate several maladaptive changes that contribute to the pathogenesis of the metabolic syndrome. Siegrist J. BDI) and work stress (effort-reward-imbalance. OC was not associated with ACTH or cortisol pre-test concentrations. Zobel AW Department of Clinical Psychology and Psychotherapy. higher OC was associated with higher repeated cortisol but not ACTH secretion. a higher reactivity of the adrenal cortex together with a normal reactivity of the pituitary is observed following CRH stimulation.de Psychoneuroendocrinology 2010. Methods: 92 men and 108 women of a wide range of OC scores were recruited to participate in this cross-sectional study. emerging evidence suggests that OC is associated with alterations in the HPA axis function. Further studies are required to determine the clinical implications of these findings (including insulin resistance. ERI) were assessed by questionnaires.Zobel@ukb. 37]. membrane-initiated non-genomic actions of aldosterone. van den Akker/Evangelia Charmandari . Although the underlying mechanisms have not been fully delineated. Results: Independent of age and gender.uni-bonn. Prospective studies have demonstrated that OC independently increases the risk for coronary heart disease (CHD) [39–41]. Future research studies should further delineate the role of mineralocorticoid receptor blockade in the management of the metabolic syndrome and resistant hypertension. This study investigated whether OC is associated with alterations in the function of HPA axis. Overcommitment (OC) is considered to be an enduring cognitive-motivational pattern of maladaptive coping with demands characterized by the inability to withdraw from obligations combined with a high need for control and approval [38]. From a clinical perspective. Food for thought Social disadvantage and overcommitment are associated with impaired HPA function Higher overcommitment to work is associated with higher plasma cortisol but not ACTH responses in the combined dexamethasone/CRH test in apparently healthy men and women Wirtz PH. OC individuals are extremely ambitious and tend to exaggerate their efforts while at the same time they overestimate their resources. OC and depression are known to increase the risk of CHD and might share a common biological mechanism of HPA axis dysregulation. Zurich. higher cortisol but not ACTH increase following CRH stimulation was predicted by higher OC.35:536–543 Background: Overcommitment (OC) is a pattern of excessive striving that has been associated with alterations in the hypothalamic-pituitary-adrenal (HPA) axis. OC. obesity. Switzerland Astrid. Depressive symptoms (BDI score) and work stress scores (effort-reward-ratio) did not relate to neuroendocrine responses to the dexamethasone/CRH test. Emerging evidence suggests that mineralocorticoid receptor blockade is useful in treating resistant hypertension and in preventing cardiovascular and chronic kidney disease in patients with the metabolic syndrome and diabetes. Maier W. and associated cardiovascular and renal structural and functional abnormalities [36. Similarly. Schuhmacher A.T. suggesting an association between OC and HPA axis dysregulation. Zobel and colleagues demonstrated that OC is independently associated with higher increases in cortisol but not ACTH concentrations following a combined dexamethasone/CRH test. hyperten- 116 Erica L. OC is associated with an increased risk of depression.

Mol Cell Endocrinol 2007. Chabre O. Coussieu C. Cell 2002.267:1244–1252. Mowzowicz I. as well as the mechanisms underlying the link between OC and CHD. The study showed that fertility problems in NC-CAH are mild compared to the classic forms of the disease [42. Ndiaye N. Boudou P.5:522–531. Endocr Rev 2001. Schibler U. Tremblay J. Results: 95 of the 190 women (age 26. 95:1182–1190 Background: Although fertility has been evaluated in women with the classic form of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. who presented with hirsutism (78%). Tardy V. Kino T: Intracellular glucocorticoid signaling: a formerly simple system turns stochastic. menstrual irregularities (61%) or infertility (12%). little is known about fertility in women with the non-classic form of the disease (NC-CAH). Biol Reprod 1991. Conclusions: Subfertility is mild in NC-CAH.17:619–638. The diagnosis had been confirmed by an ACTH stimulation test and sequencing of the CYP21A2 gene. Although fertility problems are addressed in adulthood. The present study provides a follow-up. 5. Sadie H. Lu J. which is slightly less than in the general French population (92%). Methods: 161 women with NC-CAH (age range 13–52 years). Hamet P: Ectopic and abnormal hormone receptors in adrenal Cushing’s syndrome. 43].sion and atherosclerotic cardiovascular disease). Sassone-Corsi P: A web of circadian pacemakers. He L. However. Touraine P. the group of patients not receiving glucocorticoid treatment reported a higher number of miscarriages (26%) compared with the group receiving glucocorticoid treatment (6. Nat Rev Genet 2004.3% for pregnancies obtained without treatment. Follow-up on Yearbook 2009 Fertility in non-classic congenital adrenal hyperplasia Fertility in women with non-classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency Bidet M. Ronacher K: Regulation of expression of mammalian gonadotrophin-releasing hormone receptor genes. 9. Last year’s Yearbook addressed fertility in classic CAH. van Biljon W. 6. Kuttenn F Department of Reproductive Endocrinology. Getz G. Bellanné-Chantelot C. Paris. Morel Y. JAMA 1992.5% for pregnancies obtained with glucocorticoid treatment and 26. 83% of pregnancies were obtained within 1 year. Clauin S.22:75–110. Mazzuco TL. J Neuroendocrinol 2005. Hannon GJ: MicroRNAs: small RNAs with a big role in gene regulation. Adrenals 117 . Golmard JL.kuttenn@psl.aphp. suggesting that glucocorticoid treatment should be instituted in patients who want to conceive. Interestingly. Rivier C.111:919–922. The rate of miscarriages was 6. Chrousos GP. Gold PW: The concepts of stress and stress system disorders. Nature 2005. investigating fertility in a large group (n = 190) of women with non-classic CAH. References 1. which resulted in 141 births in 82 of them.265-266:23–28. 3. the issue is often raised by the pediatric endocrinologists and is discussed with patients and their parents during adolescence. Chrousos GP. Galand-Portier MB. Rivest S: Effect of stress on the activity of the hypothalamic-pituitary-gonadal axis: peripheral and central mechanisms. 187 pregnancies occurred in 85 women. Sci STKE 2005:pe48 2.5%) or the general population (10–15%). the rate of miscarriages is lower in pregnancies occurring with glucocorticoid treatment. These findings suggest that introducing glucocorticoid treatment in women with NC-CAH who want to conceive may improve pregnancy rates. Miska EA. Hapgood JP. and 29 affected female relatives were studied. France frederique. Bachelot A.45:523–532.435:834–838. Lacroix A. Feige JJ. 7.7 ± 8. Hôpital Pitié-Salpêtrière. 8. 4. Overview of physical and behavioral homeostasis. Thomas M: Aberrant GPCR expression is a sufficient genetic event to trigger adrenocortical tumorigenesis.9 years) wanted to become pregnant.fr J Clin Endocrinol Metab 2010. et al: MicroRNA expression profiles classify human cancers. The cumulated pregnancy rate for the 90 women who wanted to become pregnant was 76% at 1 year.

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Methods: Studies were performed using perifused isolated islets. a glucagon response to an exogenous zinc switch-off signal was observed during glucose deprivation.org Diabetes 2010. In experiments with streptozotocin-treated wild-type islets. an early onset of T1D is often associated with more acute presentations. to identify subjects at increased risk of developing it. In addition. Mechanism of the year Another key role of the KATP channel ATP-sensitive K+ channel mediates the zinc switch-off signal for glucagon response during glucose deprivation Slucca M. with a doubling of new cases in children younger than 5 years [1]. there will be a 70% increase in the prevalence of T1D.Type 1 Diabetes: Clinical and Experimental Francesco Chiarelli and M. in particular when dealing with a chronic disease such as T1D and when the aim is to improve the future of our children.. to improve daily management of T1D and to identify factors which could predict subjects particularly predisposed to the long-term vascular complications. All the above-mentioned aspects are the focus of the articles chosen for the 2010 Yearbook chapter on T1D. with an annual increase over the last years of about 3–4% [1]. diazoxide. Endocrinology. Results: The expected glucagon response to an endogenous insulin switch-off signal during glucose deprivation was observed in wild-type mouse islets. Glucagon release from pancreatic -cells represents one of the main compensatory mechanisms stimulated by hypoglycemia. These data are worrisome given that a diagnosis of T1D during childhood determines a longer exposure to the metabolic derangements of the disease when compared to adult-onset T1D. Conclusions: This study shows that zinc co-release with insulin during glucose deprivation is a switch-off signal triggering glucagon secretion and that this zinc action is mediated through closure of KATP channels and consequent opening of calcium channels. Based on recent estimates. The aim of this study was to determine whether closure of the -cell ATP-sensitive K+ channel (KATP channel) is the mechanism through which the zinc switch-off signal triggers glucagon secretion during glucose deprivation. and towards whom more aggressive and intensive interventions should be directed. Chieti. The emergence of new and promising treatment options always creates optimism among clinicians and researchers. However. This response is often impaired. Loredana Marcovecchio University of Chieti. or tolbutamide or if KATP channel knockout mouse islets were used. Oseid EA. rather than the decrease in insulin itself. such as diabetic ketoacidosis and admission to hospital. Wash. this glucagon response to the zinc switch-off signal during glucose deprivation was not seen in the presence of nifedipine. which increase T1D morbidity [3]. to a variable degree. between 2005 and 2010. Italy Type 1 diabetes (T1D) is one of the most common chronic disorders of childhood and adolescence and its incidence is rising worldwide. All islets had intact glucagon responses to epinephrine. Seattle. . Many efforts are continuously made to better understand the pathogenesis of the disease. and Nutrition. Harmon JS. USA rpr@pndri. University of Washington. Department of Medicine and Department of Pharmacology. Robertson RP Pacific Northwest Diabetes Research Institute and the Division of Metabolism. in people with diabetes.59:128–134 Background: A recent hypothesis based on in vivo data from hypoglycemic rats proposes that glucagon secretion during hypoglycemia is triggered by a decrease in zinc co-secreted with insulin from -cells. therefore increasing the burden of the disease [2]. Bryan J.

The results support the hypothesis that the association of high basal glucagon in T1D could at least in part be attributed to lack of insulin-bound zinc tonically suppressing -cell function. Through a series of experiments in mice. Pisa.0001) independently of gender. Then. In the present study the authors mark a further step in the understanding of the intra-islet insulin hypothesis. for lack of -cell insulin release. p < 0.The ‘intra-islet insulin hypothesis’ is an intriguing hypothesis suggesting that glucagon secretion in conditions of glucose deprivation is mediated by the decreased intra-islet insulin secretion [4].0001) and predicted incident diabetes (p < 0.it Diabetes 2010. together with insulin could suppress glucagon secretion when insulin levels are high and stimulate its release during hypoglycemia. 2-hour glucose levels did not significantly change until 0. insulin sensitivity.78 years before diagnosis. where the SUR1 subunit of the KATP channel was knocked out. 13 mmol · l–1 · year-1). A further step in their experiments was to block calcium channels with nifedipine. -cell glucose sensitivity was significantly reduced in progressors (median 48 pmol/min/m2/mmol/l [IQR: 36] vs. Methods: 328 islet cell autoantibody-positive. The time trajectories of plasma glucose 120 Francesco Chiarelli/M. age.59:679–685 Background: In this study the mode of onset of hyperglycemia and how insulin sensitivity and -cell function contribute to the progression to T1D in relatives of patients with diabetes were assessed. zinc co-released with insulin has been shown to play an important role in several. every 6 months. they found that the channel failed to respond to the switch-off zinc signal during glucose deprivation.45 years before diagnosis. In this context. More recent studies have slightly modified this hypothesis proposing that other factors released by -cells. and 2. Italy ferranni@ifc. such as -aminobutyric acid and zinc. both insulin secretion and insulin sensitivity were essentially stable. the impaired function of the channel led to lack of response to the switch-off zinc mechanism. although not all. Sosenko JM. Loredana Marcovecchio . The first step of their studies was the confirmation that cessation of zinc co-release with insulin is a key mechanism to stimulate glucagon release during hypoglycemia. During this anticipation phase. when 115 subjects developed T1D. through manipulation of the KATP receptor with drugs known to influence its activity. experimental studies. and clinical risk. In contrast. Mari A.7 years later. and total post-glucose insulin output did not differ between progressors and non-progressors. New paradigms 1 The early decline of -cell glucose sensitivity Progression to diabetes in relatives of type 1 diabetic patients: mechanisms and mode of onset Ferrannini E. Conclusions: -Cell glucose sensitivity is the earliest parameter to be impaired in relatives of patients with T1D and represents a strong predictor of diabetes progression. In contrast. Glucose sensitivity progressively declined over time with a significant fall 1. Nofrate V. when they started to rise rapidly (approx. In a second model. non-diabetic relatives from the observational arms of the Diabetes Prevention Trial-1 Study (median age 11 years [interquartile range (IQR): 8] underwent sequential OGTT at baseline.cnr. Results: At baseline. BMI. which keeps the channel closed. or tolbutamide. they identified the closure of KATP channels as the key effector of the zinc switch-off signal for glucagon secretion during glucose deprivation. which therefore interfered with the downstream mechanisms following the closure of the KATP channels. University of Pisa School of Medicine. fasting insulin secretion. 87 pmol/min/m2/mmol/l [IQR: 67]. such as diazoxide. Skyler JS Department of Medicine. phenomenon which is lost in people with diabetes. The present study is of utmost importance as it strengthens the hypothesis that a key issue for keeping a good glycemic control is the intercellular hormonal dialogue within the pancreatic islets. which keeps the channel opened. -Cell glucose sensitivity (slope of the insulin-secretion/plasma glucose dose-response function) and insulin sensitivity were obtained by mathematical modeling of the OGTT glucose/C-peptide responses.

7 years before diagnosis. Interestingly. Colo. Zerbe GO. This study shows otherwise: an increased height velocity was associated with development of islet autoimmunity and progression to Type 1 Diabetes: Clinical and Experimental 121 . Results: Greater height growth velocity was associated with IA development (HR 1. for the development of IA (defined as the presence of autoantibodies to insulin.63 [95% CI 1.42]) for a 1 SD difference in velocity. with a slow linear increase followed by a rapid increase. Dabelea D. GAD or protein tyrosine phosphatase islet antigen 2 twice in succession) and T1D. A detailed understanding of the timeline of events characterizing the development of T1D in genetically predisposed individuals could help in defining when to intervene and with which strategy.edu Diabetologia 2009. Klingensmith GJ. this study indicates that in vivo -cell glucose insensitivity is an early defect in T1D. which developed in 143 and 21. of the 1. greater height growth velocity may be involved in the progression from genetic susceptibility to autoimmunity and then to T1D. Conclusions: In prepubertal children at increased genetic risk of T1D. In the majority of progressors plasma glucose showed a biphasic pattern. reflecting an adaptation to raising glucose levels. since 1993. At this time a further decline in glucose sensitivity was associated with a decline in insulin sensitivity and insulin secretion. and up to now the natural history of pancreatic -cells incompetence has not been well characterized. including a large cohort of predisposed individuals with serial assessments of -cell function and insulin sensitivity. and these parameters together with BMI and velocities of growth in height. which represents the ability of -cells to rapidly adapt to acute changes in plasma glucose. Aurora. based on HLA-DR. Yin X. In contrast. New paradigms 2 Growing faster increases T1D risk Height growth velocity.5 years.31– 2.714 DAISY children aged less than 11. in order to reduce the risk of progressing towards overt hyperglycemia. -DQ genotype or family history. has followed children at increased T1D risk.4 years prior to diagnosis and over time represented the strongest predictor for diabetes..05]) and even more strongly with the development of T1D (HR 3. In conclusion. those who will progress to T1D from nonprogressors. A popular hypothesis maintains that the current childhood obesity epidemic is driving the increasing incidence and earlier age of T1D onset seen around the world.73–6. in order to identify peculiar characteristics able to early distinguish. Fingerlin TE. Denver.34 [95% CI 1. which.52:2064–2071 Background: The aim of the study was to assess a potential association of childhood size and growth rate with the development of islet autoimmunity (IA) and T1D. Rewers M. A clear decline in -cell glucose sensitivity was detected 1. The present study is unique in its design. they do not give any information on the time of onset of T1D. Norris JM University of Colorado. it was found that a decrease in this parameter is the earliest defect which characterizes progressors. with an initial slow increase followed by a sudden rise around 0. respectively. islet autoimmunity and type 1 diabetes development: the Diabetes Autoimmunity Study in the Young Lamb MM.pattern over time is often biphasic. and then decreased by only 20% at the time of diagnosis in progressors. and are preceded by a further deterioration of -cell glucose sensitivity. which could be used as a valuable parameter to identify progressors to clinical diabetes. Insulin secretion showed an initial increase. Methods: The study population was represented by participants to the Diabetes Autoimmunity Study in the Young (DAISY). This study sheds light on the role of ‘ –cell glucose sensitivity’. no early alterations able to characterize predictors were found in insulin sensitivity and secretion. Although autoantibodies can be detected during the prodromic phase of T1D. among predisposed individuals. weight and BMI were assessed in relation to the development of IA and T1D. USA Jill. Height and weight were collected starting at age 2 years.Norris@ucdenver. and hopefully prevent acute presentations of T1D.

Hainsworth DP. to use the authors’ words.1%). presence or not of genetic susceptibility. Conclusions: Glycemic control during the DCCT study is a key player in the long-term complication risk. probably genetically determined. perhaps associated with higher levels of IGF-I. The finding of a lack of association between IA/T1D and weight gain is in contrast with previous data in children [6]. such as age. 7. which have also been shown to be associated with greater IGF-I levels. EDIC. it needs to be acknowledged that increased growth rate may be just an epiphenomenon or. St. These results raise the question as to whether increased height rate represents a direct stress factor for the -cell. ‘a side effect’ of the mechanisms driving the autoimmune disease process.9 vs. The DCCT undoubtedly showed that complication risk significantly 122 Francesco Chiarelli/M. Results: During 10 years of follow-up. Louis. Tamborlane WV. whereas in adolescents this beneficial effect had disappeared (32%. might explain discordant findings across different studies.13). Sun W.edu Diabetes 2010. increases insulin demand and makes the -cells more susceptible to autoimmune attacks and apoptosis [5]. The waning of the metabolic memory in the adolescent cohort at year 10 of the EDIC strongly highlights the importance of establishing a strict glycemic control as early as possible and of maintaining it over time. explained 79% of the observed differences between adults and adolescents in the metabolic effect on retinopathy progression. Interestingly. USA white_n@kids. short stature was associated with autoimmunity but not with risk of progression to T1D. mainly between the two intensively treated groups (8. p < 0.. BMI and rapid weight gain were not associated with study outcomes.055 adults and 156 adolescents. This is in contrast with previous findings showing an association between greater height and T1D and might reflect an adverse intrauterine environment associated later on with a higher growth velocity. represent landmark studies in the field of T1D and its vascular complications. The DCCT and its observational follow-up study. Danis RP. Loredana Marcovecchio . This hypothesis postulates that overload of the -cells mediated by several mechanisms. Methods: Progression of retinopathy from DCCT closeout to year 10 of the Epidemiology of Diabetes Interventions and Complications (EDIC) was evaluated in 1. which would support the ‘overload hypothesis’ [5].wustl. At EDIC year 10. HbA1c was similar between previous DCCT intensive and conventional groups and between adolescents and adults.0001). Davis MD Washington University. In contrast. differences in the characteristics of the study populations. p = 0. Mo. Important for clinical practice 1 The metabolic memory wears off! Effect of prior intensive therapy in type 1 diabetes on 10-year progression of retinopathy in the DCCT/EDIC: comparison of adults and adolescents White NH. However. However. 8.2%). The difference in the mean DCCT HbA1c between adolescents and adults (8. Cleary PA.T1D in prepubertal children genetically predisposed to T1D. which could lead to more rapid linear growth and higher demand for insulin from the -cell. It is possible that the primum movens is not the high height rate but a primary increase in insulin levels. physical and psychological stress. insulin resistance. including high growth rates.1 vs. Further studies are required to clarify the link between increased growth velocity and T1D risk and clarify whether the ‘overload hypothesis’ can truly explain this association.59:1244–1253 Background: To assess differences between adolescents and adults in the persistence of the benefits of intensive therapy 10 years after completion of the Diabetes Control and Complications Trial (DCCT). One potential explanation for the findings is that increased linear growth velocity. progression of diabetic retinopathy was still slower in the intensively than in the conventionally treated adults (adjusted hazard reduction 56%. may result in greater insulin secretion and insulin resistance.

positive likelihood ratio (441. Positivity for four antibodies was associated with the highest disease sensitivity (54. Although. Interestingly. the advantage of the previous intensively treated patients still persisted and was still significant. In contrast.0 years) were identified with ICA screening. Combining persistent ICA and IAA positivity resulted in the highest positive predictive value (91.3%) and the lowest negative likelihood ratio (0. Simell O. high ICA level. Young age at seroconversion.knip@hus. Important for clinical practice 2 Predicting T1D risk in the general population Predictive characteristics of diabetes-associated autoantibodies among children with HLA-conferred disease susceptibility in the general population Siljander HT. 79% of the difference in the metabolic effect between adults and adolescents after 10 years from the end of the DCCT was due to the difference in the mean HbA1c levels during the DCCT between the two cohorts. and/or islet antigen 2 for T1D in children with HLA-defined disease predisposition recruited from the general population. and persistent positivity for IAA were significant risk markers for T1D. Although youths with T1D rarely present advanced stages of complications. Persistent autoantibody positivity was defined as continued positivity in at least two sequential samples including the last available sample. emerges as a major player in the long run. The most intriguing finding of the study was the emergence of differences in the persistence of the metabolic memory between the DCCT adolescent and adult cohorts. which did not seem to play a major role during the DCCT and early EDIC years with regard to the outcomes. Results: Pre-diabetic ICA positivity was observed in 1. Knip M Hospital for Children and Adolescents and Folkhalsan Research Center. Lahde J. 155 of whom developed T1D.5). Although at the moment these results relate only to retinopathy. Methods: The study population was made of 7. Conclusion: The combination of HLA and autoantibody screening in the general population resulted in disease risks that are likely to be as high as those reported among autoantibody-positive siblings of children with T1D. Hekkala A. in the adolescent cohort. there is evidence that their pathogenesis starts soon after diagnosis and therefore preventive and therapeutic strategies should be implemented soon after diagnosis [9].58:2835–2842 Background: The aim of this study was to assess the predictive performance of islet cell autoantibodies (ICAs) in combination with autoantibodies against insulin (IAAs). in other words. This recent paper from White and colleagues raises the important point as to whether the benefit of a strict glycemic control during the DCCT wears off in the long run. Finland Mikael. the three other antibodies were measured in all samples available from that individual.4%). although after the end of the DCCT HbA1c levels became comparable between the intensively and conventionally treated groups. The EDIC study raised the important concept of ‘metabolic memory’. autoantibodies against GAD. If a child developed ICA positivity or diabetes. this is a key message.2 years) for -cell autoimmunity and T1D. Type 1 Diabetes: Clinical and Experimental 123 . who were observed from birth (median 9. 86% of 180 progressors (median age at diagnosis 5. particularly with regard to retinopathy. Veijola R. Vahasalo P. cumulative disease risk (100%).decreases with strict glycemic control both in adults and in adolescents [7]. Helsinki.410 children. thus indicating loss of the metabolic memory. which once again strengthens the importance of establishing a good glycemic control as soon as possible in patients with T1D.173 subjects (15. at year 10 of EDIC there was a decrease in the 3-step progression risk in the intensively treated adult group when compared with year 4. Simell T. University of Helsinki. Ilonen J. multipositivity. and specificity (100%). negative predictive values (98. patients belonging to the first group still kept an advantage from prior better HbA1c values [8]. Simell S.8%). retinopathy progression at year 10 of the EDIC did not differ between the previous intensively and conventionally treated groups.fi Diabetes 2009. This 1% difference.7%).8).

Cox NJ. Lachin JM. Below JE. Cleary PA. linear mixed models were used to take advantage of all the repeated measures. GADA and IAA. high ICAs levels and multipositivity for autoantibodies were associated with a higher risk of diabetes.3%) and the lowest likelihood ratio (0. The association of these loci with complication risk was also assessed and SORCS1 was linked with hypoglycemia. The aim of this study was to identify genetic loci associated with glycemia using longitudinal repeated measures of HbA1c from the Diabetes Control and Complications Trial (DCCT). Hospital for Sick Children.paterson@utoronto.Diabetes-associated autoantibodies. This was confirmed using A1C in the intensive treatment group (p = 0. reaching also the highest specificity and cumulative disease risk.1. The addition of GADA to ICA did not appear to improve prediction.5). Hosseini SM. Association of these loci with capillary glucose and repeated measures of multiple complications of diabetes were also assessed. 124 Francesco Chiarelli/M. Similarly to what is already known for first-degree relatives of children with T1D. Conclusion: A major locus for A1C and glucose in individuals with T1D is near SORCS1. Taken together.01) and for BNC2 in non-diabetic individuals. Ont. blood samples were collected for measurement of ICAs. Similar screening strategies will be of utmost importance. Other loci achieved evidence close to genome-wide significance: 14q32. there are no data on its potential genetic determinants in patients with T1D. During follow-up visits. Sun L. Nicolae D. once preventive programs are developed. If these autoantibodies were found in two consecutive samples. are known to predict the development of T1D in siblings [10]. as measured by both A1C and glucose Paterson AD. the findings of the present study suggest that HLA-genotyping together with regular assessment of autoantibody will represent an important tool to identify subjects at risk for T1D in the general population.ca Diabetes 2010. Wong I. which are detectable during the preclinical phase of diabetes. The combination of all four antibodies led to the highest disease sensitivity (54. New genes Genome-wide association studies finally approach HbA1c A genome-wide association study identifies a novel major locus for glycemic control in type 1 diabetes. This study is unique as it is based on a large population of 7. p = 7 × 10–10). whereas BNC2 with renal and retinal complications.01). were assessed. whereas this prediction was better when IAA were also assessed (97%). Bull SB Program in Genetics and Genome Biology. The highest positive predictive value was obtained with the combination of ICA and IAA. In contrast.59:539–549 Background: Although glycemic control is a key risk factor for diabetic complications.3 (WDR72) in the intensive group. The main inclusion criterion was carrying a high or moderate HLD haplotype for T1D susceptibility. ICAs screening allowed to identify 86% of progressors. At loci of interest. Shen E. and it was also associated with mean glucose (p = 2 × 10–5). separately in the conventional (n = 667) and intensive (n = 637) treatment groups of the DCCT. Toronto. IA-2A.5 years. which were selected as the primary screening tool for -cell autoimmunity. Loredana Marcovecchio . the other autoantibodies. The association with glycemic control was replicated for SORCS1 in Genetics of Diabetes in Kidneys (GoKinD) study control subjects (p = 0.410 children from a country with the highest risk of T1D in the world and who were observed from birth for -cell autoimmunity and diabetes. particularly in countries with a high incidence of T1D.13 (GSC) and 9p22 (BNC2) in the combined treatment groups and 15q21. Sylvestre MP.. their predictive value in the general population is unknown.4%). a younger age at seroconversion. Waggott D. Boright AP. Bharaj B. Methods: A genome-wide association study was performed using the mean of quarterly HbA1c values measured over 6. negative predictive value (98. Canada andrew. Results: A major locus for HbA1c was found in the conventional treatment group near SORCS1 (10q25. Canty AJ.

and it also showed evidence for association with hypoglycemia. Canada constantin. It is intriguing to observe that reaching a good glycemic control requires variable efforts in different patients and that glycemic control is often quite consistant in a given individual with diabetes. in non-diabetic individuals [12]. New genes 2 Confirmation of T1D genes In silico replication of the genome-wide association results of the Type 1 Diabetes Genetics Consortium Qu HQ.19:2534–2538 Background: The Type 1 Diabetes Genetics Consortium (T1DGC) recently reported 22 novel T1Dassociated loci identified by meta-analysis of three genome-wide association studies (GWASs) with a case-control design.1 in the same direction. requiring a specific and personalized treatment plan. Polychronakos C Department of Pediatrics. McGill University. a casecontrol cohort of 514 cases and 2. using longitudinal data collected during the DCCT. Li Q. The aim of this study was to replicate the association in three independent GWAS cohorts to exclude potential bias from population stratification. Methods: Three European-descent population samples were included: 483 cases and both parents. whereas the frequency of HLA alleles in the multiplex families was higher. BNC2. the association of 10 of these 22 reported loci was not confirmed in the T1DGC family cohort. Hakonarson H. a gene with some previous evidence of an association with glycemic traits. based on the concept that each patient should be considered as ‘a single one’.Hyperglycemia is a major player in the development of vascular complications of diabetes. BNC2 was replicated in a non-diabetic population (MAGIC) and was also associated with renal and retinal complications. This locus was also replicated in a separate population. such as HbA1c. the remaining were imputed. In fact.. there were high-quality genotypes for 15. Among the 22 SNPs reported by the T1DGC.and macrovascular complications. An additional eight loci had nominal significance of p < 0. and an additional cohort of 1. Bradfield JP. A major locus (rs1358030) for HbA1c and mean glucose levels was found near SORCS1. the identification of individuals genetically predisposed to a poor metabolic control and therefore at higher risk for complications represents an important step in the long and fascinating way towards a personalized medicine. Characterizing genes regulating glycemic control is fascinating and represents a major step forward in the management of patients with diabetes.ca Hum Mol Genet 2010.078 cases and 341 controls from the dbGaP database. These findings underline the potential role of a genetic background in modulating plasma glucose concentrations. Que. Frackelton E. Kim C. Results: T1D association was replicated in seven loci after Bonferroni correction for 22 independent hypotheses. However. the GoKinD control subjects. The clear definition of genetic determinants of glycemic control is not an easy task as it requires to clearly distinguish the effect of heritability from environmental influences including treatement itself. The genetic susceptibility conferred by non-HLA loci in the family cohort with 1 affected offspring was higher than the T1DGC multiplex families.polychronakos@mcgill. and WDR72.027 controls. defined on the basis of his/her risk profile. through the activation of several metabolic pathways [11]. The role of genetic factors is also supported by twin and family studies. Montreal. Among them. Type 1 Diabetes: Clinical and Experimental 125 . The present study deals with the important issue of looking for genetic determinants of glycemic control in people with T1D. Other loci achieving evidence close to genome-wide significance were GSC. Landmark studies such as the DCCT and the EDIC have highlighted the key role of glycemic control in the preventing and/or slowing the development and progression of micro. Grant SF.. which have shown the heritability of measures of glycemic control.

damaging distinct areas. T1D association with seven loci was validated with a p < 4.. Wu J. T1D is a complex disease resulting from the interaction of multiple genetic and environmental factors. In last year chapter on T1D there were two important papers dealing with the genetics of T1D and the role of GWAS in allowing identification of a large number of loci associated with the disease [13]. Black KJ. who underwent magnetic brain resonance imaging.88] = 6. Results: Greater exposure to severe hypoglycemia during childhood was associated with enlargement of the hippocampal volume (F [3. Louis. hyperglycemia exposure was not associated with hippocampal volumes.05). including 126 Francesco Chiarelli/M. Washington University School of Medicine. Weaver PM. The T1DGC reported 22 novel loci associated with T1D.6. Hyperglycemia and hypoglycemia can both alter the brain.01. weighted for duration of diabetes.138] = 3. The recent development of high-throughput single nucleotide polymorphism genotyping array technologies has enabled investigators to perform high-density GWAS in search of additional T1D loci and the results of many GWAS have been reported to data. Conclusion: The increased hippocampal volume associated with severe hypoglycemia may be due to gliosis. T1D youths were categorized as having 0 (n = 37). Therefore.edu Diabetes 2010. or 3 or more (3+. p = 0. Mo. USA tammy@wustl. other eight loci had a p < 0.01).016. thus supporting the validity of the new discoveries. In contrast. The present study aimed to extend previous genetic findings in different populations. Diabetes can alter the function and structure of many organs. The aim of this study was to assess the effect of hypoglycemia and hyperglycemia on hippocampal volume during brain development. whereas seven loci were not replicated. however. F [2. raising the point as to whether heterogeneity in the populations selected in the different studies could have influenced the results [14]. or disruption of normal developmental pruning in the developing brain.59:236–241 Background: Hippocampal neurons have been suggested to be particularly vulnerable to glycemic excursions. using three European descendent population samples. 3+ larger than all other groups. n = 17) prior severe hypoglycemic episodes. Methods: The study population was represented by 95 youths with T1D and 49 sibling control subjects aged 7–17 years. Several genetic determinants had been identified already before the era of genome-wide association studies (GWAS). 10 of these 22 loci were not replicated in the T1DGC family cohort. 3+ larger than all other groups.002. in the present study the authors attempted to validate the 22 previous identified loci. White NH Department of Psychiatry. p < 0. St. and the 3+ severe hypoglycemia group still had larger hippocampal volumes after adjusting for age of onset and hyperglycemia exposure (main effect of hypoglycemia category.Conclusion: This study replicated T1D association with at least as many of these novel loci as expected from the power of the sample size. the bigger the hippocampus Hippocampal volumes in youths with type 1 diabetes Hershey T. Stereologic measurements of hippocampal volumes were performed in atlas-registered space to correct for whole brain volume. p = 0. including the brain. Perantie DC. Data from animal studies have shown that hypoglycemia can selectively damage neurons in the medial temporal region. Over the years many efforts have been made to understand its pathogenesis. Loredana Marcovecchio .4. Hyperglycemia exposure was estimated from median lifetime A1C. reactive neurogenesis.55 × 10–3. p < 0. 1–2 (n = 41). New concerns The lower the plasma glucose. Overall this study validated the T1D association previously reported by the T1DGC and highlighted the complexity of genetics of T1D and the need of further investigations to understand the true role of the identified loci in the pathogenesis of T1D.

expressed as gliosis. Further studies will likely clarify the underlining mechanisms. Hershey et al. was strongly related to previous history of severe hypoglycemia. In this study the role of DNA methylation in the regulation of mouse and human insulin gene expression was investigated. insulin gene expression has been the focus of extensive study. For the moment. regeneration. Methods: Genomic DNA samples from several tissues were bisulfite-treated and sequenced. In mouse embryonic stem cell cultures. the Ins2 gene is fully methylated and becomes demethylated during differentiation into insulin-expressing cells in vitro. function and autoimmune reactions [15]. sex. Mullen Y. Methylation of these CpG sites suppressed insulin promoter-driven reporter gene activity by almost 90% and specific methylation of the CpG site in the cAMP-responsive element (CRE) in the promoter alone suppressed insulin promoter activity by 50%. through regulation of key molecules and processes involved in -cell development. Hippocampal volume. is a mechanism of silencing its activity. Ku HT. and as such. did not have any association with hippocampal volume. the emerging concept of ‘epigenetic modifications’ is assessed in relation to a key gene in the context of diabetes: the insulin gene. providing the mechanism by which the environment interacts with identical genotypes to produce different phenotypes. interest has been focused on the implication of this process in the pathogenesis of T1D. Pfeifer GP. The authors found that methylation of this gene.4:e6953:1–9 Background: Insulin is a critical component of metabolic control.-cells and in embryonic stem cells from the undifferentiated stage throughout the stages leading to insulin-expressing cells. Results: Cytosine-guanosine dinucleotide (CpG) sites in both the mouse Ins2 and human INS promoters are uniquely demethylated in pancreatic -cells. hyperglycemia. Conclusion: Insulin promoter CpG demethylation may play a crucial role in -cell maturation and tissuespecific insulin gene expression. These data are unique as previous studies in adults with diabetes had shown no evidence of variation in hippocampal volume or. and hyperglycemia. measured with validated and unbiased stereologic methods. Endocrinology. independently of potential confounders such as age.the hippocampus. on increased hippocampus volume in relation to severe hypoglycemic episodes. Interestingly. the available data deserve reflection on how vulnerable the developing brain to hypoglycemia can be and how the detected changes can evolve over time and influence long-term neurocognitive function. Epigenetics is a central process implicated in the control of gene expression. Todorov I. Al-Abdullah IH. and Metabolism. but inhibited ATF2 and CREB binding in vivo and conversely increased the binding of methyl-CpG binding protein 2 (MeCP2). The present findings of an increased hippocampal volume might indicate a pathological response to severe hypoglycemia. In this paper.org PLoS One 2009. Ferreri K Department of Diabetes. reactive neurogenesis. which is known to influence brain function. Duarte. Recently. whereas demethylation is associated with progressive expression of the gene and therefore increased insulin levels. disruption of normal developmental pruning or a compensatory response to damage. duration of diabetes. Rauch TA. signs of neuronal death in patients with hypoglycemia. present interesting data. USA kferreri@coh. Kandeel F. New mechanisms 1 Epigenetic modulation of the insulin gene Insulin gene expression is regulated by DNA methylation Kuroda A. as in general for other genes. Calif. Type 1 Diabetes: Clinical and Experimental 127 . Research Institute of City of Hope. However. collected in a large group of 95 youths with T1D and 49 healthy children. Methylation did not directly inhibit factor binding to the CRE in vitro.. survival. there are limited data in humans and in particular on the effect of hypoglycemia on the developing brain of young people with diabetes. DNA methylation patterns of the insulin gene were assessed in human and mouse -cells as well as in non.

Brussels. Methods: A functional genomics strategy based on massive parallel signal sequencing and microarray data obtained in human islets. with the consequent suppression of gene expression. The specific methylation/demethylation pattern that emerged from the present study is clearly a major aspect to consider and overcome in future studies.The human insulin gene appears to have nine CpG sequences in its promoter.-cells these sites are completely or in part methylated. which can interfere with binding of other factors. Demethylation of the insulin gene is a late step in the differentiation of the -cell phenotype from embryonic stem cells. Berton A. Kutlu B. Up to now. which should be then transplanted in patients with T1D. Conclusion: This study suggests human FXYD2 a as a novel -cell-specific biomarker. De Waele E. Salmon I. Marechal D. Another key finding of the study was that demethylation of the insulin promoter does not appear to be specifically involved in daily metabolic regulation. Loredana Marcovecchio .K+-ATPase. Jamar JF. Goodman N. 128 Francesco Chiarelli/M. Rooman I. In the present study the application of a systems biology approach led to the identification of a specific new -cell biomarker. Demethylation of these sites is important for both basal and stimulated insulin gene expression. purified primary rat -cells. Lonneux M. The possibility of assessing -cell mass in humans represents an essential tool in studies aiming at better understanding the pathogenesis of the diseases as well as in evaluating the effect of emerging preventive strategies. Dufrane D. Methylation of these sites induces recruitment of CpG binding protein 2 and probably of other proteins. Bouwens L. Beckers MC. The presence of FXYD2 a was restricted to pancreatic islets and selectively detected in pancreatic -cells. together with other potential epigenetic modulations of the insulin gene. Eizirik DL Laboratory of Experimental Medicine. Histological examination of pancreatic sections from individuals with T1D or sections from pancreases of streptozotocin-treated M. Universite Libre de Bruxelles. Candidate biomarkers were validated and screened using established human and macaque (Macacus cynomolgus) tissue microarrays. a regulating subunit of the Na+. For four of the proteins antibodies targeting specifically the human proteins and their splice variants were produced and allowed to confirm all four candidates as islet-specific in human pancreas. New mechanisms 2 Seeking -cell biomarkers A genomic-based approach identifies FXYD domain containing ion transport regulator 2 (FXYD2) a as a pancreatic -cell-specific biomarker Flamez D. 12 -cell-specific membrane proteins were identified. were identified as preferentially present in human pancreatic islets.-cells and INS-1E cells was applied. Van Huffel C. Clark A. Roland I.be Diabetologia 2010. cynomolgus monkeys indicated a close correlation between loss of FXYD2 a and loss of insulin-positive cells. In contrast. These findings highlight the complexity of gene regulation in humans and help to explain the difficulties met by the scientists who are trying to produce -cells in vitro.Flamez@UGent. directed at reducing -cell loss before disease onset. Analysis of human fetal pancreas samples showed the presence of FXYD2 at an early stage (15 weeks). Belgium Daisy. Results: After a series of filtering steps. in non. non.53:1372–1383 Background: Non-invasive imaging of the pancreatic -cell mass requires the identification of novel and specific -cell biomarkers. a major problem encountered in this context has been how to obtain normal levels of insulin gene expression. but it is more likely to be implicated in the development of insulin-producing -cells. Two splice variants of FXYD domain containing ion transport regulator 2 (FXYD2). In the present study a systems biology approach was used in order to identify potential -cell markers. which could have important implications for assessing -cell mass with non-invasive techniques. Gianello P. Goldman S.

the peptide loading of class II molecules is modified by the expression of the non-classical class II molecule. thereby preventing the activation of diabetogenic T cells and subsequent diabetes development. Out of these 44 genes.This study used a step-by-step approach consisting on functional genomics based on parallel sequencing and microarray data obtained from human islets. dendritic cells and thymic epithelial cells. however. However. HLA-DO (DO). therefore proposing the manipulation of antigen presentation by dendritic cells as a new potential target toward which preventive strategies should be directed. New mechanisms 3 Time to focus on antigen presentation! Targeted regulation of self peptide presentation prevents type 1 diabetes in mice without disrupting general immunocompetence Yi W. The biological role of HLA-DO-mediated regulation of DM activity in vivo remains unknown. Peptide loading of MCHII is catalyzed in late endosomal and lysosomal compartments of cells by the catalytic action of human HLA-DM. 114 were then identified as expressed at the membrane level and 44 of them were found to be preferentially expressed in -cells. such as dendritic cells. Further studies will hopefully confirm these findings and the usefulness of this biomarker firstly in the research setting and then also in clinical practice. Sant’Angelo DB. Conclusion: DO expression can shape the overall MHCII self peptide repertoire to promote T-cell tolerance. Denzin LK Immunology Program.120:1324–1336 Background: Peptide loading of MHC class II (MHCII) molecules is directly catalyzed by the MHCII-like molecule HLA-DM (DM). USA denzinl@mskcc.Y.-cells. Wucherpfennig KW. Methods: In order to test the idea that DO modulation of the MHCII self peptide repertoire mediates selftolerance. HLA-DO [17].DO mice. it has been postulated that DO expression dampens presentation of self antigens. FXYD2 a. Up to now much of the focus in the pathogenesis of T1D has been directed towards T lymphocytes. thereby modulating DM function and dampening presentation of self antigens. The present study clearly shows that subtle changes in MHCII antigen presentation can prevent disease development. In the present study performed in a NOD. In B cells. exclusively expressed in these cells.K+-ATPase [16]. Another MHCII-like molecule. Results: Diabetes development was completely blocked in NOD. purified primary rat islet -cells and non.org J Clin Invest 2010. Sloan-Kettering Institute. However. NOD. Memorial Sloan-Kettering Cancer Center. Expression of this FXYD2 a isoform emerged to be an early embryonic event and its levels decreased in parallel with -cell mass loss. thereby preventing inappropriate T-cell activation that ultimately leads to autoimmunity [18]. in the context of the MHCII molecules [17]. an important aspect in the development of self-reactive lymphocytes is represented by reaction with self antigens presented by specific antigen presenting cells. Starting from 950 islet-specific genes. the development of diabetes was prevented by HLA-DO expression in dendritic cells. and therefore their immune system function was equivalent to that in NOD mice. These results suggest this biomarker as a potential useful one for non-invasive imaging and quantification of pancreatic -cell mass. NOD. 12 were further selected based on their non-responsiveness to inflammatory cytokines.DO animals selected a diabetogenic T-cell repertoire. NOD mice (a mouse model for T1D) that constitutively overexpressed DO in DCs (referred to herein as NOD. N.DO DCs presented an altered MHCII-bound self peptide repertoire. The best candidate biomarker for -cells was FXYD2. with two of its three variants expressed in the human -cell and one. This protection appeared to be due to an inefficient presentation of self antigens by dendritic cells overexpressing HLA-DO.DO mice) were generated. the numbers and function of Tregs were normal. being T1D a T-cell-mediated autoimmune disease. therefore maintaining periph- Type 1 Diabetes: Clinical and Experimental 129 . associates with DM. New York. Martillotti T.. Seth NP.DO mice model. This molecule represents a regulatory subunit of the ubiquitously distributed Na+.

In contrast. have shown that treatment with angiotensin-converting enzyme inhibitors (ACEIs) reduces the rate of progression and can even promote regression of microalbuminuria [19]. Methods: A multicenter. Strand T. Compared with placebo. Gardiner R. independently of blood pressure changes. The study by Mauer and colleagues does not confirm the previously observed beneficial results of ACEIs therapy in patients with diabetic nephropathy and highlights the concept that blockers of the RAS do not necessarily change renal pathology in initially normotensive normoalbuminuric subjects. Chronic cough occurred in 12 patients receiving enalapril. 6 receiving losartan. Suissa S.12–0. p = 0.26).85]) and losartan by 70% (0. The Renin-Angiotensin System Study (RASS) is up to now the largest long-term study assessing the effect of a 5-year blockage of the RAS system in people with T1D. assessed through renal biopsies performed at baseline and 5 years later. Minneapolis. the study not only demonstrated that treatment with ACEIs or ARBs did not influence any structural renal parameter but it also showed that losartan increased the incidence of microalbuminuria when compared to placebo (17 vs. In addition. p = 0. Goodyer P. The 5-year cumulative incidence of microalbuminuria was 6% in the placebo group. p = 0.361:40–51 Background: It is unclear whether progression of nephropathy and retinopathy in people with T1D is slowed by early administration of drugs blocking the renin-angiotensin system (RAS). randomly assigned to receive losartan (100 mg daily).005. respectively. concepts revised To treat or not to treat? Renal and retinal effects of enalapril and losartan in type 1 diabetes Mauer M. Loredana Marcovecchio . Change in mesangial fractional volume per glomerulus over the 5-year period did not differ between the placebo (0.01) but not with enalapril (4%. the majority of previous studies had as main study endpoint changes in albumin excretion. Results: A total of 90 and 82% of patients had complete renal biopsy and retinopathy data.96). such as retinopathy [20] and potentially cardiovascular disease [21].026. was performed. Conclusion: Early blockade of the RAS in patients with T1D did not slow nephropathy progression but slowed the progression of retinopathy.35 [0. Drummond K. Surprisingly.edu N Engl J Med 2009. USA mauer002@umn.016 units) and the enalapril (0. In this study. ACEIs can also have a significant effect on other diabetic microvascular complications. 6%). but consider the numerous players involved in the autoimmune reactions.14–0. University of Minnesota. Clinical trial. which was represented by early renal structural alterations. These data suggest that when investigating the pathogenesis of T1D it is important not only to direct efforts towards autoreactive T lymphocytes. Klein R Department of Pediatrics. The primary endpoint was a change in the fraction of glomerular volume occupied by mesangium in kidney-biopsy specimens. p = 0. 130 Francesco Chiarelli/M. Sinaiko A. independently from the effect on blood pressure. enalapril (20 mg daily). Several studies. two different strategies of inhibiting the RAS were evaluated: ACEIs and angiotensin receptor inhibitors (ARBs). Gubler MC. whereas enalapril did not have any effect on this secondary study endpoint. The retinopathy end point was a progression of two steps or more. controlled trial involving 285 normotensive patients with T1D and normoalbuminuria.38) or the losartan group (0. manly performed in adults. Zinman B. and 4 receiving placebo. Donnelly S.30 [0..eral tolerance and confirming the above discussed hypothesis. a novelty of the present study was the primary study endpoint. or placebo and followed for 5 years. There were three biopsy-related serious adverse events that completely resolved. Minn. the incidence was higher with losartan (17%. enalapril reduced the odds of retinopathy progression by 65% (odds ratio [95% confidence interval]: 0. nor were there significant differences in the other renal structural variables.73]).

Hovorka T. With regard to differences from previous studies.97. independently of changes in blood pressure. 10 vs. patients’ standard pump settings were applied. Clinical trial. p = 0. Chassin LJ. ≤3.1 vs. Dunger DB Department of Paediatrics. In study 1 (n = 13). the lack of an effect on renal outcomes might be related to the fact that intervention was started at an early stage of renal pathology. a standard continuous subcutaneous insulin infusion was compared with closed-loop insulin delivery.0245. the pathogenesis of complications of diabetes is heterogeneous. p = 0. where the effect of a manual closed-loop insulin delivery system on overnight blood glucose was assessed in comparison to a standard continuous insulin infusion. University of Cambridge. During closed-loop nights. Elleri D. Xing D. Conclusions: Overnight manual closed-loop insulin delivery can improve glucose control and reduce risk of nocturnal hypoglycemia in young patients with T1D. How can this different effect on the two vascular complications be explained? As pointed out also in the accompanying editorial of this paper. which can differ or have a different effect in the different microcirculations of the kidney and retina. ≤3. 39% standard treatment.375:743–51 Background: The effect of a closed-loop system.uk Lancet 2010. the performance of this system was investigated in relation to a variable-content evening meal and moderate-intensity evening exercise. mean (SD) T1D duration: 6.00 or 3. 43% control. De Palma A. in study 2 (n = 7) closed-loop delivery was assessed after rapidly and slowly absorbed meals.0) years). glucose was assessed every 15 min and values included into a control algorithm calculating rate of insulin infusion.90 mmol/l. in patients with no sign or minimal pre-proliferative retinopathy at baseline.4 (4.90 mmol/l.0304). and study 3 (target range 78% closed loop vs. 6%. Allen JM. p = 0. UK rh347@cam. slowly absorbed meal 55%. Cambridge. with an interplay of several mechanisms. Methods: Three randomized crossover studies were performed in 19 patients (age: 5–18 years. 0%. p = 0. p = 0. ≤3. 1 vs. study 2 (target range. A secondary analysis of pooled data (study 1 + study 3) documented increased time in the target range (60 vs. Harris J. and a nurse adjusted the insulin pump. particularly during the early stages of diabetic complications. this could implicate a different role of RAS in different stages of nephropathy. p = 0.1%.90 mmol/l or lower (2. 40%. Again.0022) and reduced time for which glucose concentrations were 3. inhibition of the RAS was associated with a 65–70% reduction in retinopathy progression.In contrast. Primary outcomes were time for which plasma glucose concentration was 3. median 52% closed loop vs. p = 0.13). Hovorka et al.90 mmol/l. not significant at corrected level. Wilinska ME. on overnight blood glucose control was assessed in young people with T1D. linking continuous glucose measurements to insulin delivery.0 mmol/l compared with nine events during standard treatment. new treatments On the way towards the artificial pancreas Manual closed-loop insulin delivery in children and adolescents with type 1 diabetes: a phase 2 randomized crossover trial Hovorka R. Type 1 Diabetes: Clinical and Experimental 131 .91–8. Larsen AM. In addition. whereas in other investigations a beneficial effect was seen when applied at a more advanced stage of diabetic nephropathy. Results: Primary outcomes did not differ significantly between treatment groups in the three studies considered individually: study 1 (target range. Nodale M. During closed-loop delivery there were no events with plasma glucose concentration <3.ac.06. in study 3 (n = 10) a comparison was performed between closed-loop delivery and standard treatment after exercise. p = 0. 4.27). 0 vs. Kollman C. Acerini CL.16).90 mmol/l or lower. report the results of three randomized crossover studies performed in children and adolescents with T1D. 2%. rapidly 53% vs. During control nights.

Schatz DA. Krause-Steinrauf H. particularly after midnight when the system appears to have reached full effectiveness. T1D is an autoimmune disease in which T lymphocytes mediate damage to pancreatic -cells. whereas HbA1c and insulin dose were lower in the rituximab than in the placebo group. Indianapolis. a potential role for B lymphocytes has also been supposed and this represents the starting point for the hypothesis of the present study [23].Insulin therapy has been marked by unforgettable milestones starting from insulin discovery and followed. Wilson DM. such as T1D. Lachin JM. New hope 1 B-cell depletion as a novel therapy for T1D Rituximab. In this randomized double-blind study. Methods: In this randomized. double-blind study. assessed 1 year after the first infusion. Results: At 1 year. Secondary outcomes included safety and changes in HbA1c and insulin dose. nowadays. Ind. McGee PF. 8. HbA1c and insulin dose were reduced in the rituximab group. Greenbaum CJ. Raskin P. during most recent years. treatment is still problematic and exogenous insulin administration is still far away from mimicking the endogenous insulin pattern. aim at resembling an artificial pancreas [22]. There was no increase in infections or neutropenia with rituximab. aiming at reducing complication risk. in patients with T1D. The primary outcome. was the geometric mean area under the curve (AUC) for the serum C-peptide level during the first 2 h of a mixed-meal tolerance test. In addition. Hovorka’s study shows that this system can achieve a safe and good overnight glucose control. Rodriguez H.361:2143–2152 Background: There is growing evidence that B lymphocytes play a role in many T-lymphocyte-mediated diseases. Although further assessment and improvements of the system are required in the next years. and 22 of the study. Loredana Marcovecchio . A lower rate of decline in C-peptide levels between 3 and 12 months was detected in the rituximab than in the placebo group. 87 patients (aged 8–40 years) with newly diagnosed T1D were assigned to receive infusions of rituximab or placebo on days 1.miami. Skyler JS Indiana University School of Medicine. but levels increased to 69% of baseline values at 12 months. Marks JB. By combining the data from studies 1 and 3. Gitelman SE. although intensive insulin therapy is the cornerstone of an optimal management of diabetes. the authors found that closed-loop insulin delivery was associated with an increased likelihood of plasma glucose concentrations to be in the target range and reduced frequency of low glucose values. 15. Gottlieb PA. However. USA diabetestrialnet@med. the mean AUC for the level of C peptide was significantly higher. but also solve the fears and consequences related to uncontrolled hyperglycemic and hypoglycemic episodes in children with T1D. Goland R. although patients in the rituximab group were more likely to experience grade 1 or 2 adverse events after the first infusion. and preservation of -cell function Pescovitz MD. an anti-CD20 monoclonal antibody. a control algorithm and an insulin pump. The aim of this phase 2 study was to evaluate the role of B-lymphocyte depletion with rituximab. and these differences were explained by pres- 132 Francesco Chiarelli/M. suggesting a role of B lymphocytes in the pathogenesis of T1D. through the combination of a continuous glucose monitor. Closed-loop insulin systems. Becker DJ. by the advent of insulin analogues and the implementation of pump therapy and continuous glucose monitoring. the associated risk of hypoglycemia cannot be underestimated. CD19+ B lymphocytes were depleted in patients in the rituximab group. B-lymphocyte depletion. as for other T-cell-mediated diseases.. Moran AM. Conclusions: A four-dose course of rituximab partially preserved -cell function over a period of 1 year in patients with T1D.edu N Engl J Med 2009. However. the present results represent an important step forward in a still complex way towards the development and implementation of an artificial pancreas. which could not only ease daily life. Wherrett D. depletion of B lymphocytes with the anti-CD20 monoclonal antibody rituximab was able to preserve -cell function in patients with newly diagnosed T1D.

Pramlintide was well tolerated. In this study the pharmacokinetics. Aurora. Acetaminophen (1. 217±56 mg · h/dl). It is more likely that they enhance or facilitate T1D development without having a main role in its induction.chase@ucdenver. Although there was a higher rate of infusion reactions. 8. Insulin lispro (50% of usual mealtime dose) was injected separately. there was no increased risk of neutropenia and infections.to 3.3 h (median time to peak concentration) after administration. crossover study Chase HP. age 12–17 years. Larger and longer term studies are warranted to confirm and extend the results of this study.4%. Pramlintide reduced incremental area under the concentration curve (AUC(0–3 h)) for glucagon and glucose versus placebo (glucagon: 15-µg dose. 5±7 pg · h/ml. where plasma pramlintide concentrations increased in a dose-dependent manner..000 mg) was administered orally to provide an indicator of gastric emptying rate. and no treatment-related adverse events occurred. B lymphocytes act through the production of autoantibodies. placebo. 30-µg dose. pramlintide reduce gastric emptying. 93±9 pg/ ml. therefore supporting the safety. Results: Complete data were available for 9 participants. Given the demonstrated importance of both T and B cells in diabetes pathogenesis. 25]. median T(max) was delayed by approximately 2.6. modulation of both arms of the immune response may represent a key strategy for the development of protective immunotherapies. Zhang B. University of Colorado.edu J Pediatr 2009. which could modulate the immune process [24. Type 1 Diabetes: Clinical and Experimental 133 .ervation of C-peptide levels. Porter L Barbara Davis Center for Childhood Diabetes. single-blind. 129±43 mg · h/dl. and significantly delayed and/or reduced the onset of diabetes [25]. Mean peak plasma concentration (Cmax) (15-µg dose. placebo. USA peter. treatment with anti-CD20 antibodies was associated with B-cell depletion. clarify mechanisms beyond them and to assess the long-term safety related to immunosuppressive therapies. at least in the short term. Acetaminophen C(max) decreased with pramlintide. pramlintide showed a similar pharmacokinetic profile as in adults and was able to reduce postprandial glucagon and glucose excursions and slow gastric emptying. However. Conclusions: In adolescents with T1D. and tolerability of pramlintide in adolescents with T1D were assessed. Rituximab is a drug approved for treatment of B-cell lymphomas and its efficacy has also been shown in several autoimmune diseases [24]. improve glycemic control and reduced weight gain. Lutz K. Further research in this area is mandatory to confirm the present findings. 132±37 mg · h/dl. New hope 2 Halting glucose excursions in youths with T1D Ramlintide lowered glucose excursions and was well tolerated in adolescents with type 1 diabetes: results from a randomized.155:369–373 Background: In adults with type 1 and type 2 diabetes. However. safety. Colo. B cells can also act as islet antigen-presenting cells for autoreactive T cells and B-cell depletion is associated with the generation of regulatory T and B cells. 3 males. A1C. glucose: 15-µg dose. glucose excursions. 35±9 pg · h/ml. Pencek R. 202±21 pg/ml) occurred approximately 0. This is of relevant importance as a residual insulin capacity has been associated with a better metabolic control and reduced complication risk. pharmacodynamics. Methods: 12 subjects (9 females. In a previous animal study.8-fold. 4±7 pg · h/ml. it is controversial whether autoantibodies exert a main pathogenetic role in T1D. 30-µg dose. placebo-controlled. 30-µg dose. the hallmark of autoimmunity. How can B-cell depletion be protective against diabetes? In the context of diabetes. 25 kg/m2) were randomized to pramlintide (15 or 30 µg) or placebo administered before a standardized breakfast. The present study provides new hopes for preserving -cell function in people treated soon after diagnosis. body mass index. of this treatment.

Adjunct therapies to improve glycemic control are therefore particularly warranted in this age group. Finland per-henrik. which can influence glycemic control. Preliminary data in adolescents with T1D have shown that this molecule can delay gastric emptying. particularly in adolescents with T1D.3) years in 15–40 group (p < 0. glucagon-like peptide-1 and amylin [26]. 15 and 30 µg. The risk of proliferative retinopathy was studied in age at onset groups 0–4. this advantage disappears over time. revise this 134 Francesco Chiarelli/M.40–2. in people with diabetes. Results: The mean durations to proliferative retinopathy were 24. and 21.001). Folkhalsan Research Center. reduce plasma glucose excursions and delay gastric emptying.fi Diabetes Care 2010.vs. The long-term risk of proliferative retinopathy did not differ between those diagnosed aged 0–4 years compared with 5–14 years (p = 0. Both doses of pramlintide were equally able to decrease glucagon release. Hietala et al. but the secretion and/or the action of these other hormones may be impaired and contribute to the overall metabolic imbalance. Overall this study shows that in adolescents pramlintide has similar pharmacokinetics and safety profile than in adults and could represents a valid adjunct therapy.8–23. whereas the lowest risk is in the age at onset group 15–40 years.3 (22. No significant adverse effects were detected.48]. has been shown to decrease HbA1c and postprandial glucose excursions as well as to reduce weight gain and gastric emptying [27]. 5–14 and 15–40 years.1 (19.6 (19. However. adulthood-onset diabetes: does it matter? Age at onset and the risk of proliferative retinopathy in type 1 diabetes Hietala K. glucose homeostasis is the results of an interplay of several hormones. Risk of proliferative retinopathy was significantly higher in the age at onset group <15 years than in the age at onset group ≥15 years (HR 1. Methods: Fundus photographs and/or ophthalmic record were available for 1117 consecutively recruited patients taking part to the FinnDiane Study. which therapies should be considered? In healthy subjects.groop@helsinki. In adults with diabetes. Summanen P. Conclusions: An early age at onset of T1D confers a longer time free of proliferative retinopathy. p < 0.Achieving a good glycemic control is the cornerstone of treatment of diabetes but also a major challenge.36]. the highest risk of proliferative retinopathy was observed in 5–14 group (HR 1. pramlintide. after adjusting for potential confounders. But. Groop PH Folkhalsan Institute of Genetics. Forsblom C. glucagon.9) years in 0–4 group.90 [95% CI 1.1) years in 5–14 group. The highest risk for developing proliferative retinopathy is in age at onset group 5–14. Harjutsalo V.2). In a Cox regression model. p < 0. Biomedicum Helsinki. a synthetic analog of the pancreatic hormone amylin. Chase et al.82 [95% CI 1. Concepts revised Childhood. The DCCT study clearly highlighted this issue by showing a 1% difference in HbA1c and a higher risk of hypoglycemia and weight gain between the adolescent and adult cohorts.45–2. An early onset of diabetes has been for a long time thought to be protective with respect to the development of long-term vascular complications [29]. Plasma concentrations of pramlintide were dose-dependent. Loredana Marcovecchio .2–21. 33:1315–1319 Background: The aim of this study was to assess how age at the onset of T1D influences the long-term risk of developing proliferative retinopathy. 20. whereas there was no such an effect on time for reaching peak concentration and duration of effect. inhibit glucagon secretion and improve postprandial glucose excursions [28]. Therefore. Further larger and longer term studies are required and hopefully they will confirm and strengthen the findings of the present study.001). particularly in adolescents with fluctuating blood glucose control. in a small group of 12 adolescents. including insulin.7–25.001). present a single-blind randomized controlled cross-over trial aiming at establishing the pharmacokinetics and safety profile of two doses of pramlintide. In this recent study. Adolescence is a period characterized by several physiological and psychological changes. not only there is a lack of endogenous insulin production.

and several factors contributing to the risk were assessed. In addition. which then lead to better metabolic control. whereas the risk did not change with age at onset in the offspring of mothers with T1D.8) for the offspring of parents with adultonset diabetes.8% in the offspring of fathers. the risk in the offspring did not differ by sex of the parents: 4. The cumulative incidence decreased in parallel with the increase in age at onset of diabetes in the fathers.concept and report that. The study is based on population-based cohorts form Finland: 3. These results are similar to those reported by Amin et al. In the late-onset cohort. In Amin’s study. Age at onset of type 1 diabetes in parents and recurrence risk in offspring Harjutsalo V.821 in the early-onset cohort.881 offspring in the late-onset cohort. Karvonen M. Hietala and colleagues offer several suggestions on the mechanisms which could explain the delayed onset of complications in their youngest age group. but after 15 years of diabetes duration the risk of developing microalbuminuria was similar between subjects diagnosed with diabetes before 5 years of age and those diagnosed between 5 and 11 years of age or after puberty.59:210–214 Background: The aim of this study was to assess the recurrence risk of T1D in the offspring of parents with adult-onset (15–39 years) T1D and the transmission of diabetes within a continuum of parental age at onset of diabetes from childhood to adulthood. The cumulative incidence by 20 years was 4. after about 30-year diabetes duration. Folkhalsan Research Centre. One hypothesis is that behavioral factors might play a role. T1D developed in 318 offspring in the early-onset cohort and 97 in late-onset cohort. The majority of these studies have shown a higher risk when the father is affected by T1D than when the mother is the index case. this advantage gradually disappears over time and. Results: During 137. Helsinki. Up to now. the negative effect of puberty on glycemic control needs to be considered as a potential accelerator of complications onset. factors which have been associated with a decreased incidence of complications [31]. This is likely related to a less aggressive form of diabetes characterizing this age group.636) in two Finnish cohorts of parents with T1D was defined until the end of year 2007.harjutsalo@helsinki. their risk of developing proliferative retinopathy is comparable to that of patients diagnosed when aged 5–14 years.1–4.2% in the offspring of mothers vs. studies have been assessing the risk of diabetes recurrence in offspring of parents with onset of diabetes during childhood. Taken together. the results of these two studies suggest that an early age at the onset of diabetes does not protect from complications. a total of 413 offspring were diagnosed with type 1 diabetes. the reduced risk in the maternal offspring was most pronounced in the daughters of the mothers with a diagnosis age <10 years. In particular this could be explained by a better preservation of -cell function and of C-peptide levels. so that younger children learn easier good self-care skills. However. Another important point raised from the Hietala’s study was the lowest risk detected in patients diagnosed at an age between 15 and 40 years.0% (95% CI 3. Cumulative incidences of T1D among the offspring were estimated. Groop PH Folkhalsan Institute of Genetics. although patients diagnosed at a young age (0–4 years) have a longer time free of proliferative retinopathy. for risk of microalbuminuria in a longitudinal cohort of people with childhood-onset diabetes. Conclusion: T1D transmission ratio distortion is strongly related to the sex and age at onset of diabetes in the diabetic parents. 3. The present study represents a step forwards in the understanding of transmission of diabetes as it assesses this issue within a continuum of parental age at onset from childhood to adulthood. A more stringent diabetes management might be another implicated factor. Type 1 Diabetes: Clinical and Experimental 135 . diagnosed between 15 and 39 years of age and 5. [30] in 2008. diagnosed before the age of 15 years. where the cumulative risk was 4% by 20 years. with a similar risk in offspring of diabetic mothers and fathers. but it does affect the age at which complications are first detected. Methods: Diabetes status of all offspring (n = 9.fi Diabetes 2010.455 person-years. children with an early onset of diabetes showed a silent period. Lammi N. Finland valma. Biomedicum Helsinki.

production by Gr-1+CD11b+ cells is essential for this loss. low efficiency of islet transplantation has been a major obstacle limiting its clinical applications.production by Gr-1+CD11b+ cells is an important mediator of this early loss [33].production by NKT cells and Gr-1+CD11b+ cells. resulting in low transplantation efficiency.120:735–743 Background: Islet transplantation for the treatment of T1D is limited in its clinical application mainly due to early loss of the transplanted islets. therefore repre- 136 Francesco Chiarelli/M. In particular. Loredana Marcovecchio . resulting in a declining risk in the offspring of fathers with increased age at onset. no such trend was detected. through an upregulation of CD40 expression and an increased production of IL-12 by DCs.and late-onset cohorts were considered together. HMGB1 stimulated hepatic mononuclear cells (MNCs). Moreover.production by Gr-1+CD11b+ cells. Early loss of transplanted islet is a key problem to be solved [32]. Therefore. Islet transplantation is a promising procedure for the cure of diabetes. Sekine-Kondo E. Animal models have shown that NKT cell-dependent IFN. 35–39). an earlier onset underlines a stronger genetic component. the results of this study are in line with the concept that age at onset is an indicator of genetic susceptibility. Yamamoto H. They found that a major source of HMGB1 is represented by pancreatic islets. Maruyama I. Okamoto K. Nagata N. Conclusion: HMGB1 and related activated pathways play an important role in early islet loss and represents a potential target for intervention to improve the efficiency of islet transplantation. The findings of the present study confirm the concept that differences in the genetic. Results: A major source of HMGB1 is represented by pancreatic islets. Fukuoka. a protein which appears to play a key role in response to tissue damage and is released by inflammatory cells.ac. The present study represents a step forward in understanding this process. Treatment with an HMGB1-specific antibody prevented the early islet graft loss and inhibited IFN. Taniguchi M. Japan yasunami@fukuoka-u. However. this protection cannot be claimed for offspring of mothers with adult-onset diabetes.9 for 15–19 years vs.Interestingly. Watarai H. focusing on the role of HMGB1. Food for thought Can we improve islet transplantation success? High-mobility group box 1 is involved in the initial events of early loss of transplanted islets in mice Matsuoka N.jp J Clin Invest 2010. but the upstream events in the process remain undetermined. whereas in the offspring of fathers from the late-onset cohort the risk decreased with age at diagnosis (HR = 2. leading to NKT cell activation and subsequent NKT cell-dependent augmented IFN. Yasunami Y Department of Regenerative Medicine and Transplantation. NKT cell-dependent IFN. Itoh T. Methods: A mouse model of diabetes was used to assess the involvement of high-mobility group box 1 (HMGB1) in the initial events of early loss of transplanted islets. and macrophages [34]. mice lacking either of the known HMGB1 receptors TLR2 or receptor for advanced glycation end products (RAGE). failed to exhibit early islet graft loss. although when considering only the offspring of mother diagnosed before 10 years of age girls showed a higher risk than boys. Although in previous studies the lower risk in offspring of mothers was explained by a certain protection of the diabetic intrauterine environment. autoimmune and clinical aspects exist between childhood versus adulthood-onset diabetes. this was not the case for the offspring of mothers. For the mothers.or CD40L-specific antibody prevented the early islet graft loss. Mera T. such as dendritic cells. the authors reached some key conclusions. and this is clearly evident from the pattern of risk in the offspring of diabetic fathers. but not the known HMGB1 receptor TLR4. Yamada S. Through a series of elegant and detailed experiments in a mouse model of diabetes. Fukuoka University. from where this protein is released into the circulation soon after islet transplantation. where the protein is localized mainly in nuclei and its plasma levels increase soon after transplantation. This age-related trend was even more evident when both the early. Treatment with either IL-12. NK cells.

increased mitochondrial superoxide production consequent to hyperglycemia can induce not only immediate effects. and there are several lines of evidence showing a key roles of these intracellular organelles in the pathogenesis not only of diabetes but also of its complications [35]. cancer and diabetes. Also. through the involvement of bcl-2 family. In this review a summary of the main findings supporting such a key role of the mitochondria in -cell death are summarized. mitochondrial dysfunction underlies both the functional derangement of glucose-stimulated insulin secretion and stress-induced apoptotic/necrotic -cell death. mitochondrial increased oxidant generation seems to play an important role also in the context of the ‘metabolic memory’. -cell death is directly linked to the autoimmune process. even in presence of physiological glucose levels [35]. which characterize type 2 diabetes. These inflammatory cytokines in turn further contribute to damage of the transplanted islets. INF. represented by mitochondrial membrane permeation.B activation. which in turn could stimulate NKT-dependent INF. Reviews Mitochondria-mediated cell death in diabetes Szabadkai G. including neurodegenerative diseases. leading to synthesis of altered mitochondrial respiratory channel subunits.14:1405–1423 Overview: Mitochondrial dysfunction play a role in the pathogenesis of a wide range of diseases that involve disordered cellular fuel metabolism and survival/death pathways.szabadkai@ucl. the cellular aerobic bioenergy production sites. University College London. -cell death in both conditions appears to be mediated by a common final mechanism.and TNF. based on receptor expression pattern. the main soluble mediator of -cell apoptosis produced by CD4+ T cells and macrophages are IL-1 ..ac. where they stimulate IL-12 production. Mitochondrial Biology Group. The identification and definition of this complex network represents an important discovery. Duchen MR Department of Cell and Developmental Biology. Mitochondria. which stimulate NF. that in turn mediates the pro-apoptotic signal. are involved in a variety of metabolic activities. but it might also damage mitochondrial DNA and proteins. In the context of T1D. the study showed that the first cell line target for HMGB is represented by dendritic cells. which could produce increased amount of superoxide. In particular. In fact. Additional mechanisms linking -cell death in T1D with mitochondria dysfunction are activation of poly(ADP-ribose) polymerase and NO competition for molecular oxygen at the level of complex IV of the mitochondria. Based on these data. CD8+ T-cell-mediated -cell death appears to be linked to mitochondria.senting a potential early marker of transplant failure. In T1D. whereas in type 2 diabetes metabolic stress induces -cell apoptosis/necrosis. In this review the authors report and discuss the current level of evidence supporting a key role of mitochondria in -cell death in the context of both T1D and type 2 diabetes.uk Apoptosis 2009. London. mitochondria appear to be an important cellular component towards which further research should be directed to clarify aspects of the pathogenesis of diabetes. UK g. virus recognition and cellular stress pathways converging on mitochondria cause apoptotic and/or necrotic cell death of -cells in T1D.production. Type 1 Diabetes: Clinical and Experimental 137 .. Cytokine. Interestingly. Although the pathogenesis of the two diseases is distinct. which highlights potential new targets for interventions aiming at increasing the rate of success of islet transplantation. HMGB1 activates the production of inflammatory cytokines including IL-12 and INF. In addition.

References
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Brownlee M: Biochemistry and molecular cell biology of diabetic complications. Nature 2001;414:813–820. 12. Meigs JB, Panhuysen CI, Myers RH, Wilson PW, Cupples LA: A genome-wide scan for loci linked to plasma levels of glucose and HbA1c in a community-based sample of caucasian pedigrees: The framingham Offspring Study. Diabetes 2002;51:833–840. 13. Chiarelli F, Giannini C: Type 1 diabetes: clinical and experimental; in Carel J, Hochberg Z (eds): Yearbook of Pediatric Endocrinology 2009. Basel, Karger, 2009, pp 123–124. 14. Barrett JC, Clayton DG, Concannon P, Akolkar B, Cooper JD, Erlich HA, et al: Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 2009. 15. MacFarlane AJ, Strom A, Scott FW: Epigenetics: deciphering how environmental factors may modify autoimmune type 1 diabetes. Mamm Genome 2009;20:624–632. 16. Li C, Grosdidier A, Crambert G, Horisberger JD, Michielin O, Geering K: Structural and functional interaction sites between Na,K-ATPase and FXYD proteins. J Biol Chem 2004;279:38895–38902. 17. Hudson AW, Ploegh HL: The cell biology of antigen presentation. Exp Cell Res 2002;272:1–7. 18. Denzin LK, Fallas JL, Prendes M, Yi W: Right place, right time, right peptide: DO keeps DM focused. Immunol Rev 2005;207:279–292. 19. Lovell HG: Angiotensin-converting enzyme inhibitors in normotensive diabetic patients with microalbuminuria. Cochrane Database Syst Rev 2001:CD002183. 20. Chaturvedi N, Sjolie AK, Stephenson JM, Abrahamian H, Keipes M, Castellarin A, et al: Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The Euclid Study Group. Eurodiab controlled trial of lisinopril in insulin-dependent diabetes mellitus. Lancet 1998;351:28–31. 21. Cravedi P, Remuzzi G: Treating the kidney to cure the heart. Kidney Int 2008;74:S2–S3. 22. 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Obesity and Weight Regulation
Martin Wabitsch, Daniel Tews, Michaela Keuper, Carsten Posovszky, Christian Denzer, Anja Moss, Julia von Schnurbein and Pamela Fischer-Posovszky
Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University of Ulm, Ulm, Germany

The literature on obesity and weight regulation published in the last 12 months demonstrates the activity and interest of this field of science and medicine. For the Yearbook selection this year, only articles published in journals with a high impact factor were considered, assuming that relevant findings were published in these journals. The highlights are papers about new molecules involved in the regulation of eating and physical activity behavior as well as in addiction-like reward dysfunction and compulsive eating; papers on early programming of metabolic and endocrine regulation of body weight and papers demonstrating that the search for copy number variants (CNVs) are a new strategy to discover obesity genes which might contribute to the missing heritability of obesity. In Yearbook 2009 the identification and importance of brown adipose tissue in adult humans has been demonstrated in three independent articles in the New England Journal of Medicine [1]. These findings have stimulated research in the molecular regulation of energy expenditure coming up with exciting new data presented in this year’s volume. In Yearbook 2007, two papers published in Nature showed for the first time that gut microbiota are a contributing factor to the pathophysiology of body weight regulation [2]. This story goes on as shown in an article published in Science, 2010.

Adipose tissue New molecule responsible for preadipocyte determination

Transcriptional control of preadipocytes determination by Zfp423
Gupta RK, Arany Z, Seale P, Mepani RJ, Ye L, Conroe HM, Roby YA, Kulaga H, Reed RR, Spiegelman BM Department of Cancer Biology and Division of Metabolism and Chronic Disease, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Mass., USA Nature 2010;464:619–623
Background: Obesity is increasing in an epidemic manner. The size of the adipose tissue mass is determined by the number of fat cells as well as their volume. It is important to understand which mechanisms control the development of fat cells. The differentiation of committed preadipocytes to adipocytes is controlled by PPAR and other transcription factors. However, the molecular basis for preadipocyte determination is not understood. Methods: The authors used a new method for the quantitative analysis of transcriptional components (‘Quanttrx’) to identify new proteins involved in preadipocyte commitment. Results were confirmed using genetic approaches (ectopic expression, shRNA). Results: The zinc-finger protein Zfp423 was identified as a protein that is enriched in preadipose versus non-preadipose fibroblasts. Expression of Zfp423 in non-preadipose fibroblasts activates PPARg expression and permits cells to undergo adipocyte differentiation under permissive conditions. Knockdown of Zpf423 in preadipose 3T3-L1 cells blunts PPARg expression and diminished the ability for adipogenic differentiation. Conclusion: This study identifies Zpf423 as a transcriptional regulator of preadipocyte determination and suggests a model in which the regulation of the preadipocyte levels of PPARg by Zpf423 represents a crucial determinant of preadipocyte commitment.

There is a high turnover of fat cells in human white adipose tissue [3]. Additionally, the white adipose tissue keeps the ability to expand throughout adult life by an increase in adipocyte number [4]. For a

better understanding of the dynamics of adipose tissue and development of obesity it will be crucial to elucidate the whole adipogenic process – from stem cell precursor, via preadipose fibroblast to the mature adipocyte. The transcriptional pathways controlling adipocyte differentiation from committed preadipose fibroblasts were intensely investigated and there has been great progress. However, the transcriptional mechanisms underlying the preceding steps, the commitment of the embryonic stem cell precursor to the adipocyte lineage, remain to be characterized. The major problem seems to be that the preadipose commitment is more a quantitative than a qualitative trait [5]. Till now there is no specific marker which enables researchers to separate preadipose fibroblast from non-adipogenic fibroblast. In the present paper, for the first time, the authors were able to identify one protein that seems to be the important determinant – Zfp423. The authors showed in cell culture and in vivo (Zpf423 knockout mice) studies a genetic requirement for Zfp423 in the initial formation of both brown and white adipocytes. Taken together, this protein might help to gain more insight into the molecular basis of adipose tissue formation in physiological and pathophysiological states, thereby helping to provide new means to develop therapeutic strategies for the treatment and prevention of obesity.

New molecules involved in the regulation of eating and physical activity behavior

Regulation of adaptive behavior during fasting by hypothalamic Foxa2
Silva JP, von Meyenn F, Howell J, Thorens B, Wolfrum C, Stoffel M The Rockefeller University, Laboratory of Metabolic Diseases, New York, N.Y., USA Nature 2010;462:646–651
Background: Neurons in the lateral hypothalamus are important for feeding, behavioral arousal and addiction. These behaviors are stimulated by orexin and melanin-concentrating hormone (MCH). The aim of the study was to further understand the responsible molecular mechanisms. Methods: Mouse and metabolic studies were performed including nuclear translocation experiments, laser scanning confocal microscopy, transfection and transactivation assays, and knockout mice. Results: Forkhead box transcription factor Foxa2 is a downstream target of insulin signaling and is expressed in two distinct neuronal cell populations, namely MCH and orexin neurons. In the absence of insulin signaling, Foxa2 is recruited to the MCH and orexin promoters to activate their expression. Accordingly, during fasting resulting in low insulin levels Foxa2 binds to MCH and orexin promoters and stimulates their expression. By contrast, in the presence of insulin these two neuropeptides are down-regulated due to a change in the subcellular localization of Foxa2 which is regulated by plasma insulin concentrations. In fed and in hyperinsulinemic obese mice, Foxa2 is phosphorylated by insulin/ PI3K/Akt signaling which leads to Foxa2 inactivation and nuclear exclusion and finally to a reduced expression of MCH and orexin. Constitutive nuclear activation of Foxa2 simulating the situation in the low insulinemic state in the brain results in increased MCH and orexin expression and increased food consumption, metabolism, and also in peripheral insulin sensitivity. In addition, spontaneous physical activity is significantly increased. Conclusion: These data show that Foxa2 is a metabolic sensor in the lateral hypothalamus and integrates metabolic signals, adaptive behavior, and physiological responses.

Foxa2 in melanin-concentrating hormone- and orexin-expressing neurons is permanently inactivated in hyperinsulinemic mice with diet-induced obesity [6]. The authors show that insulin down-regulates Foxa2 expression by changing the subcellular localization of Foxa2 which is excluded from the nucleus by insulin. Hence, these studies show that there is a molecular explanation for the inverse associations of hyperinsulinemia/insulin resistance and physical activity/energy expenditure which has been observed in humans in several studies. Interestingly, the authors could show convincingly that constitutive nuclear activation of brain Foxa2 mimicking hypoinsulinemia results in increased neuronal melanin-concentrating hormone and orexin expression in obese mice and leads to increased food consumption, improved glucose homeostasis,

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decreased fat and increased lean body mass linked to an increase in physical activity in these obese animals. Pharmacological inhibition of Foxa2 phosphorylation may be a possibility to increase the levels of physical activity, overall health and longevity.

Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats
Johnson PM, Kenny PJ Laboratory of Behavioral and Molecular Neuroscience, Department of Molecular Therapeutics, The Scripps Research Institute, Fla., USA pjkenny@scripps.edu Nature Neurosci 2010;13:635–641
Background: Food consumption is influenced by pleasure and reward. Obtaining food reward is a drive highly motivating food consumption. The hedonic mechanisms behind these observations which also might contribute to obesity remain poorly understood. The aim of the study was to investigate the effects of extended access to a palatable high-fat diet on the sensitivity of brain reward systems in rats. In addition, the role of striatal dopamine D2 receptors (D2R) in the resulting addiction-like behavioral responses was investigated. Methods: Studies were performed with Wistar rats. Methods included bipolar stimulating of the lateral hypothalamus by an electrode, training of animals in a current-threshold brain stimulation reward (BSR) procedure, and lentivirus-mediated knockdown of striatal D2R expression. Results: In the BSR procedure, rats respond vigorously to obtain rewarding electrical self-stimulation through the indwelling stimulating electrode, with the minimal stimulation intensity that maintains self-stimulation behavior termed the reward threshold. The development of obesity in rats with extended access to a cafeteria style diet consisting of palatable energy dense food was closely associated with a worsening deficit in brain reward function, reflected in progressively elevated BSR thresholds. These animals showed addiction-like reward deficits, overeating and loss of homeostatic energy balance. By contrast, restricted access to palatable food gave rise to binge-like patterns of consumption, but did not disrupt the brain reward function. Animals with extended food access took twice as much energy as compared to the restricted-access animals. Striatal expression of the D2R was lower in the extendedaccess rats than in the restricted-access or chow-only fed rats. There was also a clear inverse relationship between body weight and striatal D2R expression. There was a persistent reward dysfunction and hypophagia during abstinence in rats with extended access to a cafeteria diet. Knockdown of striatal D2R increased vulnerability to reward dysfunction in rats with extended access to a cafeteria diet. Knockdown of striatal D2 receptors markedly accelerated compulsive-like eating of palatable food. This was only observed in rats with a history of extended access to palatable food. Conclusion: These data demonstrate that overconsumption of palatable food triggers addiction-like neuroadaptive responses in brain reward circuits and raises the development of compulsive eating.

Feeding is influenced by pleasure and reward. Easy access to palatable high-fat food is considered to be an important environmental risk factor for obesity [7]. The authors show that overstimulation of brain reward systems through excessive consumption of palatable, energy-dense food induce a profound state of reward hyposensitivity and the development of compulsive-like eating. The maladaptive behavioral responses in obese rats probably arise from diet-induced deficits in striatal D2 receptor signaling. Similarly, substance abuse decreases striatal D2R density, induces a profound state of reward hypofunction and triggers the emergence of compulsive-like drug-taking behaviors. Thus, the findings of the present paper support previous work [7–22] indicating that obesity and drug addiction may arise from similar neuroadaptive responses in brain reward circuits. Conversely, individuals with anorexia nervosa have elevated striatal D2R. Weight loss after bariatric surgery is associated with elevated striatal D2R density [23, 24]. The gene polymorphism referred to as the TaqIA A1 allele results in decreased striatal D2R density, and individuals harboring this allele are over-represented in obese population [8]. So far the hedonic mechanisms contributing to obesity remain poorly understood. Interestingly in hyperphagic humans with congenital leptin deficiency, activity in the dorsal and ventral striatum, which are core components of brain reward circuits, increases markedly in response to images of food. Leptin replacement therapy attenuates both striatal activity and self-reported ‘liking’ of food

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[25]. These data already suggest that the striatum is important in hedonic aspects of feeding behavior. It also has been shown that activation of the striatum in response to highly palatable food is blunted in obese individuals when compared with lean controls [8]. Extended access to palatable high-fat food can induce addiction-like deficits in rat brain reward function. This might be an important source of motivation that may drive overeating and contribute to the development of obesity.

Regulation of energy homeostasis by bombesin receptor subtype-3: selective receptor agonists for the treatment of obesity
Guan X-M, Chen H, Dobbelaar PH, Dong Y, Fong TM, Gagen K, Gorski J, He S, Howard AD, Jian T, Jiang M, Kan Y, Kelly TM, Kosinski J, Lin LS, Liu J, Marsh DJ, Metzger JM, Miller R, Nargund RP, Palyha O, Shearman L, Shen Z, Stearns R, Strack AM, Stribling S, Tang YS, Wang S-P, White A, Yu H, Reitman ML Merck Research Laboratories, Rahway, N.J., USA Xiaoming_guan@merck.com, marc_reitman@merck.com Cell Metabolism 2010;11:101–112
Background: Pharmacotherapy of obesity has limited success so far, due to the existence of multiple redundant and compensatory pathways in energy homeostasis. Bombesin receptor subtype-3 (BRS-3) is primarily expressed in the brain but its biological functions are not yet well investigated. Its natural ligands are unknown. The aim of the present study was to develop potent BRS-3 agonist and antagonist ligands that are suitable for exploring the role of BRS-3 in the regulation of food intake, metabolic rate, and body weight. Methods: Rat and mice studies were performed including metabolic rate measurements and binding assays. Studies were also performed using several knockdown animals. Results: A BRS-3 antagonist ligand increases food intake, body weight, and adipose tissue mass. A BRS-3 agonist reduces food intake and increases metabolic rate. BRS-3 binding sites were identified in the hypothalamus, caudal brainstem, and several midbrain nuclei. Prolonged high levels of receptor occupancy increased weight loss, suggesting a lack of tachyphylaxis. BRS-3 agonist effectiveness was maintained in several knockdown animals (Npy–/–, Agrp –/–, Mc4r–/–, Cnr1–/– and Leprdb/db mice). BRS-3 null mice lost weight upon treatment with either a MC4R agonist or a CB1R inverse agonist. Conclusion: This study shows that BRS-3 has an important role in energy homeostasis, complementary to several well-known pathways. BRS-3 agonists may be a potential approach for the treatment of obesity.

Bombesin receptor substrate 3 (BRS-3) is a G-protein-coupled receptor whose natural ligand is unknown. In the present study the authors developed potent, selective agonist and antagonist ligands to explore BRS-3 function. Pharmacological activation of BRS-3 presents a potential therapy for obesity. Since the data also show that the regulation of energy homeostasis by BRS-3 is complementary to the Mc4R and CB1R pathways it could be suggested that such potential therapies involving BRS-3 could also be performed in combination with the pharmacological modulation of other pathways. Food intake is under the control of both homeostatic and non-homeostatic (e.g. hedonic) mechanisms. The study supports the concept that natural BRS-3 ligands are peptides that signal BRS-3 sites at least in part in the hypothalamus. These natural ligands probably regulate energy supplies and/or hedonic drive by reaching. The precise mechanisms, including neuron types and pathways, by which BRS-3 signaling regulates energy metabolism, remain unclear. These mechanisms however seem to be complementary to the action of other factors regulating energy metabolism such as leptin, melanocortin, neuropeptide Y, and endocannabinoid.

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At postnatal 16 and in adulthood. Yu Y. Grove KL Oregon National Primate Research Center.cn Mol Cell Biol 2010. Evans AE. Results: Compared to control pups. and Graduate School of the Chinese Academy of Sciences. Gonzalez L. Shanghai Institutes for Biological Sciences. Enriori PJ. leptin activates multiple signaling pathways in the hypothalamus to regulate food intake and energy expenditure. Fisher SK. whereas young homozygous Y985F animals were slightly leaner. a subset of mice was placed on high-fat diet. These roles act as an age/diet-dependent regulatory switch to counteract age-associated or diet-induced obesity. China liuy@sibs. CPO mice exhibited an increased body weight and hyperleptinemia in the pre-weaning period. Early programming of metabolic and endocrine regulation of body weight Early overnutrition results in early-onset arcuate leptin resistance and increased sensitivity to high-fat diet Glavas MM. Oreg.Signaling through Tyr985 of leptin receptor as an age/diet-dependent switch in the regulation of energy balance You J. Conclusion: The study shows that there are distinct binary roles for OBR Tyr985-mediated signaling in energy metabolism.30:1650–1659 Background: Diminished leptin signaling occurs in association with aging or feeding a high-fat diet. Altogether this animal model confirms the role of the leptin receptor in the regulation of fat stores and energy metabolism and shows that mild impairment of leptin receptor signaling can produce more subtle phenotypes than those observed in human and mice so far. one of the three intracellular tyrosines that mediate leptin’s signaling actions. Reducing the size of a mice litter and exposing thereby mice to chronic postnatal overnutrition (CPO) is an interesting animal model to analyze mechanisms and consequences of early overfeeding. On the 23rd postnatal day all were weaned onto standard chow. Acting through its receptor in distinct classes of leptin-responsive neurons. Methods: Litters from Swiss Webster dams were culled to 3 pups (CPO) or 10 pups (control). glucose and insulin tolerance were examined at 16–17 weeks of age. Yu X. leptin levels were measured and leptin sensitivity was determined by measurement of food intake and hypothalamic phosphorylated signal transducer and activator of transcription-3 (STAT3) immunoreactivity after intraperitoneal leptin injection. Xiao XQ. Jiang L.ac. Shanghai. Kirigiti MA. Oregon Health and Science University. Cowley MA. Leptin is an adipose-secreted hormone that plays a pivotal role in the regulation of energy metabolism. Methods: Knock-in line of mice (Y985F) expressing a mutant Ob-Rb. Smith MS. Li C. they exhibit adultonset or diet-induced obesity. This leptin resistance was mainly attributable to attenuation of leptin-responsive hypothalamic STAT3 activation and elevated expression of hypothalamic SOCS3. The study shows here that the loss of Tyr985 in the long form of the leptin receptor (Ob-Rb) leads to adult onset of obesity. The aim of the present study is to identify the exact physiological mechanisms linking the environmental factors to the impairment in the leptin-mediated regulation of energy metabolism. but we are far from understanding all mechanisms behind this trend. In all subgroups. Grayson BE. Beaverton. Li W. but only a slightly heavier body weight and normal glucose tolerance in Obesity and Weight Regulation 143 . the long form of the leptin receptor with a phenylalanine substitution for Tyr985. Ke Z.151:1598–1610 Background: Childhood obesity is rising at an alarming rate. At an age of 6 weeks. Institute for Nutritional Sciences. Yang G. Adult Y985F mice exhibit impairments in both food intake and energy expenditure and a loss of Tyr985-mediated actions that exacerbates high-fat diet-induced obesity. Liu Y Key Laboratory of Nutrition and Metabolism. USA Endocrinology 2010. The observed age-dependent or diet-induced deterioration of energy balance was paralleled with pronounced leptin resistance. Results: Surprisingly.. Li W.

5 vs. Methods: Anthropometry and fasting blood levels were studied in 49 women who had lost 36 ± 1. p = 0. the mechanism by which postnatal overfeeding in mice enhances the risk of adulthood obesity and insulin resistance might essentially be comparable to the consequences of human obesity during pregnancy. 35%. highdensity lipoprotein cholesterol 1. [31] is the first to examine the long-term impact of maternal weight loss through bariatric surgery on obesity rate and co-morbidity in offspring. 14.05 mmol/l. each decision for bariatric surgery has to be made cautiously.9 ± 0. and leptin (11.96 ± 0.28 ± 0.50 ± 0. p = 0.4 ± 0. Lescelleur O. lower C-reactive protein (0.03).17 vs. Conclusion: Early overfeeding leads to early and persistent leptin resistance and increases the susceptibility for overweight and insulin resistance.03 ng/ml ± 0.02) improved lipid profile (cholesterol/high-density lipoprotein cholesterol 2. p = 0.88 ± 0. Preconceptive bariatric surgery decreases rates of gestational diabetes and neonatal macrosomia [32–35].1 vs.8 vs. Results: AMS children had a lower birth weight than BMS children (2. In a previous study they were able to show an impressive reduction in childhood/adolescence obesity. Lebel S. Therefore.5 ± 1. It has already been demonstrated that in postnatally overfed rats leptin shows a decreased inhibition of neuronal activity in the arcuate nucleus [29]. p = 0.00 ± 0. P Institut Universitaire de Cardiologie et Pneumologie de Quebec. in humans the major part of neuronal development occurs before birth [30]. 3. Biron S. Kral JG. p = 0. Furthermore.3 ± 0.5–26 years.24 µg/ml.7 ± 2. CPO mice demonstrated an attenuated clinical leptin-responsiveness and a reduced STAT3 activation in the nucleus arcuatus. Apart from the academic interest of this finding. 1. despite normalized leptin levels. 4.06 vs. Marceau.8%.40 ± 0.8% body weight and sustained this weight-loss for 12 ± 0. Biertho L.04). Pre-conceptive biliopancreatic diversion bariatric surgery provides a highly specific model to study the transmission of metabolic risk factors in humans by comparing children born before (BMS) and after maternal surgery (AMS). AMS children had a higher insulin sensitivity (HOMA index 3. At the time of follow-up. Quebec. Simard S.03. Throughout their whole life however. The study group of Kral et al. 144 Martin Wabitsch et al. This proves elegantly the influence of potentially modifiable epigenetic factors on childhood obesity and associated morbidity. 2.004). 1. but this study definitely strengthens the recommendation of bariatric surgery prior to conception in severely obese women. albeit in two completely different approaches. p = 0. In response to high-fat diet. Now they completed this examination by showing an associate improvement in cardiometabolic risk markers which was sustained into adolescence and young adulthood. Hould FS. . 37] and severe nutritional deficiencies [38] during pregnancy.5 ng/ml. it also has important practical implications.005) and increased ghrelin (1.05 vs.35 ± 0.adulthood on standard chow.8 years and in their 111 children (54 BMS and 57 AMS) aged 2.06) than BMS offspring.004).11 vs. Cianflone K. Marceau S. 36. however it increases the risk for internal hernias [32. p = 0.5.94:4275–4283 Background: Maternal pre-pregnancy weight.1 kg. p = 0. 19. Men are not mice and whereas in rodents the neuronal network responsible for food intake regulation is progressively established during early postnatal life. The reduced effect of leptin and a reduced induction of STAT3 expression seen here further strengthens the hypothesis that early leptin resistance might play an integral part in raising the long-term risk of obesity and metabolic derangements. Canada J Clin Endocrinol Metab 2009. AMS children showed a lower prevalence of obesity compared to BMS children (11 vs. Conclusion: Improved intrauterine environment via pre-conceptive bariatric surgery not only lowers the risk of childhood/adolescence obesity but also reduces accompanying cardio-vascular risk factors. 3. CPO mice gained weight more rapidly and in contrast to control mice displayed a pathological response to an insulin tolerance test. Therefore.8 ± 0.003) and a lower prevalence of macrosomia (1. Effects of maternal surgical weight loss in mothers on intergenerational transmission of obesity Smith J.18. pregnancy weight gain and metabolic derangements during pregnancy influence offspring obesity rate and co-morbidities.3 vs. The first group used an animal model of early overnutrition which leads to an increased susceptibility to overweight and hyperinsulinemia [26–28]. These two studies address the interesting topic of the influence of metabolic and endocrine programming on the development of obesity and co-morbidities. Laval University.

Isidor B. Search for copy number variants (CNVs) a new strategy to discover obesity genes Large. Holder-Espinasse M. Guilmatre A. Obesity and Weight Regulation 145 . Pigeyre M. Ambresin AE. studies in patients with severe early-onset obesity have led to the detection of rare variants with significant impact on body weight. Goldenberg A. Cuisset JM. Bochukova EG. The aim of the present study was to explore the contribution of copy number variants (CNVs) to obesity. Blaumeiser B. In contrast.froguel@imperial. Hurles ME. a 16p11. Keogh J. Sjostrom L. A new highly penetrant form of obesity due to deletions on chromosome 16p11. Results: Large (>500 kb). Calmels N. UK p. Jacobson P. Cambridge. Vollenweider P. UK Isf20@cam. O’Rahilly S. Huang N. Blaszczyk K.ac.ac.0 by Aros. Mathieu-Dramard M. Clayton-Smith J. Kooy RF. rare chromosomal deletions associated with severe early-onset obesity Bochukova EG. Campion D. Pattou F. Mandel JL. Jarvelin MR. However. Fellmann F. Bergmann S. Waterworth D. Bouquillon S. Hamilton-Shield J.2 Walters RG. Philippe A. van Haelst MM.463:666–670 Background: Genome-wide association studies have identified common single nucleotide polymorphisms (SNPs) associated with increased body mass index. de Smith AJ. Inc. McCarthy MI. together these account for a small percentage of inherited variations in BMI. Hartikainen AL. Valsesia A. Jonveaux P.uk Nature 2010. Dupuis-Girod S. Chen F. Le Caignec C. Hurles ME. O’Rahilly S.ch Nature 2010. Walley AJ. Mannik K.463:671–677 Background: Copy number variants (CNVs) might contribute to the missing heritability of common disorders and also of obesity. Metspalu A. All 16p11. Martinet D. Keogh J. Conclusion: The CNVs contribute significantly to the genetic architecture of human obesity. Sladek R. However. El-Sayed Moustafa JS. the lower leptin levels in BMS children point to the fact that early development of leptin resistance may be a major player of increased obesity susceptibility in humans as well as in rodents. Caiazzo R. Palta P.2 deletions encompass several genes but include SH2B1.uk. Elliott P. Brioschi A.uk. Henning E. Ounap K. Farooqi IS. Deletion carriers exhibited hyperphagia and severe insulin resistance disproportionate for the degree of obesity. Chiesa J. Ellis RJ. Gaillard M. Meyre D. Leheup B. Hadjikhani N. Lecoeur C. Methods: 300 UK Caucasian patients with severe obesity defined as a BMI standard deviation score >3 and onset of obesity before 10 years of age were selected from the Genetics of Obesity Study Cohort. Saeed S. DNA samples were run on Affymetrix genomewide human SNP arrays 6. Department of Epidemiology and Public Health. Froguel P. David A. Balkau B. Of these individuals. Five patients with overlapping deletions on chromosome 16p11. Huang N. Sanlaville D. In an independent sample of >1. Waeber G.000 controls. Jacques. In 3 patients the deletion co-segregated with severe obesity. Labalme A. Andersson J. Esko T. Mooser V. Imperial College London. Addenbrooke’s Hospital. Henning E. Macdermot KD. Kurg A. Jacquemont S. Andrieux J.2 were identified. Malan V. Beckmann JS Section of Genomic Medicine. Buxton JL. Peltonen L. Cordier MP. Vatin V. Chevre JC.beckmann@chuv. Falchi M.Leptin resistance cannot be evaluated easily in children.2 deletion was found in an additional 2 patients.ac. Blakemore AI. Institute of Metabolic Science. Boute O. Giusti V. rare (<1%) deletions were significantly enriched in patients compared to >7. Stutzmann F. Coin LJ. Purmann C. Ferrarini A. which is known to be involved in leptin and insulin signaling. Farooqi IS University of Cambridge Metabolic Research Laboratories. meh@sanger.000 patients with severe obesity alone. Nelis M. Reymond A. Vincent-Delorme C. Beri-Dexheimer M. Touraine R. Carlsson L. Several CNVs were recurrent in patients but absent or at much lower prevalence in controls. Lobbens S. Lemaitre MP. 143 had developmental delay. Plessis G. Delobel B.

Coupling of phos- 146 Martin Wabitsch et al. ATP-sensitive K+ channels are involved in setting muscle energy expenditure. leading to a lean phenotype. Different combinations of Kir6. well-phenotyped cohorts with targeted follow-up and large population cohorts. It seems to be very productive to combine ‘the power of the extreme’ [40]: small. while locomotor activity and blood substrate availability were unaltered. Cohorts with extreme phenotypes are likely to be enriched for rare variants. KATP channels are hetero-octameric proteins composed of inwardly rectifying K+ channel (Kir6. Minn.11:58–69 Background: Energy-conserving mechanisms promote obesity in an environment of hyperalimentation and sedentary lifestyle. The prevalence of the SH2B1 containing deletion in patients with severe early-onset obesity was significantly greater than in controls. Methods: Two mouse models of KATP channel deficiency were characterized in terms of energy metabolism. Zingman LV Department of Medicine. SH2B1 encodes an adaptor protein involved in leptin and insulin signaling. Strategies aimed at looking for rare variants near common susceptibility loci may well prove to be fruitful in other common complex disease. Gerbin M. Terzic A. Hodgson-Zingman DM. These deletions were absent from healthy non-obese controls and accounted for 0. with increased chance of discovery. Comprehension of these mechanisms could help to interfere with their efficiency to advance obesity treatment and prevention. USA Cell Metab 2010.2 for obesity. Goldhamer DJ. Zhu Z. Results: A highly penetrant form of obesity was initially observed in 31 subjects who were heterozygous for deletions at 16p11. Algorithmic analyses of GWAS data were performed.x) and sulfonylurea receptor (SUR) subunits.7% of the morbid obesity cases (BMI ≥40 or BMI-SDS ≥4). Molecular regulation of energy expenditure Sarcolemmal ATP-sensitive K+ channels control energy expenditure determining body weight Alekseev AE. However. As a consequence of this fuel metabolism inefficiency.000 individuals from eight European cohorts. Conclusion: These data demonstrate the potential importance of rare variants with strong effects in common diseases as it could be shown here for a CNV in 16p11. this obesity retardation was accompanied by a decreased workload endurance. The study by Bochukova et al. Conclusions: Downregulation of sarcolemmal KATP channels could provide a novel option against obesity by interfering with muscle energy efficiency. .Methods: Subjects ascertained for cognitive deficit (malformations) with or without obesity were selected from those clinically referred for genetic testing. Coetzee WA. glycogen and body fat depots were reduced. These two studies show a promising strategy for identifying missing heritability in obesity (and other complex traits).. showed that a deletion of 16p11. Reyes S.2 deletions were identified in these individuals by standard clinical diagnostic procedures. SierraA. Sattiraju S. the phenotype of a reduced body weight of KATP channel-deficient mice persisted.x and SUR subunits comprise KATP channels with distinct electrophysiological and pharmacological properties. the phenotype is consistent with a role for SH2B1 in human energy homeostasis and glucose metabolism. 16p11. Rochester. Nineteen similar deletions were identified from GWAS data in >16. Under high-fat diet. The loci identified by this strategy may be subsequently analyzed and reveal additional rare variants that further contribute to the missing heritability.2 and who had also cognitive deficits. Disruption of SH2B1 in mice results in obesity and severe insulin resistance [39]. The data suggest that although the contribution of other genes or non-coding genetic material cannot be excluded. Results: The disruption of KATP channel function raised energy expenditure in both cardiac and skeletal muscle. Mayo Clinic.2 is associated with highly penetrant familial severe early-onset obesity and severe insulin resistance. Yamada S.

elevated energy expenditure. Fyn is a negative regulator of fatty acid oxidation through inhibition of the AMP-dependent protein kinase (AMPK). The authors propose that the protective effect of the downregulation of KATP channels may be a novel option for obesity therapy. lean). Inhibition of Fyn kinase results in a reduced rate of nuclear import of LKB1.. But due to its important role in the brain as well. USA claire.Y. for instance by interfering with lifestyle intervention programs. Methods: The authors inhibited Fyn kinase with SU6656 in WT mice.2-deficient mice suggest a role for these channels in skeletal muscle glucose uptake [42]. The finding of Yamada and colleagues’ suggest that this enzyme which belongs to the Src family of nonreceptor tyrosine kinases might offer a useful target for obesity therapy. AMPK is regarded as an energy sensor. an important player in energy metabolism. Results: Selective pharmacological inhibition of Fyn in wild-type mice resulted in a similar phenotype as Fyn-null mice (increased fatty acid oxidation. However. central neurons and skeletal and smooth muscle [41]. the inhibitor SU6656 used in the present study is not a drug candidate. It is regulated directly by the intracellular AMP/ATP ratio. this publication shows a new possible target for obesity therapy – the Fyn kinase. An upstream kinase activator of AMPK in peripheral tissue is LKB1 which is inactive as long as it is localized in the nucleus.photransfer pathways with KATP channels permits a transduction of nucleotide fluxes into changes in membrane excitability. Both Fyn kinase as well as the downstream target of Fyn. even under high-fat diet. It will be essential to map Obesity and Weight Regulation 147 . Green tea has already been associated with weight loss which was explained by thermogenic effects probably partly due to the caffeine in the green tea [45–47]. These data highlight the therapeutic potential of inhibiting Fyn kinase signaling for obesity and its related disorders. resulting for instance in an increased fatty acid storage. Schwartz GJ. they treated murine muscle and adipocyte cell lines with SU6656 followed by localization studies of LKB1. thereby increasing the fatty acid oxidation and the energy expenditure. However.yu. A higher amount of LKB1 in the cytoplasm leads to activation of AMPK. the authors showed an increased energy expenditure and increased fatty acid oxidation leading to a decreased fat mass in mice. By inhibiting the Fyn kinases. are important in the brain besides their action in fat and muscle. Pessin JE. Former studies with Kir6. KATP channels are expressed in various tissues including heart.11:113–124 Background: Fyn null mice show an increased fatty acid oxidation and energy expenditure resulting in a reduced adipose tissue mass and enhanced insulin sensitivity. In a state of caloric excess. kidney. AMPK is inactive. The authors showed that Fyn-dependent phosphorylation of LKB1 is responsible for the nuclear localization of LKB1. increased energy expenditure) can be reproduced by the acute pharmacological inhibition of Fyn activity. Diabetes Research and Training Center. Lack of these channels led to an increase in energy expenditure which resulted in the decrease of body glycogen and fat stores promoting a lean phenotype. more research has to be done.edu Cell Metabolism 2010. Fyn-dependent regulation of energy expenditure and body weight is mediated by tyrosine phosphorylation of LKB1 Yamada E. AMPK. Another possible way might be to manipulate the Fyn kinase gently with nutrients. The role of Fyn in this context has now to be considered. Bronx. pancreatic cells. physiological conditions. Fatty acid oxidation was assessed in isolated skeletal muscles.bastie@einstein. Taken together. Bastie CC Department of Medicine. the described reductions in workload endurance will limit this approach. They determined whole-body energy expenditure via indirect calorimetry and total fat mass by magnetic resonance. Albert Einstein College of Medicine. matching energy demands with metabolic resources. Additionally. For instance. Validation experiments were performed with genetic approaches. N. there functioning as metabolic sensors assigned to protective responses under severe energy insult. it will be necessary to find something acting only on adipose tissue and muscle. epigallocatechin gallate which can be found in green tea inhibits Fyn kinase [44] and mimics thereby the action of the SU6656. Kurland IJ. These effects are similar to those they already observed in a knockout mouse for Fyn [43]. Conclusion: The positive metabolic effects seen in Fyn-null mice (decreased adiposity. The present study describes a novel role for sarcolemmal KATP channels under non-stressed. Therefore.

148 Martin Wabitsch et al. Harvard Medical School. Md. DIT was paradoxically increased in knock-out mice. Mutations of this protein lead to an obesogenic phenotype in both mice and patients with Albright hereditary osteodystrophy (AHO). These mice were cold-intolerant due to disruption of SNS signaling to BAT indicating a defect in cold-induced thermogenesis. Gupta D. USA Cell Metabolism 2010. Bethesda. Wang J. . Weinstein S Metabolic Diseases Branch. Pacak K. DIT is due to an increase in energy expenditure after changes in nutrient uptake. Department of Cell Biology. This came along with impaired cold tolerance and reduced brown adipose tissue (BAT) response to sympathetic stimuli. is involved in adipogenesis and adipose tissue function. Under high-fat diet. Gygi SP. suggestively the skeletal muscle.11:320–330 Gs. a G-protein-mediating receptor-stimulated cAMP production. Spiegelman BM Dana-Farber Cancer Institute. wild-type mice displayed enhanced sympathetic nerve activity in muscle. Frangioni JV. studies with human brown adipocytes ex vivo are needed. Altogether. Brown adipocytes arise from precursors expressing the myoblast lineage marker Myf5. BAT is not the tissue responsible for diet-induced thermogenesis. 50]. Gs deficiency in adipose tissue leads to a lean phenotype with divergent effects on cold tolerance and diet-induced thermogenesis Chen M. Seale P. Results: Heterozygeous animals did not show an obvious phenotype. Quon MJ. In the absence of BAT thermogenesis this indicates that another tissue must be responsible for DIT.. In the present study. Nguyen A.. National Institutes of Health.and diet-induced thermogenesis occurs in different tissues. Mass. Chen H. Kubota K. However. Methods: An adipose-specific Gs-deficient mouse model was generated and analyzed in terms of adipose function and thermogenic properties. According to these data. National Institute of Diabetes and Digestive and Kidney Diseases. So far. UCP-1-ablated mice do not show an obesogenic phenotype unless they are housed at physiological temperatures [49. USA Nature 2009. the mechanism of this determination is currently unknown.all regulatory elements of this signaling pathway to identify its regulatory actions and to elucidate how this pathway functionally integrates with other pathways to further support the potential of Fyn as a drug target for the treatment of obesity. a ubiquitously expressed G protein which couples hormone and neurotransmitter receptors to the generation of intracellular ATP. The mechanisms for obesity in Gs deficiency in humans remain elusive. pointing to a role of Gs in adipogenesis. Background: Brown adipose tissue (BAT) is the site of active glucose uptake in humans as recently demonstrated by PET/CT imaging. diet-induced thermogenesis and fatty acid oxidation in skeletal muscle were increased. Beth Israel Deaconess Medical Center. this model questions the involvement of BAT tissue in DIT and points to additional tissue sites involved. It stimulates brown fat-selective gene expression while suppressing the expression of genes selective for white fat cells. Conclusion: The results of this study indicate that cold. However. Gavrilova O. Under high-fat diet. it was thought to result from adrenergic stimulation of BAT and to be mediated by BAT uncoupling protein UCP-1 [48]. To further confirm these data. Lai EW.460:1154–1159 Background: Recent publications by this group identified PRDM16 (PR domain zinc finger protein 16) as a factor of brown fat determination. SNS induced thermogenesis in BAT is partially mediated by Gs . However. Lunsford E. Diet-induced thermogenesis (DIT) results from increased energy expenditure secondary to changes in nutrient uptake and is partly mediated by the sympathetic nervous system (SNS). Initiation of myoblast to brown fat switch by a PRDM16–C/EBPtranscriptional complex Kajimura S. but not in BAT. indicating that obesity seen in AHO is not caused by an adipose-specific Gs deficiency. Homozygotes displayed a strong reduction of adipose tissue. the authors investigated the participation of this protein in thermogenesis in a Gs -deficient mouse model. This has led to a renewed interest in the function of BAT thermogenesis in the regulation of body weight. Division of Hematology/ Oncology.

Gut microbiota The story goes on Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5 Vijay-Kumar M. Srinivasan S. Emory University.. Conclusions: The data show that the induction of brown fat is under the control of PRDM16 by formation of a transcription complex with C/EBP. Recent studies suggest different origins of brown and white adipose tissue. PRDM16 coactivates the transcriptional regulators PGC-1 and PPAR . Ga. This study provides a detailed insight into brown adipocyte determination and introduces a new potential target for enhancing brown adipose tissue in the context of obesity therapy. this fat pad was shown to act as a sink for glucose similar to endogenous brown adipose tissue. In mammals. Serum triglycerides.as a binding partner of PRDM16 which is involved in adipocyte development. Ley RE. cholesterol and blood pressure Obesity and Weight Regulation 149 . 20% higher body mass index than WT mice. Transplants of fibroblasts expressing both PRDM16 and C/EBP. The authors suggested therefore that PRDM16 acts predominantly by protein-protein interactions rather than by DNA interaction. Since recruitment of brown adipose tissue is currently discussed as a strategy to eliminate excess energy in obesity. Overexpression of both factors in fibroblastic cells including mouse and human skin fibroblasts was sufficient to induce a fully functional brown fat program. Beneath several transcriptional regulators. the authors could show here C/EBP. Carvalho FA. Mwangi S.as a binding partner of PRDM16. This process is driven by uncoupling mitochondrial respiratory chain from ATP production by the protein UCP-1 (uncoupling protein 1). Methods: By using mice genetically deficient in Toll-like receptor 5 (TLR5). By using PET-CT scans. Subsequently. There is growing evidence for a role of gut microbiota in both chronic inflammation and insulin resistance. This might offer novel therapeutic opportunities for obesity or type 2 diabetes. However. disruption of DNA binding of PRDM16 does not interfere with its ability to induce a brown phenotype [53]. Atit et al. there are two types of adipose tissue with distinct functions. at 20 weeks of age. PRDM16 was recently described as a switch in brown fat cell development by inducing brown adipocyte differentiation from white preadipocytes and myoblastic precursors [52]. altered microbiota composition and development of metabolic syndrome. the expressions of these candidates in white and brown adipose tissue were analyzed and their function in the process of myoblast to brown fat conversion by PRDM16 was investigated. Indeed.edu Science 2010. Mice embryos were transplanted into standard mice to standardize the microbiota in KO and control mice. Knight R. Results: Genetically deficient in TLR5. brown adipose tissue regulates the body temperature by dissipating energy in the form of heat. Sitaraman SV. Aitken JD. it is important to understand the molecular mechanisms of brown fat cell determination. [51] proposed a common lineage for muscle and brown fat on the basis of their finding that specific Myf5-expressing cells of the dermomyotome give rise to both muscle and brown fat cells but not to white adipocytes. this study supports a direct relationship between impairment of the innate immune system. Results: Proteomic analyses and expression profiling revealed C/EBP.328:228–231 Background: Recent research has linked the mammalian host-gut microbial relationship to human obesity. Gewirtz AT Department of Pathology. Cullender TC. Atlanta. While white adipose tissue is the main storage organ of the body.. By proteomic analyses. T5KO mice had a mild colitis and paradoxically. USA agewirt@emory.Methods: The authors identified putative binding partners of PRDM16 by proteomic analysis of transcriptional complexes formed with wild-type and differentiation-incompetent mutant PRDM16.into mice led to the development of a fat pad with morphological and biochemical characteristics of brown adipose tissue.

Bariatric surgery in adolescents Laparoscopic adjustable gastric banding in severely obese adolescents: a randomized trial O’Brien PE. results in serum antibody production against commensal microbiota and disturbed host-commensal mutualism [56].au JAMA 2010. fat pad and fasting glucose. In contrast to WT mice. Extreme obesity in adolescents is associated with both immediate and late health effects. a higher ex vivo production of proinflammatory cytokines such as interferon. elevated basal serum insulin levels and insulin resistance with high lipocalin-2 levels and increased number and size of pancreatic islets. Nutritional and genetic factors alter the intestinal microbiota and may predispose individuals to the metabolic syndrome. Innate immune dysfunction. but increased fat mass and typical signs of metabolic syndrome. T5KO became diabetic with fasting blood glucose concentrations above 120 mg/dl. Australia paul. physical limitations such as an inability to play 150 Martin Wabitsch et al. Alfred Hospital. Laurie C. but results from the gut microbiota. which also showed significant increase in body mass. The metabolic syndrome depends on hyperphagia since T5KO consume about 10% more food than WT littermates. changes in gut microbiota and the metabolic syndrome. Twelve weeks of food restriction prevented many of the metabolic abnormalities in T5KO mice. follow-up visits during 2 years. Eligibility criteria included identifiable medical complications such as hypertension. Sawyer SM. Bariatric surgery has been shown to be the only effective treatment in obese adults leading to sizeable weight reduction. randomized. The metabolic syndrome in T5KO mice is independent of the adaptive immune system and TLR2/ TLR4.edu. controlled study with 50 adolescents (age 14–18 years. The aim of the study therefore was to compare the outcomes of gastric banding with an optimal lifestyle program in adolescent obesity. Veit F.were increased compared to WT mice. T5KO mice also exhibited hyperglycemia after fasting and an impaired glucose tolerance. TLR5 is the main component of the innate immune system in the intestine. Vic. Anderson M. The gut microbiota by broad-spectrum antibiotics in 4-week-old mice lowered the bacterial load by 90% and corrected food intake. Vijay-Kumar presented a TLR5 null mice phenotype with only mild colitis. Burton PR. Skinner S. . weight gain and lower insulin sensitivity with increase of inflammatory cytokine production in these mice. Alterations in host-microbiota interactions may drive obesity and metabolic syndrome. Monash University Medical School. back pain. Methods: Prospective. Conclusion: Malfunctions of the innate immune system in TLR5-deficient mice alter the gut microbiota and contribute to the development of an increased fat mass and the metabolic syndrome in mice. 55]. Even the gut microbiota from T5KO mice intragastrically transferred in 4-week old WT germ-free mice induced elevated food intake. There are only a few observative studies in adolescents applying bariatric surgery. such as Toll-like receptor deficiency.303:519–526 Background: Adolescents with extreme obesity is a serious health challenge. The influence of gut microbiota on nutrient absorption and metabolic regulation has been demonstrated in human and animal studies showing alterations of the gut microbiota [54. Additional studies will show whether it is possible to change the microbiota in a way that ameliorates the metabolic profile in terms of food absorption or energy storage and hyperphagia. asthma. Centre for Obesity Research and Education. Surprisingly.obrien@med.and interleukin-1 was observed in adipose tissue of T5KO than in WT mice. metabolic syndrome. In addition. Obesity is associated with inflammation which might contribute to the increased risk of cardiovascular disease and type 2 diabetes. Melbourne.monash. They developed hepatic steatosis and inflammatory infiltrates in the pancreatic islets. Paul E. Metabolic syndrome developed in T5KO after administering an 8-week high-fat diet. McGrice M. This is the first link between malfunction of the innate immune system. Dixon JB FRACS. Brown WA.. BMI >35).

and an increased risk for later cardiovascular and other diseases. Conclusion: Gastric banding in obese adolescents resulted in much greater weight losses than lifestyle intervention and was associated with more favorable benefits to health and quality of life. For more than 5 years the Australian government has supported the so-called active-after-school-communities (AASC) program within a comprehensive national initiated program for obesity prevention. Nov 5. In the context of the study it should be mentioned that the Endocrine Society has published guidelines for bariatric surgery in obese adolescents [1]. additional education and supervision of eating are necessary to reduce the need for revisions. it requires long-term supportive follow-up by trained health professionals. Diligent application of these approaches should remain the first option for obese adolescents.4 to 1. For adolescents. laparoscopic adjustable gastric banding may be a future option for these patients. Severe obesity in adolescents is associated with multiple serious diseases. Therefore.1–8. Public Health Research Evaluation and Policy Cluster. In the gastric banding group a more favorable improvement in metabolic factors was observed as well as in quality of life. Obesity prevention in schools No clarity about cost-effectiveness The cost-effectiveness of Australia’s active after-school communities program Moodie ML.4 to 23.0 kg (2. Results: In the gastric banding group a weight loss of 34. conducted by health economists using simulation and modeling not described here showed that the program is not cost-effective as such. the majority of patients do not respond to this approach. The authors suggest to improve the cost-effectiveness by increasing the duration of physical activity and raising the number of participating school children..edu.moodie@deakin. difficulties with activities of daily lining.3 was achieved. So-called ‘after-school programs’ are therefore reasonable because the time after school lessons is an optimal time to increase the physical activity within sport programs and simultaneous reduce the common consumption of sugar and fatty snacks at this time of day. Carter RC. 8 operations (33%) were required in 7 patients for revisional procedures either for proximal pouch dilatation or tubing injury during follow-up. Epub ahead of print The school is an ideal place for obesity prevention programs.2–39.1) representing excess weight loss of 13% and a BMI z score change from 2. For optimal effectiveness. Haby MM Deakin Health Economics. This study confirms that lifestyle treatments can achieve weight loss and improvement in health for some individuals. It should however be mentioned that the gastric banding approach to weight loss is not a quick fix. impaired quality of life.a sport. Cost-effectiveness analysis.au Obesity (Silver Spring). The mean weight loss in the lifestyle group was 3. It also has been argued that adolescents with severe obesity need treatment during adolescence rather than deferring until adulthood. or psychosocial difficulties such as isolation or low self-esteem and evidence of attempts to lose weight by lifestyle means more than 3 years. Swinburn BA. There were no perioperative adverse events.6 kg (30. This study shows that gastric banding in obese adolescents proves to be an effective intervention leading to substantial and durable reduction of obesity and to better health. Vic. Obesity and Weight Regulation 151 . However. Australia Marj.0) representing an excess weight loss of 79% and a BMI z score change from 2. However. 2009. The need for additional surgery for enlargement of the stomach above the band or injury to the tubing is intrinsic to the gastric banding procedure. Eating small meals slowly is central to avoiding this problem after the gastric banding procedure. Burwood. Deakin University.

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Smith GD. p = 0. Power C. Jarvelin MR. McCarthy MI. p = 2 × 10–5. Results: T2M risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95% CI 11–31]. The 4% of offspring carrying four risk alleles at these two loci were 80 g (95% CI 39–120) lighter at birth than the 8% carrying none (ptrend = 5 × 10–7). Ramat-Gan and Maccabi Juvenile Diabetes Center. Exeter. Peninsula Medical School. since insulin is a key fetal growth factor. Raanana.986 mothers and 19. and SLC30A8) were genotyped in 7. Methods: Single-nucleotide polymorphisms (SNPs) at five recently identified T2DM loci (CDKAL1. Pouta A. including abnormalities in carotid structure and function. Hyperlipidemia among children and adolescents continues to be on the front line. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to both T2DM and also reduce birth weight. Ruokonen A. Lindgren CM. Tel-Aviv University. Research on metformin treatment as protection against cancer incidence and mortality in patients with T2DM is presented.004. genome-wide association (GWA) studies have revealed not only new loci but also new possible underlying mechanisms and hypotheses of T2DM pathogenesis. HHEX-IDE. Finally. now celebrating its 50th anniversary on lipids. Sheba Medical Center. IGF2BP2.Type 2 Diabetes Mellitus. and 14 g [4–23]. Hattersley AT Genetics of Complex Traits. Hypponen E. Timpson NJ. Rapid weight gain in newborns with intrauterine growth retardation and precocious puberty has both been found to be associated with the development of the MetS. as expressed in an editorial entitled ‘a decade of progress’ [3] and as manifested by the emergence of new drugs for children with familial hyperlipidemia. Hyperlipidemia has been associated to another ‘hot topic’. lower birth weight per risk allele. as well as revelations and challenges [1. Weedon MN. A number of articles published this year have highlighted dilemmas in definitions of the MetS.58:1428–1433 Background: Low birth weight is associated with an increased risk of T2DM. Sackler School of Medicine. Frayling TM. Lipids Orit Pinhas-Hamiel Pediatric Endocrinology and Diabetes Unit. Strachan DP. The impact of T2DM during childhood on the early development of diabetes complications. CDKN2A/B. we discuss the impact of the contraception pill. UK Diabetes 2009. New paradigms Type 2 diabetes risk alleles are associated with reduced size at birth Freathy RM. 2]. Perry JR. Ring SM. Edmond and Lily Safra Children’s Hospital. vitamin D. Lango H. Longitudinal follow-up has demonstrated a high risk of premature mortality among subjects who had features of the metabolic syndrome (MetS) during their childhood. Zeggini E. Metabolic Syndrome. The association between maternal or fetal genotype at each locus and birth weight of the offspring was tested. . respectively). Elliott P. Institute of Biomedical and Clinical Science. Bennett AJ. Shields B. In the search to identify diabetes susceptibility genes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. There were no associations between birth weight and fetal genotypes at the three other loci or maternal genotypes at any locus. Groves CJ. has been the subject of a number of recent studies. as well as the development and progression of microalbuminuria in children with T2DM. Israel Identifying the genetic variants that increase the risk of type 2 diabetes mellitus (T2DM) in humans continues to be a challenge.200 offspring white Europeans.

Froguel P. Nathan DM. Loos RJ. Le Bacquer O. Scott LJ. Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge Saxena R. Bonnycastle LL. ratio of insulin to glucose area under the curve. Bornstein SR. Sijbrands E. Sladek R. Groop L. Forouhi NG. Payne F. Chines PS. patients with monogenic neonatal diabetes have reduced birth weights. Walker M. Two observations support this hypothesis. Sayer AA. p = 1.2 × 10–16). Charpentier G. Erdos MR.0 × 10–17. Stumvoll M. Hivert MF. Tonjes A. Mitchell BD. Voight BF. Jackson AU. were associated with reduced birth weight. Hu FB. Interestingly. Syddall H. Meigs JB. p = 4. Firmann M. Kivimaki M. Shrader P. Rotter JI. Boerwinkle E. Aulchenko YS. insulinogenic index. Lyssenko V. Bonnefond A. Couper DJ. Cornelis M. Walley A. offspring of fathers who develop diabetes later in life have. Ingelsson E. Laakso M. Alternatively. Weedon MN. p = 7. Schwarz P. Glazer NL. Sampson M. p = 1. according to the fetal insulin hypothesis. Tuomilehto J. Meyre D. Luan J. Hattersley AT. The authors hypothesized that reduced fetal insulin secretion in utero results in reduced fetal size at birth. Brunner E. p = 4. CDKAL1 and HHEX-IDE. lower birth weights than those born to fathers who do not develop diabetes. Crawford GJ. The GIPR A-allele carriers also showed decreased insulin secretion (n = 22. Siscovick DS. Kuusisto J. Doney A. Kao WH. Pearson D. results later in adult life in a range of metabolic abnormalities.492. p = 2. p = 4. USA Nat Genet 2010.Conclusions: These findings provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype. the authors investigated the relationship between the size of the fetus at birth and five known T2DM variants identified through genomic-wide association. Boesgaard TW. Goodarzi MO.234 non-diabetic individuals) and a follow-up of 29 independent loci (n = 6. Borch-Johnsen K. Sharp SJ. Jorgensen T. Smith NL. Langenberg C. Cavalcanti-Proenca C. Levy-Marchal C. Barroso I. Rathmann W.01) mmol/l per A allele. Pankow JS. Zhao JH.2 × 156 Orit Pinhas-Hamiel . Frayling TM. This is consistent with the fact that the fetus inherits about 50% of the father’s genetic predisposition to diabetes. Delplanque J. Pedersen O. Lauritzen T. van Duijn C. Watanabe RM Broad Institute of Harvard and Massachusetts Institute of Technology. Tuomi T. Li M. Wichmann HE. Mohlke KL. Singleton A. Narisu N. van Hoek M. Illig T. Florez JC. Stefansson K. Meier discusses the idea that the pathogenesis of T2DM likely involves a combination of several mechanisms with varying contributions in different people. Kottgen A. Palmer CN.3 × 10–4).1 × 10–11) and TCF7L2 (rs7903146. Sparso T. Thorleifsson G. Cooper C. Song K. Fox CS. Boehnke M. Mass. Two risk alleles that have been associated with reduced -cell function. Steinthorsdottir V. Methods: A meta-analysis of 9 genome-wide association studies (n = 15. p = 4. Marmot M. on average. Chen YD. Williams GH. Prokopenko I. Krohn K. The example presented of two phenotypes for a common genotype is compelling.3 × 10–16) and diminished incretin effect (n = 804. Second. Thorsteinsdottir U. Collins FS. Morken MA. McAteer JB. Ardlie K. GCKR (rs1260326.42:142–148 Background: Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of T2DM. as well as the genetic predisposition to reduced fetal growth. Hingorani A. Psaty BM. Altshuler D. Nevertheless.1 × 10–8). Nilsson P. in the editorial accompanying this article [4]. Cambridge. Hansen T. fetal programming. An explanation based on the insulin resistance model suggests that metabolic adaptation to fetal undernutrition persists into adult life. Buchanan TA. Johnson T. First. Valle TT. Bielinski SJ. Dina C. Sandbaek A. (SEM) = 0.620).09 (0.. Pattou F. Grarup N. Ferrucci L. Mooser V. which basically expresses plasticity for shortterm survival. Isomaa B. Grallert H. According to this theory. Vollenweider P. Bergman RN. Waterworth DM. Lecoeur C. McCarthy MI. Pakyz R. and subsequently leads to T2DM. O’Connell J. Waeber G. the authors discuss that maternal genotypes cannot help us understand such inheritance. since the effect of maternal genes is confounded by that of maternal hyperglycemia on birth weight. Low birth weight is an established risk factor for the development of T2DM. Qi L. Dupuis J. Egan JM. Taneera J. Kovacs P. Results and Conclusion: Variants at the gastric inhibitory polypeptide receptor (GIPR) locus associated with 2 h glucose level (rs10423928. Morris AD. Bouatia-Naji N. Andreasen CH. To test the fetal insulin hypothesis. Wilson JF. VPS13C (rs17271305. Kumari M. Tanaka T. Mayor V. Graessler J. Syvanen AC. Bumpstead SJ. Wareham NJ.0 × 10–15) were identified. Bottcher Y. Rice K. Shuldiner AR. the same genetic variants that reduce insulin secretion or insulin sensitivity also reduce birth weight. Swift AJ.958–30. Rybin D. Stringham HM. Zeggini E. Balkau B. Other variants at ADCY5 (rs2877716. Manning AK. Pascoe L.

cIMT measurements in both obese and T2DM groups were thicker than in the lean group. The GIPR variant. GIPR variation was not associated with insulin measures of intravenous glucose tolerance test. As expected. the secretion of GIP appears to be relatively unchanged. despite the reduced insulinotropic effect in patients with T2DM. anthropometric and laboratory values and blood pressure were measured in 182 lean. McCoy CE. Cincinnati. systolic blood pressure. and diastolic blood pressure were determinants of all measures of carotid Type 2 Diabetes Mellitus. Cincinnati Children’s Hospital and University of Cincinnati. Khoury PR. but normal response to an intraperitoneal glucose challenge. The ‘incretin effect’ denotes the phenomenon by which plasma insulin levels increase more from oral glucose intake than from the same amount of glucose administered intravenously. and 128 T2DM youth (aged 10–24 years). representing reduction in the early phase of insulin secretion.508 individuals without diabetes. Age.org Circulation 2009. which is an integrated measure of insulin response over the 2-h OGTT. For the internal carotid artery. act in an additive manner and are considered responsible for 50–70% of the postprandial insulin responses.17). Investigations of the latter two loci did not reveal a role in early insulin secretion. group × age interaction. T2DM subjects had greater cIMT than that in lean and obese subjects for the common carotid artery and bulb. VPS13C [vacuolar protein sorting 13 homolog C]) and ADCY5 (adenylate cyclase). 89.09–1. In patients with T2DM. New concerns Youth with obesity and obesity-related type 2 diabetes mellitus demonstrate abnormalities in carotid structure and function Urbina EM.15. Of the three newly implicated loci (GIPR. Increased carotid intima-media thickness (cIMT) and stiffness are associated with these adverse outcomes. Genomic-wide association (GWAS) has contributed to the identification of many T2DM-associated loci. only ADCY5 was found to be associated with T2DM in collaborating studies (n = 35. They potentiate glucose-stimulated insulin secretion from islet -cells. In the current study. The aim of this study was to determine whether similar changes exist in youth with obesity and T2DM. Results: Cardiovascular risk factors worsened from lean to obese to T2DM groups. age. p = 4. race. Methods: Carotid ultrasound for cIMT measurement was performed. Metabolic Syndrome. as well as measures of stiffness (the Young elastic modulus and stiffness index). 95% CI 1. The carotid arteries were stiffer in obese and T2DM groups than in the lean group. Kimball TR.10–10) were also associated with 2 h glucose. however. Interestingly. a lower insulinogenic index.16).869 cases. and systolic blood pressure for the common carotid artery (r2 = 0. rs10423928. their contribution was found to be less than 20%. The incretins are hormones secreted from the gastrointestinal tract into the circulation in response to nutrient ingestion. the SNP rs10423928 A allele. These data support the hypothesis that a defect of the GIPR could be part of the T2D pathophysiology [4]. race. Daniels SR. also known as gastric inhibitory polypeptide (GIP). 136 obese. USA Elaine. and age.12. OR = 1.Urbina@cchmc.119:2913–1919 Background: Adults with obesity or T2DM are at higher risk for stroke and myocardial infarction. a lower ratio of insulin to glucose area under the curve. and total cholesterol for the internal carotid artery (r2 = 0. the rs10423928 A allele was moderately associated with an increased risk of T2D in 19.798 controls.8 × 10–18). Dolan LM Department of Pediatrics. Lipids 157 . Interestingly. and glucagon-like peptide-1 (GLP-1). sex. Determinants of cIMT were group. Ohio. deletion of GIPR in an animal model shows mild glucose intolerance and reduced insulin secretion in response to an oral glucose challenge. and a lower 2-h insulin level.091 individuals with diabetes. GWAS revealed 3 new loci associated with 2-h glucose: GIPR (gastric inhibitory polypeptide receptor. was associated with increased 2-h glucose. however. suggesting a possible problem with its receptor GIPR. Glucose-dependent insulinotropic polypeptide. Finally. and systolic blood pressure for the bulb (r2 = 0. compared with 38. systolic blood pressure.21). sex. ADCY5 and VPS13C).

org J Clin Endocrinol Metab 2009. However. subjecting affected people to many years of morbidity. bulb IMT in 16.0001).5%. metabolic syndrome or type 1 diabetes mellitus (T1DM). which have been used as a surrogate endpoint for the progression and regression of atherosclerotic cardiovascular disease since the 1990s. and body mass index Z score.94:3740–1745 Background: Carotid intima-media thickness (IMT) provides a mechanism for detecting early atherosclerosis. Moreover. The study by Urbina et al. enable identification of target organ damage. and internal carotid IMT in 18. Gao Z. Factors that may contribute to early changes in carotid IMT in youth with T2DM were studied. IMT was shown to be significantly increased in those with familial hypercholesterolemia. and traditional cardiovascular risk factors on early atherosclerotic vascular changes in adolescents and young adults with type 2 diabetes mellitus Shah AS. One of the main concerns with the new epidemic of ‘Diabesity’ is the secondary morbidity associated with these disorders. Logistic regression analysis demonstrated that each 1% increase in HbA1c or each year increase in duration of T2DM is associated with approximately 30% increased odds of a thicker carotid IMT. Dolan LM. Hyperlipidemia. Cincinnati. ‘For the thing which I did fear is come upon me.9%. all p < 0. there is light in the tunnel. including blood pressure. diabetes and smoking are risk factors for the acceleration of atherosclerosis both in adults and in children. These adverse effects appear to be more prominent in males. These prevalence rates are concerning. predictors of increased carotid IMT were sought. 158 Orit Pinhas-Hamiel . common carotid IMT was elevated in 13. is the first to examine the effect of T2DM on IMT among adolescents. glycemic control. Although the clinical manifestations of cardiovascular disease appear in adulthood. Early changes in both vascular structure and function are demonstrated in obese adolescents. laboratory data and carotid imaging were obtained in 129 youth of mixed ethnicity. In children. USA amy. These data establish HbA1c and duration of diabetes as independent factors in the progressive thickening of carotid IMT. In addition. Results: Carotid IMT increased with higher glycosylated hemoglobin (HbA1c) levels and longer duration of diabetes. morbid obesity. verse 25). Carotid intima-media thickness (IMT) measurements. obesity. Ohio. Conclusions: Poorer glycemic control and longer disease duration have independent adverse effects on carotid IMT in youth with T2DM. Regression modeling showed that HbA1c and duration of diabetes in the presence of traditional cardiovascular risk factors (male sex.stiffness. Daniels SR. and blood pressure) were independent determinants of carotid IMT. Influence of duration of diabetes. it is well known that atherosclerosis begins already in childhood. the traditional cardiovascular risk factors. LDL cholesterol and male sex were also important determinants of carotid IMT in this population. non-invasive techniques now enable detection of early anatomical and physiological changes.4%. Shah et al. Of youth with T2DM. hypertension. anthropometric. Division of Endocrinology. Evidence that improvement in glucose control at an early age may reduce the progression of atherosclerosis should encourage clinicians to aggressive interventions for risk reduction. group. LDL cholesterol. and more severely in those with T2DM.’s study investigated factors that may contribute to changes in carotid IMT. Methods: Demographic. Conclusions: Youth with obesity and T2DM have abnormalities in carotid thickness and stiffness that should alert healthcare practitioners to address cardiovascular risk factors early to prevent an increase in the incidence of stroke and myocardial infarction. and mainly the appearance of complications early in life. While the development of atherosclerosis in children was initially based on autopsy studies. and that which I was afraid of hath overtaken me’ (Job chapter 3. as young adults with increased IMT have increased likelihood of myocardial infarction and stroke. Urbina EM Cincinnati Children’s Hospital Medical Center. Kimball TR.31. An association between IMT and the presence and severity of atherosclerosis has been documented in adults. These two articles describe early atherosclerotic changes in obese and T2DM patients. Elevated carotid IMT was found to be associated with higher HbA1c concentrations and longer duration of T2DM.23). Khoury PR.shah@cchmc. ages 10–23 years. with sex adding to the Young elastic modulus (r2 = 0. and group × age interaction contributing to the stiffness index (r2 = 0.

Importantly. Prevalence and sequential changes in the level of microalbuminuria (30 < or = albumin-to-creatinine ratio [ACR] < 300 mg/g) and macroalbuminuria (ACR > or = 300 mg/g) and incidence of macroalbuminuria were computed according to the presence or absence of T2DM. The cooperative research between the Pima Indians and the NIH.6) higher in the diabetic than in the non-diabetic youth. Gans RO. the incidence of macroalbuminuria was 15. Microalbuminuria strongly predicted progression to macroalbuminuria. National Institutes of Health.9% in the 103 youth with diabetes.d.5 vs. USA Pediatrics 2010. The Netherlands g. The authors concluded that the findings of this population afford examination of the impact of albuminuria in other populations. subsequent to the increasing prevalence and degree of obesity at younger ages [5]. Weil EJ. with 27% of youth with T2DM progressing to macroalbuminuria. which began in 1963. Lipids 159 . the incidence of diabetes among those less than 15 years of age has increased nearly 6-fold. Phoenix.4%) non-diabetic youth. but only 1 of 14 (7. Microalbuminuria in youth with T2DM strongly predicts progression to macroalbuminuria. The current prospective study reported a 3-fold higher incidence of microalbuminuria in youth with T2DM than in those without (18.856 non-diabetic youth and 18.w..landman@isala. Zwolle. has been invited to participate in a study investigation every other year.1 years. Nelson RG Diabetes Epidemiology and Clinical Research Section.5 and 2. compared to only 7% of those with diabetes. Bennett PH. While the overall incidence of diabetes in the Pima Indians has not changed over the past 40 years. New hopes Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16 Landman GW.5%).33:322–326 Background: Several studies have suggested an association between specific diabetes treatment and cancer mortality. Metabolic Syndrome. which supports annual screening for albuminuria. microalbuminuria preceded the diagnosis of T2DM. Type 2 Diabetes Mellitus. respectively. in more than half of the individuals with diabetes. Isala Clinics.1–22. van Hateren KJ. Objective: Methods: The Pima Indians have been called ‘pathfinders for health’ because of their high level of volunteering to participate in research studies.1%) diabetic youth with an elevated ACR (> or = 30 mg/g) regressed to an undetectable or normal ACR (<30 mg/g) on subsequent examination.666 youth with a median follow-up of 8. continues to this day. For a given ACR. National Institute of Diabetes and Digestive and Kidney Diseases.Predictive value of albuminuria in American-Indian youth with or without type 2 diabetes Kim NH. 6.125:e844–851 To examine the prognostic significance of elevated albuminuria in youth with T2DM. In a subset of 2. Bilo HJ Internal Medicine. The authors studied the association between metformin use and cancer mortality in a prospectively followed cohort. biopsy results demonstrated a non-diabetic renal disease in the form of immune complex diseases or glomerulosclerosis in all cases [6]. but it is relatively frequent and largely persistent in those with diabetes. Curtis JM. Kleefstra N. Cross-sectional and prospective studies were conducted on Pima Indian youth aged 5–19 years at baseline between 1982 and 2007. Results: The prevalence of microalbuminuria and macroalbuminuria was 6. Groenier KH. Conclusions: Elevated albuminuria is infrequent and largely transient in non-diabetic youth. 36 non-diabetic and 30 diabetic youth with baseline ACRs of <300 mg/g developed macroalbuminuria. Since 1965. 141 of 187 (75. Of note. each member of the population. although microalbuminuria was initially attributed to diabetes among Canadian First Nation Children.6% in the 3. Hanson RL.nl Diabetes Care 2010. Pavkov ME. Ariz.5 and 0. aged 5 years and older. Microalbuminuria was transient in 75% of individuals without diabetes.9-fold (95% CI 11. Knowler WC.

the mechanism involved targeting cancer stem cells. 3 (2%) patients had T2DM and 23 (12%) had IGT. could be a potent antitumor medicine [7]. Vital status was assessed in January 2009. animal models and humans suggests that metformin.7.58 (95% CI 0. whereas HOMA-IR values are not. in patients with diabetes. Kublaoui BM. Conclusions: In general.76). Recent reports suggest a relationship between childhood obesity. which appear to resist conventional chemotherapies. Increasing evidence from cells. of which 122 died of malignancies. Results: Median follow-up time was 9.5-anhydroglucitol (insulin-resistant subgroup only) levels. In this study. The SMR for cancer mortality was 1. and 93% at a fasting BG level of 104 mg/dl. Of the patients. 88.5-anhydroglucitol <17. 9 (2%) patients had T2DM and 44 (9%) had IGT. and with every increase of 1 g of metformin hazard ratio was 0. In the entire study group.23–0. data suggest a protective effect of metformin on cancer mortality.. Optimal sensitivity and specificity to detect T2DM were respectively 99 and 96% at HbA1c > or = 6.5-anhydroglucitol are excellent predictors of T2DM in insulin-resistant obese children. epidemiological studies reported treatment with metformin to be associated with a lower overall risk for cancer than without treatment.47 (95% CI 1.5%. and average HbA1c was 7. or it may directly affect cell proliferation and apoptosis of cancer cells. HbA1c and 1. a mainstay of T2DM.93). In vitro studies with cell cultures demonstrated that metformin benefited human lung. In patients taking metformin compared with patients not taking metformin at baseline. and 96 and 88% at 1. metformin use was associated with lower cancer mortality. Optimal sensitivity and specificity to detect T2DM were respectively 86 and 85% at HbA1c levels of 5. breast. Oden JD.0 µg/ml. Results: In the insulin-resistant subgroup. In humans. with lower values for fasting BG and the HOMA-IR. Tex. the adjusted hazard ratio for cancer mortality was 0. including a subgroup with serum fasting insulin levels of >15 µIU/ml. were studied. All values and calculated HOMA-IR were used as predictors for exceeding various 2-hour BG cut-offs.9. White PC Department of Pediatrics. and an increased risk of adult pancreatic and colon cancer. It has been suggested that metformin may influence cancer cells indirectly through insulin-mediated effects.43 (95% CI 0. and 1. In a recent study in mice. Screening for type 2 diabetes in obese youth Shah S.Methods: In 1998 and 1999. 570 died. and fasting BG levels are good predictors of T2DM in obese children. Thus. Pediatricians need to follow these data closely. Conclusions: HbA1c. Although the design cannot provide a conclusion about causality. or than treatment with insulin or antidiabetic drugs.124:573–579 Objective: To assess available blood tests as potential screening tools for impaired glucose tolerance (IGT) and T2DM. and 62 and 70% at an HOMA-IR of 7.80).6 years. average age at baseline was 68 years.4 kg/m2) children. 1. 1.22–1. 160 Orit Pinhas-Hamiel . This prospective study showed that use of metformin in patients with diabetes was associated with a lower rate of cancer-related mortality. Finally. University of Texas Southwestern Medical Center. if indeed metformin treatment will be found to have antitumorgenic effect.353 patients with T2DM were enrolled in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) study in the Netherlands. metformin use was associated with lower cancer mortality compared with non-use of metformin. An oral glucose tolerance test was performed on each patient. USA Pediatrics 2009.0%. fasting and 2-hour post-load serum glucose and insulin levels were obtained as well as HbA1c. patients with T2DM are at increased risk for cancer mortality. Methods: 468 obese (mean BMI >34. colon and ovarian cancers.36–0. as presented in the current article. Cancer mortality rate was evaluated using standardized mortality ratios (SMRs). Dallas. Patients with breast cancer who were treated with both neoadjuvant chemotherapy and metformin had a higher response rate than those treated with other diabetes medications. Adults with T2DM are at increased risk to develop cancer. Most importantly. prostate. low doses of metformin combined with chemotherapy reduced tumors faster and prolonged remission to a greater degree than did chemotherapy alone. it will be essential for children and youth with T2DM.5-anhydroglucitol.

5-anhydroglucitol as simpler screening tests. hypertension. to diagnose the MetS.5-AG indicate hyperglycemia. Basically. hypertension and abnormal glucose metabolism (fasting glucose. Thus. The metabolic syndrome (MetS) comprises the clustering of risk factors that identify individuals at increased risk of CVD and diabetes. is a naturally occurring monosaccharide found in nearly all foods. dyslipidemia including elevated TG and/or low HDL. Normally. and even when their baseline results are normal. Children and adults ethnic differences in the epidemiologic study of conditions associated with the MetS. In children and in youth. In contrast. even in the presence of relatively low HbA1c levels. impaired glucose tolerance). These characteristics are low high-density lipoprotein levels. the authors found 1. Ethnic differences in lipid levels may largely explain why blacks have a lower than expected prevalence of the MetS. as well as focus on each of the parameters of the MetS are reviewed. Paradoxically. Compared with whites. 1. When blood glucose exceeds 180 mg/dl. increased triglyceride levels. and diabetes.niddk. screening tests need be repeated periodically. a small amount of 1. Performing an oral glucose tolerance test (OGTT) on all obese children is a cumbersome task. competitive inhibition blocks 1. HbA1c. Indeed. NIDDK. is excreted in the urine. and its blood level decreases. as the authors of the current study point out. blacks are less likely than whites to have either elevated triglyceride or low high-density lipoprotein levels. Conclusions: An ethnic-specific formulation of the lipid criteria in the MetS may lead to better identification of blacks at high risk for development of diabetes and cardiovascular disease. However.The escalating epidemic of childhood obesity calls for a simple diagnostic tool to identify those with impaired glucose tolerance and those with undiagnosed T2DM. the concept of the metabolic syndrome in children and adolescents has undergone long and painful labor.5-AG levels to only modestly predict impaired glucose tolerance among children. According to the criteria set by National Cholesterol Education Treatment Program-Adult Treatment Panel III. HOMA-IR and 1. 1.5-AG from being reabsorbed.nih. this assay indicates excessive glycemic variability. also known as 1. Between 1995 and 2000. many clinicians fail to follow the ADA guidelines for performing OGTT in obese children. blacks have a lower prevalence of the MetS. Moreover. about 10 papers regarding the metabolic syndrome in children were published.5-AG. First. NIH. and the International Type 2 Diabetes Mellitus. Food for thought Ethnic differences in triglyceride levels and high-density lipoprotein lead to underdiagnosis of the metabolic syndrome in black children and adults Sumner AE Clinical Endocrinology Branch. especially when children continue to gain weight. Md. and fasting BG levels were found to be easily implemented screening tests for T2DM in obese children.5-Anhydroglucitol. However. in subjects with diabetes. the European Group for the Study of Insulin Resistance. HbA1c. central obesity. low levels of 1. and fasting hyperglycemia.5-AG is metabolized. Metabolic Syndrome.gov J Pediatr 2009.. Since hardly any of 1. hypertension. and the newborn still has many developmental disorders. and glycosuria occurs. several definitions were proposed by the WHO. 3 of 5 characteristics must be present. blacks have higher rates of diabetes and cardiovascular disease. Examining each of these factors individually. its level remains relatively constant in the blood and tissues. The aim of this study was to investigate the possible utilization of fasting glucose. compared to around 300–400 articles per year over the last 3 years.5-AG. In the current study.155:S7 e7–11 Background: The metabolic syndrome (MetS) was designed to identify individuals at high risk for the T2DM and cardiovascular disease. Moreover. Bethesda. equal to the amount ingested. it involves the co-occurrence of at least three of the following: obesity (defined either by BMI or waist circumference).5-AG. the National Cholesterol Education Program Adult Treatment Panel III (ATP III) [5]. the metabolic syndrome may be a particularly important tool to predict and prevent adult diseases. blacks are more likely than whites to have obesity. USA AnneS@intra. Lipids 161 .

In rodent models. The lack of unified criteria makes it difficult to compare prevalence rates between populations and at-risk groups.. Rates of death from endogenous causes among children in the highest quartile of glucose intolerance were 73% higher than those among children in the lowest quartile (incidence-rate ratio 1. Sumner’s recent article is one of several that elucidate problems in defining the metabolic syndrome. and hypertension in childhood were strongly associated with increased rates of premature death from endogenous causes in this population. 95% CI 1. who were born between 1945 and 1984. SIRT1 was downregulated in individuals with prediabetes compared 162 Orit Pinhas-Hamiel . blood pressure and cholesterol levels in 4. Risk factors were standardized according to sex and age. No significant associations were seen between rates of death from endogenous or external causes and childhood cholesterol levels or systolic or diastolic blood-pressure levels on a continuous scale. by disease or self-inflicted injury. although childhood hypertension was significantly associated with premature death from endogenous causes (incidence-rate ratio 1. Rates of death from endogenous causes among children in the highest quartile of BMI were more than double those among children in the lowest BMI quartile (incidence-rate ratio 2.Diabetes Federation (IDF). These data may be relevant to other ethnic populations. were studied to assess whether BMI. The study assessed BMI.30.73. Looker HC Diabetes Epidemiology and Clinical Research Section. as high triglyceride and low HDL levels occur together. the determination of cut-off points is even more complicated than in adults. Bennett PH. family history. Thus childhood obesity predicted premature death. Methods: A cohort of 4. SIRT1–SIRT7. In children. She points out that while obesity. alcoholic liver disease accounted for the majority (59%).57. followed by cardiovascular disease (22%). age of puberty. Ariz.857 American-Indian children and adolescents (aged 5–20 years) without diabetes. In a combined in vivo and in vitro study. Sirtuins are a family of seven proteins.franks@medicin. whereas hypercholesterolemia was not. 95% CI 1. Hanson RL. National Institutes of Health. a deacetylase that regulates lifespan in response to caloric restriction in many organisms. Sirtuin 1 (SIRT1) is the mammalian homologue of the evolutionarily conserved silent information regulator 2 (SIR2). The opening sentence of this article is overwhelming: ‘Despite recent increases in life expectancy. 95% CI 1.62). 33 deaths were attributed to other causes.46–3. Childhood obesity. i. physical activity. Caloric restriction has been shown to extend lifespan through induction of sirtuins. other cardiovascular risk factors. and LDL cholesterol level. Knowler WC. It is suggested that the factor of dyslipidemia has a disproportionate effect on metabolic syndrome diagnosis. USA paul. such as birth weight.10–2.24). it seems that we might need other tools for risk prediction.4% of the cohort) during a median follow-up period of 23. insulin resistance. and premature death Franks PW. Moreover. glucose tolerance. the rising global prevalence of obesity may reverse this trend…’. Sievers ML. Results: There were 166 deaths from endogenous causes (3. Of these. gene and protein expression of SIRT1 were significantly reduced in relation to insulin resistance and MetS [8]. as age must also be considered.e. due to their reciprocal clearance from blood circulation. During a 24-year follow-up.362:485–493 Background: The effect of childhood risk factors for cardiovascular disease on adult mortality is poorly understood. 3. High BMI. In contrast. The mirror image of obesity and premature death is interesting. glucose tolerance. Conclusions: Obesity.3 years). the prevalence of the metabolic syndrome is lower in blacks. blood pressure and cholesterol levels predicted premature death. diabetes and hypertension are much more prevalent in blacks than in whites.857 American-Indian children without diabetes (mean age 11.74). longevity has been associated with caloric restriction. Phoenix. glucose intolerance. National Institute of Diabetes and Digestive and Kidney Diseases.09–2. childhood hypercholesterolemia was not a major predictor of premature death from endogenous causes. with implications on the predictive value of the metabolic syndrome for future morbidity.9 years. diabetes or diabetic nephropathy (10%) and acute alcoholic poisoning or drug overdose (9%). cancer (12%).umu. glucose intolerance and hypertension in childhood were strongly associated with increased rates of premature death from endogenous causes.4% died prematurely (before age 55 years) from endogenous causes.se N Engl J Med 2010. infections (21%). considering established risk factors that are not included in the metabolic syndrome.

72%. and genetic factors associated with postnatal weight gain are likely to also contribute to risks for adult disease.437. aged 18–24 years.066– Type 2 Diabetes Mellitus.301:2234–2242 Background: Growth during infancy appears to be an important determinant of cardiovascular disease and type 2 diabetes later in life. Heritability estimates (additive genetic components) were calculated using variance components models for: birth weight. Stijnen T. body mass index. 58% of monozygotic twins and 59% of dizygotic twins showed rapid weight gain (a change of more than +0. childhood height.15.223. Kerkhof GF.0005). including a relatively large sample of participants born small for gestational age and participants with short stature. University of Cambridge. Ong KK. Timing and tempo of first-year rapid growth in relation to cardiovascular and metabolic risk profile in early adulthood Leunissen RW. fasting insulin levels (r = 0. 80%. and diastolic BP. not only to realize the promise of longevity. Rotterdam. Methods: 100 pairs of healthy twins aged 8. sum of skinfolds. It is therefore not surprising that in 2008. 65%. and anthropometry assessed. was associated with childhood risk markers for adult metabolic disease. I wait eagerly. The association of cardiovascular disease and T2DM with tempo of weight gain was assessed in a subgroup of 87 participants. Erasmus Medical Center/Sophia Children’s Hospital.51. Decreased SIRT1 was associated with a shorter lifespan.leunissen@erasmusmc. Postnatal weight gain was positively associated with sum of skinfolds (r = 0. Results: Weight gain in the first 3 months of life was inversely associated with insulin sensitivity ( –0. 29%. Addenbrooke’s Hospital. postnatal weight gain.060) and serum high-density lipoprotein cholesterol level ( –0. Ahmed ML.0005).9 years (range 7.94:3708–3713 Objective: Associations between size at birth. 95% CI –0. and potential risk for adult disease have been variably explained by in utero exposures or genetic risk that could affect both outcomes. GlaxoSmithKline bought the company who developed a small molecule drug aimed at increasing SIRT1 activity as an ‘anti-aging drug’. rather than birth weight. Peeters MW. Lipids 163 . Murphy N. Hokken-Koelega A Department of Pediatrics. Results: Mean birth weights in both monozygotic and dizygotic twins were –0.016) and positively associated with waist circumference ( 1. In postnatal life. postnatal weight gain. p < 0.to those with normal glucose metabolism. 89%.67 in weight SDS) from birth.386 to –0. 95% CI 0.30. To specify which period in the first year of life is related to determinants of cardiovascular disease and T2DM in early adulthood and to investigate the association between tempo of first-year weight gain (>0. blood pressure (BP) measured. Cambridge.05) at follow-up. waist circumference. Metabolic Syndrome.67 SDs) and these determinants. Methods: Observational study using longitudinal data collected in the Programming Factors for Growth and Metabolism (PROGRAM) study of 217 healthy participants.9) had fasting blood samples collected.0005). systolic BP (r = 0.35. Subdivision of Endocrinology. Dunger DB Department of Paediatrics. 74%. systolic BP. Concepts revised Heritability of childhood weight gain from birth and risk markers for adult metabolic disease in prepubertal twins Beardsall K. Zhao JH. 95% CI –0. Conclusions: Postnatal weight gain from birth. A twin model to explore these hypotheses was utilized. 33%. p < 0. fasting insulin. These data suggest that SIRT1 might be a new therapeutic target for the prevention of disease related to insulin resistance.2–10.090 to –0.nl JAMA 2009.053. UK J Clin Endocrinol Metab 2009. 89%. Childhood weight gain was highly heritable. The Netherlands r. p < 0. p < 0.90 SDS lower than the UK reference. but to be skinny as well. and diastolic BP (r = 0. 44%.

Conclusions: The analyses disclosed a clear separation between early and late maturers in the appearance of these risk factors in young adulthood. ratio of total cholesterol to high-density lipoprotein cholesterol ( 0. the use of nutrient-enriched formulas may be one explanation for rapid weight gain. Both MZ and DZ twins. and T2DM later in life by use of serial data of 237 study participants (119 men and 118 women) enrolled in the Fels Longitudinal Study. and not just fetal life. after the president of Antioch College in Yellow Springs.’s study did not investigate the exact timing of catch-up growth. In light of these findings. low insulin sensitivity. maternal environment and postnatal weight gain. including adiposity. arterial blood pressure and fasting insulin levels. Children with rapid weight gain within the first 3 months had higher percentages of body fat. This elegant model enables estimation of the contribution of fetal genotype. showed catch-up growth in both weight and height by ages 7–11 years. Leunissen et al. and level of triglycerides ( 0. posed the question. an increased gain in weight. Results: Children who matured early tended to have greater body mass index. Methods: Prolongation of a juvenile state as a retarded tempo of growth was determined by the timing of peak height velocity in each subject and relate the retarded tempo of growth to metabolic syndrome.052. who were growth restricted at birth. Schubert CM Department of Biostatistics. and fasting plasma insulin. Although nutritional data was not available. Beardsall et al. ‘What makes people different?’ He believed that a longi- 164 Orit Pinhas-Hamiel . acute insulin response ( 0. Conclusion: Rapid weight gain in the first 3 months of life is associated with several determinants of cardiovascular disease and T2DM in early adulthood. parents often implement aggressive dietary management with considerable caloric intake supplementation. Anxious to see their ‘malnourished baby’ achieving normal weight percentiles as soon as possible. was associated with all the important determinants of the metabolic syndrome. low HDL and increased triglyceride levels in early adulthood.003–0. relative to height. cardiovascular disease. 95% CI 0.155:S7 e1–6 Background: The influence of a prolonged juvenile state on the onset of the metabolic syndrome.2. While Beardsall et al. we should be cautious in our aims for rapid catch-up.094). the tempo of weight gain was also found important. waist circumference. USA stephen_cook@urmc. central adiposity and reduced insulin sensitivity later.129) in early adulthood. 95% CI 0. and T2DM later in life was studied.395).’s study found that in the first 3 months of life. to be an important determinant of adult disease risk.010–0. used models of monozygotic (MZ) and dizygotic (DZ) twins to explore the contribution of postnatal weight gain to markers of adult metabolic disease states.024–0. Since the introduction of Barker’s hypothesis regarding the developmental origins of adult diseases. Ohio. coronary heart disease. 95% CI 0.808). cardiovascular disease. The Fels Longitudinal Study began in 1929. Va.rochester. and reduced insulin sensitivity in early adulthood than when slower weight gain occurred during the entire first year.. specifically: increased waist circumference. The differences in these risk factors between early and late maturers were significant for percent body fat. Prolonged juvenile states and delay of cardiovascular and metabolic risk factors: the Fels Longitudinal Study Sun SS. and percent of body fat and were more likely to have adverse cardiovascular risk profiles than children who matured late. hypertension and stroke. The heritability of postnatal weight gain and fasting insulin were assessed at 80 and 65% respectively. Richmond.edu J Pediatr 2009. Rapid weight gain during the first 3 months of life resulted in a higher percentage of body fat. In the first article. Neither birth weight nor discordance between twin pairs was associated with markers of metabolic disease. The above two articles show the period of postnatal catch-up growth. more central adiposity.066.210. Moreover. fasting plasma triglycerides. This study demonstrates the value and power of longitudinal studies in revealing predictors of certain conditions. Outcomes were strongly related to postnatal weight gain. many epidemiological studies have reported a strong association between growth retardation in uterus and long-term adverse effects such as T2DM. Virginia Commonwealth University. School of Medicine.

In healthy people.. Since glucose can be labeled with a stable isotope tracer (13C). non-invasive 13C-glucose breath test to estimate insulin resistance in obese prepubertal children Jetha MM.53.22. quantitative insulin sensitivity check index (QUICKI). Methods: For the 13C-glucose breath test. the 13C-glucose breath test can provide a proxy estimate of IR when gold-standard techniques are either unavailable or impractical. 2-hour insulin. QUICKI (r = 0. insulin area-under-the-curve (AUC).05). though moderate. So far. A significant. p <0. Among adults. concordance was found between 13CO2 in breath and fasting insulin. but moderate. applicable in both private clinical and non-clinical settings.01). 2-hour insulin (r = –0. A novel. and children with family histories of T2DM. Children who matured early tended to have greater BMI and waist circumference. associations between the 13C-glucose breath test and fasting insulin (r = –0. including pubertal children.22:1051–1059 Background: Insulin resistance (IR) is an important risk factor for the development of T2DM in obese boys and girls. as in the OGTT. It is known that overweight children. p <0. particularly those of certain minority groups. should be investigated in different populations. its metabolism to CO2 can be determined quantitatively. Ball GD Department of Pediatrics. and elevated levels of fasting plasma triglycerides and fasting plasma insulin in adulthood compared with late maturers. insulin AUC (r = –0. are at risk for developing the MetS. Samuel Fels. As such. p < 0. producing CO2. Edmonton. noninvasive test. 30. estimates of IR generated by the 13C-glucose breath test were compared to indices derived from OGTT in prepubertal obese children. The objective of this cross-sectional study of obese prepubertal children (n = 39) was to compare estimates of IR using a novel.01). This may be useful. samples were collected before and 90 min after ingestion of 25 mg 13C-labeled glucose. females with PCOS. The homeostatic model assessment of insulin resistance (HOMA-IR). a Philadelphia businessman and philanthropist. the 13C-glucose breath test was found to be highly correlated (r ≥ 0.50. and children of different ethnicities. p <0. University of Alberta. NS).69) with IR determined by a hyperinsulinemiceuglycemic clamp [9]. established the Fels Research Institute. since clinicians often avoid testing children when repeated blood tests are necessary. Alta.40. 90 and 120 min. those born small for gestational age. For the OGTT. Such an easy to perform. Faculty of Medicine and Dentistry. Canada J Pediatr Endocrinol Metab 2009. non-invasive technique (13C-glucose breath test) with common indices of IR derived from an oral glucose tolerance test (OGTT).48. p <0. 60.51. a higher percentage of body fat. for which careful follow-up is needed. HOMA-IR (r = –0. Results: A significant. and sum-of-insulin (r = –0. which is eliminated by the lungs through expiration. The current study is the first to elucidate the effects of maturation rate on metabolic variables and risk factors for cardiovascular disease over 40 years of lifespan. Early maturation is now shown to be another risk factor for developing the MetS. Conclusions: In obese prepubertal children. and calculated estimates of insulin resistance such as HOMA and QUICKI. Lewanczuk RZ. ingested glucose is metabolized in the presence of insulin. 45. and sum-of-insulin were calculated as indices of IR. glucose and insulin samples were collected at 0. 15. a new risk group for development of the MetS has been identified. Among subjects with insulin resistance. Data measured by the Fels Longitudinal Study has since become the core of numerous works.01). Lipids 165 .05). In the current study.tudinal study from birth to adulthood would be required to answer this question. Metabolic Syndrome. glucose uptake is impaired and less CO2 is produced. Type 2 Diabetes Mellitus. Nzekwu U. it seems a promising and practical means of assessing insulin resistance in children.

edu Obstet Gynecol 2009. HDL levels initially decreased for 6 months but then returned to baseline.. stroke. and Hispanic women using DMPA. triglyceride. Mixed-model regression analyses and general-estimating-equations procedures were used to estimate changes over time in lipids by method along with their predictors. USA abberens@utmb. Methods: Serum lipids were measured at baseline and every 6 months thereafter for 3 years in 703 white. Tex. pulmonary embolism. OC users experienced statistically significant increases in levels of triglycerides. and HDL levels were significantly higher in women who used OCs than in those who chose non-hormonal (p < 0. In the year 2010 we mark the 50th anniversary of the approval of oral contraception (OC). total cholesterol. total cholesterol. The strength of the study is the long-term follow-up: over 3 years of contraceptive use. 166 Orit Pinhas-Hamiel . The Center for Interdisciplinary Research in Women’s Health.5 times more likely than non-hormonal contraceptive users to have a level of HDL ≤35 mg/dl. During the study period. and an ‘equalizer’ that afforded women the same sexual freedom that men had traditionally enjoyed. After DMPA was discontinued. The LDL:HDL ratio rose in the first 6 months of DMPA use but then dropped back to baseline over the next 24 months. Those who discontinued DMPA were followed for up to 2 additional years. no difference was noted in the lowdensity lipoprotein (LDL) cholesterol:HDL ratio between OC users and non-hormonal-contraceptive users. heart attacks and breast cancer. Among DMPA users. VLDL and HDL cholesterol. The net effect of OC on lipid levels seems to depend on the balance between increased HDL cholesterol and increased triglycerides. OC users were 3-fold more likely to have triglycerides level >170 mg/dl. although these effects appeared to be temporary.15 mg desogestrel. or non-hormonal birth control. greater than those experienced by non-hormonal contraceptive users. Of particular concern is the use of OC by adolescents with PCOS who tend to have dyslipidemia as part of their metabolic syndrome. and almost 3-fold more likely to have abnormal LDL levels. This revolutionary degree of autonomy. In fact. The University of Texas Medical Branch. equality and freedom led to women’s modern economic role. OC. These findings highlight the importance of monitoring lipid profiles in adolescents treated with OC.15 mg desogestrel on serum lipid levels.Important for clinical practice Effect of injectable and oral contraceptives on serum lipids Berenson AB.05) methods. However. The current article aimed to resolve controversies on the effect of OC on lipid levels. Users of DMPA were at increased risk of developing an abnormally low HDL level as well as an abnormally high LDL level and an increase in the LDL:HDL cholesterol ratio. and high-density lipoprotein (HDL) cholesterol than did non-hormonal-contraceptive users (p < 0. specifically those of both depot medroxyprogesterone acetate (DMPA) and of the third-generation OC containing only 20 µg. very-low-density lipoprotein (VLDL) cholesterol. The most serious risks associated with OC use include blood clots. Wilkinson G Department of Obstetrics and Gynecology. The enormous social impact of the pill is without question [10]. Galveston. African-American. It was key to women’s gaining control over their fertility. Rahman M. DMPA users were 2. VLDL. ethinyl estradiol and 0. and 4-fold more likely to have LDL >160 mg/dl.114:786–794 Objective: To estimate the effects of using depot medroxyprogesterone acetate (DMPA) or oral contraceptives (OCs) containing 20 µg ethinyl estradiol and 0.001). Results: Users of OCs experienced significantly greater increases in levels of triglycerides. Participants completed questionnaires containing demographic and behavioral measures every 6 months and underwent 24-hour dietary recalls annually. Conclusions: Use of very-low-dose OCs containing desogestrel can elevate lipid levels. The UN estimates that more than 100 million women worldwide take some form of hormonal contraception.

Methods: This is a retrospective record review of pediatric outpatients (age 2–18 years) with simultaneous measurement of 25-hydroxyvitamin D (25[OH]D) and fasting plasma glucose (n = 302) or 25(OH) D and a lipid panel (n = 177). body mass index Z-score. p < or = 0. regulated by vitamin D. ‘Where the sun is. These relationships persisted independent of adiposity. Plasma glucose and lipid levels were compared in subjects with 25(OH)D concentrations greater or less than 30 ng/ml. low vitamin levels were associated with low HDL levels. glucose intolerance. vitamin D. No wonder that common wisdom says.002) and lower HDL levels (p < 0. In 2008 the American Academy of Pediatrics Committee on Nutrition recommended a minimum daily intake of 400 IU vitamin D for all infants and children. hypertension. Results: 25(OH)D levels were inversely correlated with fasting plasma glucose levels (r = –0. Pearson correlation coefficient was used to estimate the correlation between 25(OH)D and logarithmic transformed plasma glucose or lipid levels. earning him a Nobel Prize in 1903 for the use of a form of ‘concentrated light radiation’ to treat tuberculosis skin lesions. Metabolic Syndrome. The discovery of the critical roles of vitamin D for overall health is a fascinating story in the history of medicine. age. including adolescents.41. stroke and cancer. USA J Pediatr 2010. VITAL (VITamin D and OmegA-3 TriaL). In the above study the authors examined the association between vitamin D. One systemic review found only weak evidence of the benefit from vitamin D supplementation [13]. until the discovery of cathelicidin – an antimicrobial peptide. Currently available data preclude definitive conclusion.001). the most important question is if supplementation will prevent cardiovascular events. Type 2 Diabetes Mellitus. Rochester. Lipids 167 .001). that serves a critical role in mammalian innate immune defense against invasive bacterial infection. T1DM and cancer. Recent studies indicate that the sunlight-generated hormone. glucose and lipid levels.156:444–449 Objective: To study the relationships between serum vitamin D levels and plasma glucose or lipid levels in children and adolescents. The relationship between 25(OH)D levels and fasting glucose and HDL levels did not vary significantly with sex. the most abundant being oily fish like salmon. or season. which are not often consumed by children.. Currently. mackerel. The editorial by Chesney [11] is highly recommended. Relatively few foods naturally contain vitamin D. age and sex. It is now believed that vitamin D can protect against multiple sclerosis. as features of the metabolic syndrome. triglyceride and non-HDL.20. through the sanatoriums built to treat patients with sunbathing. sustains health throughout the body. and another found no evidence [14]. Then came the discovery of its anti-infectious role. Weaver AL. First are its osseous effects and the association to rickets. Mayo Clinic College of Medicine. and their effects on heart disease. T2DM and cardiovascular disease [12].000 IU) and –3-fatty acid supplementation. which will study vitamin D (2. Children who were vitamin D insufficient (25(OH)D < or =30 ng/ml) had higher fasting plasma glucose (p = 0. Kumar S Department of Pediatric and Adolescent Medicine. Among adults.Relationships between 25-hydroxyvitamin D levels and plasma glucose and lipid levels in pediatric outpatients Johnson MD. While no correlations were found between vitamin D levels and total serum cholesterol. Nader NS.001) than children who were vitamin D sufficient (25(OH)D >30 ng/ml). Lower 25(OH)D levels were also associated with lower serum high-density lipoprotein cholesterol (HDL) concentrations (r = 0. Singh R. sardines. and cod liver oil. from the breakthrough by Niels Finsen. with its plethora of biological effects on diverse tissues. low levels of vitamin D have been shown to be associated with increased risks of obesity. Decreased levels of vitamin D were significantly associated with increasing levels of glucose. Conclusions: Low 25(OH)D levels in children and adolescents are associated with higher plasma glucose and lower HDL concentrations. the doctor ain’t’. Minn. We await the results of the National Institutes of Health sponsored trial. p < 0.

Raal FJ. Gagne C. its introduction to clinical practice in the absence of reliable data about efficacy and safety was sharply criticized. or 20 mg once daily. 168 Orit Pinhas-Hamiel . With a maximum allowed dose of 20 mg. 10. and other undesired side effects. The Netherlands J Am Coll Cardiol 2010. ages 10–17 years. reflecting these patients’ high baseline LDL-C levels (mean 232 mg/dl). This study is the first to evaluate the efficacy and safety of rosuvastatin in children aged 10–17 years. however its capture of the market has followed a rough course. McCrindle BW. Hsia J. Results: Compared with placebo. and improved safety for children taking certain drugs [15]. Ohio. For rosuvastatin.001 for each group vs. Langslet G. the American Congress passed the FDA Modernization Act. 45. skeletal or renal is a concern. Schurr D. USA ESteinMRL@aol. Nonetheless. Academic Medical Center. in 2008 the JUPITER (Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin) trial was stopped early due to unequivocal evidence from an independent Data and Safety Monitoring Board of reduced cardiovascular morbidity and mortality in patients treated with rosuvastatin compared with placebo. placebo-controlled trial. Participants were randomly assigned to placebo or rosuvastatin 5. It is a competitive inhibitor of the enzyme HMG-CoA reductase. the FDA refused to withdraw Resuvastatin from the market. The consequent increase in pediatric clinical studies has resulted in improved understanding of the pharmacokinetics of drugs prescribed in pediatric medicine. followed by a 40-week open-label. Wiegman A. restoring flow-mediated dilation. statins have been shown to be effective in reducing LDL-C. Xu J. titration-to-goal extension phase in 177 pubertal children. as with all statins. and 50%. with familial hypercholesterolemia. Cincinnati. be they hepatic. and slowing carotid intima-media thickening. 10. with no apparent adverse impact on growth or development. As much as 50–75% of drugs used in pediatric medicine have not been studied adequately to provide appropriate labeling information. thus resulting in increased clearance of low-density lipoprotein (LDL) from the bloodstream. Hutten BA. titration-to-goal phase. important dose changes. Urbina EM. Amsterdam. Kastelein JJ. In children. However. Its importance therefore lies in testing doses. Stein EA Department of Vascular Medicine. Rosuvastatin was first launched in 2003. respectively (p < 0. Szamosi T. 40% achieved the treatment goal of <110 mg/dl during the open-label. only 40% attained the consensus LDL-C target of <110 mg/dl. University of Amsterdam. compliance and safety profile. Misir S. Karki S. Hopkins PN. rosuvastatin 5. For a happy ending. Rosuvastatin was well tolerated. new treatments Efficacy and safety of rosuvastatin therapy for children with familial hypercholesterolemia Avis HJ.com J Pediatr 2010. Melino M Metabolic and Atherosclerosis Research Center. few children in these trials achieved current LDL-C goals. the risk of rhabdomyolysis. In 1997. which encouraged pediatric drug development by providing an incentive in the form of additional marketing exclusivity.Clinical trials. which is the rate-limiting enzyme of cholesterol synthesis. while increasing synthesis of LDL receptors. Colesevelam hydrochloride: efficacy and safety in pediatric subjects with heterozygous familial hypercholesterolemia Stein EA. randomized. rosuvastatin 20 mg daily reduced LDL-C by 50%. Methods: This study comprised a 12-week double-blind.156:231–236 e1–3 Objective: Efficacy and safety of colesevelam hydrochloride were evaluated in children with heterozygous familial hypercholesterolemia (heFH). Marais AD. Though the drug was marketed as a ‘super-statin’. Inhibition of this HMG-CoA reductase in the liver decreases cholesterol synthesis. Nonetheless. and 20 mg reduced LDL-C by 38. Rosuvastatin is the highest potency statin presently on the market.55:1121–1126 Background: The efficacy and safety of rosuvastatin therapy for children with familial hypercholesterolemia was studied. Conclusions: In children with familial hypercholesterolemia. placebo).

As the bile acid pool becomes depleted.75 g/day (n = 64) for 8 weeks (period II). After a 4-week stabilization period (period I). resulting in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme. The authors therefore offer suggestions to create a supportive environment for Santa’s dieting: ceasing the tradition of leaving him cookies. In the current study. The drug was well tolerated with relatively good compliance. this is not necessarily for the good. Lipids 169 . Collingwood.031) and colesevelam 3.75 g/day (–12.9%). hyperlipidemia and T2DM! Type 2 Diabetes Mellitus. colesevelam 1. Significant treatment effects were also reported for total cholesterol (–7. In October 2009 the FDA approved colesevelam HCl tablets and a new powder for oral suspension to reduce LDL-C levels in boys and postmenarchal girls aged 10–17 years with heterozygous familial hypercholesterolemia. These treatment effects were maintained during period III. and for statin-intolerant patients who may benefit from colesevelam monotherapy. encouraging him to share the carrots and celery sticks commonly left for Rudolf. and possible side effects in children. Results: At week 8. As the drug is approved only for children with LDL-C levels above 190. colesevelam has been shown to reduce LDL-C by up to 15%. the metabolic syndrome.1%) with colesevelam 3. and encouraging him to adopt a more active means of delivering toys. From a public health point of view.001) compared with placebo. the hepatic enzyme. mince pies. apolipoprotein A-I (+6. he has considerable potential to influence individual and societal behavior. we now know the causes and have a solution for preventing obesity. cholesterol 7 -hydroxylase.4%). thus increasing the conversion of cholesterol to bile acids. is near universal.5%. Colesevelam belongs to the bile acid sequestrant class of drugs. Monash University. Gastrointestinal disorders were the most common adverse effects. Santa Claus: a public health pariah? a Grills NJa. or clotting factors were observed.75 g/day for 18 weeks (period III).9%). Metabolic Syndrome. is upregulated. Melbourne. colesevelam use will not reach target levels. impeding their reabsorption.875 g/day (n = 65). p = 0. Two important implications from this study are the reduction of LDL-C by colesevelam. HMG-CoA reductase. Therefore. Epidemiological studies show there is a correlation between countries that venerate Santa Claus and those that have high levels of childhood obesity. Given Santa’s fame. Australia nathangrills@gmail.5%. double-blind.. a significant difference from baseline in LDL cholesterol was reported with colesevelam 1. and b Department of Health. However. Halyday Bb Department of Epidemiology and Preventative Medicine. and apolipoprotein B (–8. the childhood icon.1%). and increasing the number of hepatic LDL-C receptors. lipid-lowering polymer that was engineered specifically to enhance the binding capacity for bile acids in the intestine. Although the causality has not been proven.75 g/day compared with placebo at week 8. it significantly lowered LDL-C by 12. Conclusions: Colesevelam significantly lowered LDL cholesterol levels in children with heFH. it appears that Santa promotes a message that obesity is synonymous with cheerfulness and joviality. milk.875 g/day (–6. or colesevelam 3. fat-soluble vitamin levels.com BMJ 2009. This increases demand for cholesterol in the liver cells.3%. p < 0. HDL cholesterol (+6. the use of colesevelam is of particular value in patients who do not reach their LDL-C target levels with maximal tolerable dosages of statins. and indeed there were no safety or laboratory issues in this study.Methods: This was a randomized. The drug is a non-absorbed. subjects were randomized to placebo (n = 65).3%) and a non-significant effect for triglycerides (+5. Bile acid sequestrants are not systematically absorbed. brandy or sherry. Among adults. according to the authors. All patients then received open-label colesevelam 3. such as swapping his reindeer for a bike or simply walking or jogging. multicenter site study in 194 boys and postmenarchal girls aged 10–17 years with heFH (statin-naive or on a stable statin regimen). Vic. sexual maturation. non-HDL cholesterol (–10.339:b5261 It appears that the awareness of Santa Claus. No significant effects on growth.

17:113–119.16:506–508. Ann Intern Med 2010.121:530–539. Steinberger J.59:1117–1125. Toth EL: Comparison of the [13C]glucose breath test to the hyperinsulinemic-euglycemic clamp when determining insulin resistance. Nat Med 2010. and Council on Nutrition. Council on Cardiovascular Nursing. Pavkov ME. Paty BW. Wang L. et al: Systematic review: vitamin D and cardiometabolic outcomes.27:441–447. J Pediatr 2010. and Metabolism. 10. Chesney RW: Vitamin D and The Magic Mountain: the anti-infectious role of the vitamin. Nauck MA: Is the diminished incretin effect in type 2 diabetes just an epi-phenomenon of impaired -cell function? Diabetes 2010.156:698–703. Diabetes Care 2004. Diabetologia 2010.152:315–323. 13. et al: Downregulation of the longevity-associated protein sirtuin-1 in insulin resistance and metabolic syndrome: potential biochemical mechanisms. Simmons RK. De Kreutzenberg SV. 8.53:600–605. Goldfine AB: The impact of vitamin D deficiency on diabetes and cardiovascular risk. Meier JJ. 3. et al: The metabolic syndrome: useful concept or clinical tool? Report of a WHO Expert Consultation. 6.References 1. Gidding SS: Familial hypercholesterolemia: a decade of progress. et al: Macroalbuminuria and renal pathology in First Nation youth with type 2 diabetes. Friedrichs E: On the pill. 5. J Pediatr 2010. Physical Activity. Sellers EA. 4.156:176–177. et al: Improving pediatric dosing through pediatric initiatives: what we have learned? Pediatrics 2008. 15. Lewanczuk RZ. 9.32:786–790.30:1758– 1763. Diabetes Care 2009. Hypertension. 12. et al: Progress and challenges in metabolic syndrome in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis. Oncologist 2009. 2. Chong CR. Diabetes Care 2007. 170 Orit Pinhas-Hamiel . 11. Chabner BA: Mysterious metformin. and Obesity in the Young Committee of the Council on Cardiovascular Disease in the Young. 14. Circulation 2009. 7.14:1178–1181. Baz-Hecht M. Diabetes 2010.119:628–647. Pittas AG. et al: Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events. et al: Changing patterns of type 2 diabetes incidence among Pima Indians. Rodriguez W. Curr Opin Endocrinol Diabetes Obes 2010.152:307–314.59:1006–1015. Ann Intern Med 2010.

Irikat RK. Bainbridge M. causative mutations in SH3TC2 (the SH3 domain and tetratricopeptide repeats 2 gene) were identified and validated. However. University of Cambridge. McGuire AL. and Department of Paediatrics. Onga. even in cases with simple patterns of inheritance and unambiguous diagnoses. Genome-wide association studies continue to generate dozens of new loci for common diseases and continuous traits. including the carpal tunnel syndrome. Stankiewicz P. Gonzaga-Jauregui C. This year’s review starts with four such studies all published during the first few months of 2010. heterozygous mutations confer susceptibility to neuropathy. Nazareth L. Rio DD. Methods: A family was identified with a recessive form of Charcot-Marie-Tooth disease of yet unknown genetic basis. Jing C. Chen DC. Cambridge. The whole genome of the proband was sequenced and potential functional variants were genotyped in other family members. Baylor College of Medicine. Whether you see this position as a future opportunity or as an indictment against the current efforts. Guo D. the relationship between disease phenotypes and their corresponding genetic changes can be complicated. Dinh H.. Yang C. Zhang F. Conclusion: This study of a family with Charcot-Marie-Tooth disease shows that whole-genome sequencing can identify etiological variants and provide clinically relevant diagnostic information. Tom W. Mechanism of the year The clinical utility of genome sequencing Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy Lupski JR. Muzny DM. Novel analytical approaches to genome-wide association data have described variants with parent-of-origin associations with both type 1 and type 2 diabetes. it is clear that we will need new analytical strategies and likely new large familybased studies to decipher the remaining genetic basis of human phenotypic variation and disease risks. heterozygous. insulin resistance and birth weight. and examples described below include fasting glucose. whole-genome and whole-exome sequencing studies are now demonstrating their power to shed novel insights into human genetic architecture and disease etiology. Halperin JJ. USA N Engl J Med 2010. the percentage of disease susceptibility that can be explained remains surprisingly small. . while the limits of the genome are now clearly definable and we have the tools to see it in its entirety. UK Rapid technological advances continue to pave the way for exciting genetic discoveries. Fantin NJ. Gibbs RA Department of Molecular and Human Genetics. Wheeler DA.362:1181–1191 Background: Whole-genome sequencing may revolutionize medical diagnostics through rapid identification of alleles that cause disease.b and Cathy Elksa a b Medical Research Council Epidemiology Unit. Separate subclinical phenotypes segregated independently with each of the two mutations. Gehman C. Reid JG. Tex. Results: Two compound. Extension of genetic studies to African-derived populations with greater power for fine mapping has finally pinpointed the first genome-wide obesity locus to the FTO gene. Just a handful of years since the appearance of genome-wide association studies that have rapidly expanded the number of common variants robustly linked to multigenic diseases and traits. However. This study aimed to assess the usefulness of human whole-genome sequencing for genetic diagnosis in a patient with Charcot-Marie-Tooth disease. Houston.Population Genetics and Pharmacogenetics Ken K.

in contrast to around USD 15. USA Nat Genet 2010. Firstly is the realisation of non-classical mendelian inheritance patterns.069 were predicted to be amino-acid changing. two major difficulties in interpreting the data may quickly become apparent.e. of which 1 million were within gene regions. splice site or insertion/deletion variants in ~4. Firstly. whole-genome sequencing unearthed over 3 million variants compared to the human genome reference sequence. Seattle. Other studies described below illustrate further ways to interpret the data. Conclusion: Exome sequencing of a small number of unrelated affected individuals is a powerful. Tabor HK. digenic. Even within the 6-month duration of this study. Methods: For 4 affected individuals in three independent kindreds. Shendure J. Nickerson DA. was identified which encodes a key enzyme in the pyrimidine de novo biosynthesis pathway. the authors argued that they could safely filter out all the variants found in existing databases. only ~5% of the whole-genome sequencing load is required. In this patient. many seemingly deleterious mutations will be found in each individual. This and the following articles illustrate the potential that rapid-sequencing technology could have for personalised medicine. However this sledgehammer is rapidly becoming lighter due to technological advances. and the presence of modifying genes. this study is one of the first to apply whole-genome sequencing in a clinical context. The authors found non-synonymous. efficient strategy for identifying the genes underlying rare mendelian disorders and will likely transform the genetic analysis of monogenic traits. these are compound (as illustrated in this study). with only ~30 cases to date. University of Washington. family history. By focusing on exons. Sequencing the whole genome to find one or two causative mutations may seem like a sledgehammer to crack a small nut. Buckingham KJ. Thirdly. The estimated cost per genome in April 2009 was USD 50. Current costs for whole-exome sequencing are only about USD 4. they 172 Ken K. Dent KM. the authors chose a recessive disorder. For example the (male) proband had a mutation in ABCD1 which causes the X-linked disorder adrenoleukodystrophy (which he did not have!). The authors therefore focussed only on the 54 coding SNPs in the 40 genes with previous links to neurological conditions. Yet. as Miller syndrome is so rare. rather than ‘whole-genome’. gene-coding regions were captured and sequenced to a mean coverage of 40× and sufficient depth to call variants at approximately 97% of each targeted exome. Exome sequencing identifies the cause of a mendelian disorder Ng SB. particularly if most of the data is uninterpretable. and this approach could have led to the same conclusion – see article below. The justification for the smaller ‘whole-exome’. and most of these will be silent or ‘non-penetrant’. 9. which meant they could focus on those genes with at least two variants. Wash. i.. Lee C. This study demonstrates the first successful application of exome sequencing to discover the gene for a rare mendelian disorder of unknown cause. Secondly. 21 have been described to cause mendelian disease. Jabs EW. Shannon PT. predicted to lead to truncation of the protein. Bamshad MJ Department of Genome Sciences. and trigenic inheritance patterns. Results: A single candidate gene.000 for a diagnostic panel for Charcot-Marie-Tooth covering only 15 genes. and 121 were non-sense mutations. DHODH. and still results in a huge number of potential causal variants to sift through. While several whole genomes of healthy individuals have been published.Personalised medicine is used to include a patient’s lifestyle. sequencing approach is that the majority of known variants for monogenic disorders disrupt the protein-coding sequence.600 genes! Several factors increased the chances of successfully choosing the causal gene in this landmark study. allelic variants underlying fewer than half of all monogenic disorders have been discovered. Beyond the acquisition of an accurate genome sequence. Bigham AW. and environment. Miller syndrome. Huff CD. Filtering against public SNP databases and eight HapMap exomes for genes with two previously unknown variants in each of the 4 individuals. Two SNPs were in SH3TC2 and one showed complete segregation with disease status in other family members. Secondly.42:30–35 Background: To date. Sanger sequencing confirmed the presence of DHODH mutations in three additional families with Miller syndrome.000. the sequence yield increased threefold with no appreciable increase in cost. plus splice acceptor and donor sites. this is still vast. Ong/Cathy Elks . involving more than one mutation in the same or even different genes.000.

The authors describe how in a nuclear family of 4. as the authors point out that inborn errors of metabolism rarely cause birth defects. We used to consider multiple genetic defects unique to consanguineous families. and they were consequently diagnosed with primary ciliary dyskinesia. for which causative genes have been previously identified. the current study illustrates how family-based data would have markedly narrowed the search for the disease-causing variant. While this explained their non-Miller syndrome features of recurrent lung infections and bronchiectasis. Jorde LB. The characteristic features of Miller syndrome include severe micrognathia. consisting of 2 siblings and their parents. Goodman N. cleft lip and/or palate. They show for the first time how whole genomes from the same family permit powerful inheritance analyses to greatly improve the detection and understanding of sequencing errors. it illustrates the potential for surprise genetic findings with clinical. It was therefore a surprise to locate gene mutations to DHODH. for which the gene was concurrently identified. Bamshad M. the identification of 70% of the sequencing errors (resulting in >99. and recombination must have occurred between these blocks. This paper. Glusman G. The directly estimated human intergeneration mutation rate was approximately 1. from the same group who reported the genetic etiology of Miller syndrome. Family-based sequencing allowed the precise delineation of recombination sites.328:636–639 Background: Whole-genome sequences from 4 members of a family represent a qualitatively different type of genetic data than whole-genome sequences from individual or sets of unrelated genomes. Shannon PT. Huff CD. Wash. The 4 family members showed different genotypes at 3. Analysis of genetic inheritance in a family quartet by whole-genome sequencing Roach JC. Family-based genome analysis narrowed the candidate genes for both of these mendelian disorders to only four. The authors found further mutations in the dihydroorotate dehydrogenase gene (DHODH) in several other probands. Drmanac R. and coloboma of the eyelids. Both offspring in this family have two recessive disorders: Miller syndrome. Seattle. Such data. Shendure J. (iii) the same allele from the father. Hood L. sequencing genomes of families will be an economical strategy for the identification of many disease-causing genes. along with relevant environmental and medical information. or (iv) opposites from both parents. Rowen L.999% accuracy). and even ethical. were analyzed. USA Science 2010. Furthermore. and primary ciliary dyskinesia. Conclusions: These results demonstrate the value of complete genome sequencing in families. each variant position can be allocated to one of four inheritance states with the 2 children receiving (i) the same allele from both the mother and the father (identical).. and the identification of very rare single-nucleotide polymorphisms. blocks of variants that do not conform to these inheritance patterns (mendelian inheritance errors) must be either sequencing errors or result from hemizygous deletions.1 × 10–8 per position per haploid genome. Intriguingly. It may be more common that we expect. The paper includes a thought-provoking discussion linking inhibitors of pyrimidine biosynthesis (such as methotrexate) to birth defects via TNF. (ii) the same allele from the mother but opposites from the father. Hubley R. is based on that same family and now includes their parents’ genomes. while the authors identified the gene for Miller syndrome in their earlier paper. the brothers were also compound heterozygotes for variants in DNAH5. but opposites from the mother.sequenced 2 affected brothers. which further narrowed the search to those variants that were present in both exomes. which encodes a ciliary dynein heavy chain.6 million known variants. Adjacent variants with the same inheritance states delineate inheritance blocks.. consequences. Galas DJ Institute for Systems Biology.B and Shh (the sonic hedgehog homolog). In contrast. and these formed the basis for inheritance analyses. and allow precise estimates of human mutation rates and the precise locations of recombination events. Pant KP. which encodes an enzyme that catalyzes the conversion of dihydroorotate to orotic acid. Smit AF. hypoplasia or aplasia of the posterior elements of the limbs. NF.’ Population Genetics and Pharmacogenetics 173 . They conclude that ‘When the cost of recruiting additional families is expensive relative to sequencing costs. Methods: Whole-genome sequences of a family of 4. will characterize the integrated medical records of the future.

375:1525–1535 Background: The cost of genomic information has fallen steeply.6 million single nucleotide polymorphisms and 752 copy number variations showed increased genetic risk for myocardial infarction.. DSP. but the clinical translation of genetic risk estimates remains unclear. clopidogrel might be less effective. Ong/Cathy Elks . duty of care to other family members. these results suggest that whole-genome sequencing can yield useful and clinically relevant information for individual patients. the clinical value of sequence data will rapidly increase. Neff NF. Thakuria JV. Chou MF. Sangkuhl K. Methods: A 40-year-old man with a family history of vascular disease and early sudden death underwent a routine clinical assessment plus analysis of his full genome sequence. several variants associated with a positive response to lipid-lowering therapy. Dewey FE. Gong L. Dudley JT. Chen R. Church GM.edu Lancet 2010. needs to be balanced against confidentiality. Morgan AA. with increasing knowledge gained from genome-wide association studies and wholegenome and whole-exome sequencing studies. This study aimed to undertake an integrated analysis of a complete human genome in a clinical context. A variant in LPA was consistent with a family history of coronary artery disease. which showed that we each carry many mutations for mendelian disease that are somehow silenced. Nevertheless. type 2 diabetes. and his genome was informative for future drug choices and dosing. Butte AJ. Secondly. Were he to need warfarin. and variants in CYP4F2 and VKORC1 that suggest he might have a low initial dosing requirement for warfarin. Klein TE. Whaley R. his initial doses are likely to be low. Sagreiya H. Zaranek AW. Greely HT. Results: Analysis of 2. but it is uncertain whether surveillance and testing for these conditions should continue. 174 Ken K. Hudgins L. clinical and ethical dilemmas need to be tackled. Division of Cardiovascular Medicine. Remarkably. Stanford. Knowles JW. this assessment was performed on just 2 ml of whole blood. Other than his family history. Rare variants were found in three genes that are clinically associated with sudden cardiac death – TMEM43. and some cancers. Stanford University School of Medicine. This approach assumes that all the identified variants are expressed and this contrasts with the findings of other studies. and MYBPC3. USA euan@stanford. Quake SR. Ormond KE. it will be increasingly important to defend the principle that health insurers cannot use our genetic information to calculate our premiums. Rosenbaum AM. Calif. he is likely to respond well to statins and to be at lower risk of statin-induced myopathy. He had no evidence of either. The patient was found to have potentially damaging variants associated with haemochromatosis and also parathyroid tumors. The authors relied on disease-specific mutation databases and pharmacogenomic databases to identify genes and mutations with known associations with disease and drug response. by contrast. While other studies have applied genome sequencing to rare mendelian diseases. The patient had a heterozygous null mutation in CYP2C19 suggesting probable clopidogrel resistance. Hodges LM. the patient was healthy and was found to have increased risks for coronary artery disease and sudden cardiac death. Berlin DS. In addition to identifying risk variants associated with mendelian disease. Furthermore. Thorn CF. Pushkarev D. There were compelling findings related to drug responses. including 63 known pharmacogenomic variants that could affect the patient’s response to commonly used drugs. For example.Clinical assessment incorporating a personal genome Ashley EA. Conclusions: Although challenges remain. Wheeler MT. Altman RB Center for Inherited Cardiovascular Disease. this is the first to explore its utility in risk prediction for more complex multigenic disorders. by informing them of their disease risks. Pavlovic A. post-test probabilities of disease were estimated by applying likelihood ratios derived from integration of multiple common variants to age-appropriate and sexappropriate pre-test probabilities. Hebert JM. However. Woon M.

de Geus EJ. Pedersen NL. Magi R. Perry JR. such as glucose levels. Voight BF. Vogelzangs N. Coin LJ. The aim of this study was to identify new genetic loci associated with various glycemic traits. Orru M. Kovacs P. Gloyn AL. Hingorani AD. Zhao JH. Benediktsson R. Ward KL. Paolisso G.186 non-diabetic participants. Varma D. Tichet J. The top 25 loci were followed up in a further 76. other loci are associated with a modest elevation in glucose levels but not overt diabetes. Rivadeneira F. Nathan DM. Polasek O. Langenberg C. An P. Randall J. Frants R. fasting insulin and indices of -cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46. Egan JM. Day IN. Psaty BM. Goel A. Simpson L. studying the underlying continuous traits. Walley A. GLIS3. Heath SC. Pouta A. Chen YD. Le BO. Cornelis M. Narisu N. Scheet P. ADRA2A. Dehghan A. GCK. Morris AP. Franzosi MG. Walters GB. insulin resistance and birth weight New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk Dupuis J. Hallmans G. Mukherjee S. McCulloch LJ. Magnusson PK. Martinez-Larrad MT. Ingelsson E. Hadjadj S. Shields B. Jula A. Johnson PR. Qi L. Hansen T. Knight B. Lecoeur C. Elliott A. Schwarz P. Kaakinen M. Pfeiffer AF. Rybin D. Jorgensen T. or its complications.42:105–116 Background: Levels of circulating glucose are tightly regulated. Rocheleau G. development. MADD. Ardlie K. Smith GD. Grarup N. Pedersen O. Conclusions: These findings demonstrate that genetic studies of continuous glycemic traits can identify novel type 2 diabetes risk loci. there are caveats in this approach. Witteman JC. Indeed. Province MA. Sovio U. Ariyurek Y. Kao WH. Mahley R. Ripatti S. Tonjes A. Ebrahim S. FADS1. SLC2A2. Watkins H. Kyvik KO. Sandhu M. Uitterlinden AG. Forouhi NG. Hofman A. Neville MJ. Meyre D. Hillman DR. Li Y. Sayer AA. Henneman P. Elliott P. Kivimaki M. Visvikis-Siest S. distinct diseases. Beilby JP. Meneton P. Fox CS. Lawlor DA.. McAteer JB. Melzer D. Morris AD. Palmer LJ. Pattou F. Boerwinkle E. Naitza S. Payne F. Sampson MJ. Balkau B. Singleton A. Rayner NW. Franklin CS. Galan P. Hattersley AT. Prokopenko I. Swift A. Lindgren CM. Dina C. Timpson NJ. Cavalcanti-Proenca C. Loos RJ. Syvanen AC. Boston. Roden M. Tanaka T. Pakyz R. cell proliferation.New genetic associations T2DM.558 participants. Clarke R. Crisponi L. Kesaniemi YA. Morken MA. Bonnycastle LL. Karpe F. some variants that affect glucose metabolism may raise glucose levels only marginally and not sufficiently to contribute to risks for T2DM. such as type 2 diabetes (T2DM). Pichler I. Cooper C. Lathrop GM. Meisinger C. PROX1. Seedorf U. Wagner PJ. Graessler J. O’Connell J. Crawford G. Borch-Johnsen K. Hicks AA. Hassanali N. Hammond N. Spranger J. studies for BMI have been more powerful and fruitful that studies of obesity. Zelenika D. Laakso M. Sandbaek A. Goodarzi MO. Shrader P. Serrano-Rios M. Borecki IB. Mangino M. Wild SH. Sanna S. Hung J. Soranzo N. Luan J. Silander K. Oostra BA. Pankow JS. Tuomi T. Brunner E. Methods: A meta-analyses of 21 genome-wide association studies was performed for fasting glucose. Bennett AJ. Waeber G. Thorleifsson G. Grundy S. Marmot M. Bonnefond A. Palmer CN. Kumari M. Hartikainen AL. Barter P. Weedon MN. Lind L. McCarroll SA. Cooper MN. Salomaa V. Delplanque J. Silveira A. Syddall H. Lyssenko V. Scott LJ. GCKR and DGKB-TMEM195 were also demonstrated to be associated with risk of type 2 diabetes. Herder C. Ben-Shlomo Y. However. Mass. USA Nat Genet 2010. Peden JF. ADCY5. Yarnell JW. Doney A. Groves CJ. Vitart V. CRY2. Posthuma D. Hayward C. These include 9 loci newly associated with fasting glucose (in or near ADCY5. Pramstaller PP Department of Biostatistics. Franks PW. Han X. Bottcher Y. Sijbrands EJ. Koskinen S. Manning AK. Hercberg S. Perola M. Dedoussis GV. Steinthorsdottir V. may uncover further genetic loci that are relevant for disease risks. Pattaro C. Zhai G. Smith NL. Zabena C. In addition to large GWA studies. Kuusisto J. Fischer-Rosinsky A. Gwilliam R. Kaprio J. Sharp SJ. Bochud M. Rathmann W. Williams GH. PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF-1). Pearson D. Potter SC. Johnson T. Fedson AC. Navarro P. Hu FB. Mitchell BD. Zeggini E. Stringham HM. Boston University School of Public Health. The likely biological candidate genes within these loci influence signal transduction. Saxena R. Bouatia-Naji N. Hui J. Bumpstead SJ. Charpentier G. In further analyses. Jackson AU. Rice K. Thorand B. Lajunen T. Song K. Rolandsson O. Bergmann S. van Dijk KW. Zillikens MC. Sigurethsson G. McPherson R. However. Li M. Chines P. Erdos MR. Sparso T. Sethupathy P. Gyllensten U. Isomaa B. Hottenga JJ. Zethelius B. Bornstein SR. Roccasecca RM. Firstly. Grallert H. Results: Altogether 16 loci were identified associated with fasting glucose and HOMA-B and 2 loci associated with fasting insulin and HOMA-IR. This is akin to the rare glucokinase mutations that cause the benign condition Population Genetics and Pharmacogenetics 175 . glucose-sensing and circadian regulation. Glazer NL. Kanoni S. Wheeler E. Willemsen G. Shuldiner AR. van HM. Gieger C.

MODY type 2. Secondly, a recent genetic variant for HbA1c levels was surprisingly shown subsequently to influence hemoglobin levels rather than glycemia, despite being located in the hexokinase gene [1]. It is therefore reassuring to see that several of the new loci described in this study were confirmed to influence T2DM risk per se. The size of the combined effects of the 16 loci associated with fasting glucose was substantial. There was a mean differences of ~0.4 mmol/l (5.93 vs. 5.51 mmol/l) in fasting glucose when comparing the highest genetic risk group (5.6% of the sample) to the lowest (2.9% of the sample). This represents a shift of approximately 25 centile points in the distribution of fasting glucose, and corresponded to a relative risk of 1.54–1.73 for future T2DM. The one locus for insulin resistance (HOMA-IR) was near to the strongly plausible gene IGF-1, however this variant failed to reach significance in follow-up studies of over 50,000 individuals. The lack of further loci for insulin resistance is surprising as the estimates of heritability are similar for insulin resistance and insulin secretion (HOMA-B) in family studies. The authors argue that different traits could have distinct genetic architectures. For example, some such as fasting glucose could be influenced by several common variants each with modest effects. Others, such as HOMA-IR, could be putatively influenced by fewer loci, rarer variants, or by stronger environmental modifications on their genetic effects.

Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia
Rung J, Cauchi S, Albrechtsen A, Shen L, Rocheleau G, Cavalcanti-Proenca C, Bacot F, Balkau B, Belisle A, Borch-Johnsen K, Charpentier G, Dina C, Durand E, Elliott P, Hadjadj S, Jarvelin MR, Laitinen J, Lauritzen T, Marre M, Mazur A, Meyre D, Montpetit A, Pisinger C, Posner B, Poulsen P, Pouta A, Prentki M, Ribel-Madsen R, Ruokonen A, Sandbaek A, Serre D, Tichet J, Vaxillaire M, Wojtaszewski JF, Vaag A, Hansen T, Polychronakos C, Pedersen O, Froguel P, Sladek R McGill University and Genome Quebec Innovation Centre, Montreal, Que., Canada Nat Genet 2009;41:1110–1115
Background: Previous genome-wide association studies have identified common variants that only partially explain the genetic risk for type 2 diabetes (T2D). Methods: 392,365 SNPs were tested for association with T2D in 1,376 French cases and controls. The 5% of variants most significantly associated with T2D (16,360 SNPs) were followed up in an independent sample of 4,977 French individuals using a custom designed array. The best 28 hits from this stage were subsequently selected for replication in 7,698 Danish subjects. Finally, the most significant novel locus was followed up in 14,358 French, Danish and Finnish participants from population-based cohorts with detailed T2D-related phenotypes. Results: Four SNPs were identified which showed genome-wide significant association with T2D (p < 5.0 × 10–8), one of which (rs2943641, p = 9.3 × 10–12, OR = 1.19) was located adjacent to the insulin receptor substrate 1 gene (IRS1). The C allele of rs2943641 was associated with insulin resistance and hyperinsulinemia; this allele was also associated with reduced basal levels of IRS1 protein and decreased insulin induction of IRS1-associated phosphatidylinositol-3-OH kinase activity in human skeletal muscle biopsies. Conclusions: Genetic variation near to IRS1 is associated with T2D, insulin resistance and hyperinsulinemia. Unlike previous T2D risk loci, which predominantly associate with impaired -cell function, this highlights the role of insulin resistance in T2D risk.

In GWA studies of complex traits, efforts to uncover further ‘missing heritability’ have been largely focussed on increasing statistical power by combining studies in large-scale meta-analyses. Here, the authors adopted an alternative multistage strategy whereby a GWA study was first used to test genetic association with T2D in a large well-phenotyped cohort before selecting a fraction of SNPs showing the strongest association to study in well-powered subsequent stages. The advantage of this is that statistical power is maximised cost-effectively since each stage contains a smaller number of SNPs and an increased number of individuals. The authors were rewarded by the discovery of a novel T2D locus in a possible regulatory region of the insulin receptor substrate gene (IRS1). In addition to being associated with T2D risk (OR = 1.19), the C allele at rs2943641 was also associated with insulin resistance and hyperinsulinemia, independently of BMI. In a subset of French individuals,

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the variant was associated with a 35% increased risk of T2D and a 14% increased incidence of the development of hyperglycaemia after 9 years of follow-up. In functional studies, the authors described likely regulatory effects of rs2943641 on IRS1 and insulin signaling. Interestingly, this SNP is in the same LD block as a previously identified coronary artery disease (CAD) risk locus (rs2943634, r2 = 0.8), suggesting that genetic variation near IRS1 may predispose to CAD through increased susceptibility to T2D, a known cardiovascular risk factor. Alternatively this gene region may have pleiotrophic effects on both phenotypes. In contrast to previously identified T2D loci, this variant is the first to be associated with insulin resistance and hyperinsulinemia, rather than impaired insulin secretion. This will give us new insight into the contribution of insulin sensitivity in establishing T2D risk.

Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight
Freathy RM, Mook-Kanamori DO, Sovio U, Prokopenko I, Timpson NJ, Berry DJ, Warrington NM, Widen E, Hottenga JJ, Kaakinen M, Lange LA, Bradfield JP, Kerkhof M, Marsh JA, Magi R, Chen CM, Lyon HN, Kirin M, Adair LS, Aulchenko YS, Bennett AJ, Borja JB, Bouatia-Naji N, Charoen P, Coin LJ, Cousminer DL, de Geus EJ, Deloukas P, Elliott P, Evans DM, Froguel P, Glaser B, Groves CJ, Hartikainen AL, Hassanali N, Hirschhorn JN, Hofman A, Holly JM, Hypponen E, Kanoni S, Knight BA, Laitinen J, Lindgren CM, McArdle WL, O’Reilly PF, Pennell CE, Postma DS, Pouta A, Ramasamy A, Rayner NW, Ring SM, Rivadeneira F, Shields BM, Strachan DP, Surakka I, Taanila A, Tiesler C, Uitterlinden AG, van Duijn CM, Wijga AH, Willemsen G, Zhang H, Zhao J, Wilson JF, Steegers EA, Hattersley AT, Eriksson JG, Peltonen L, Mohlke KL, Grant SF, Hakonarson H, Koppelman GH, Dedoussis GV, Heinrich J, Gillman MW, Palmer LJ, Frayling TM, Boomsma DI, Davey SG, Power C, Jaddoe VW, Jarvelin MR, McCarthy MI Genetics of Complex Traits, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK Nat Genet 2010;42:430–435
Background: Birth weight is a complex multifactorial trait. This study aimed to identify genetic variants associated with birth weight. Methods: The results of six genome-wide association (GWA) studies (n = 10,623 Europeans from pregnancy/birth cohorts) were meta-analyzed. Two lead signals were followed up in 13 replication studies (n = 27,591). Results: rs900400 near LEKR1 and CCNL1 (p = 2 × 10–35) and rs9883204 in ADCY5 (p = 7 × 10–15) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and susceptibility to type 2 diabetes, providing evidence that the welldescribed association between lower birth weight and subsequent type 2 diabetes has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, the 9% of Europeans carrying four birth weight-lowering alleles were, on average, 113 g (95% CI 89–137 g) lighter at birth than the 24% with zero or one alleles (Ptrend = 7 × 10–30). Conclusion: The impact on birth weight is similar to that of a mother smoking 4–5 cigarettes per day in the third trimester of pregnancy.

The birth weight-lowering C allele of rs9883204 is in linkage disequilibrium (LD) (r2 = 0.75) with the A allele of rs11708067, which was independently shown to be associated with increased risk of type 2 diabetes, higher fasting glucose, and reduced insulin secretion. Fetal insulin is a key fetal growth factor, and these metabolic associations suggest that one mechanism explaining the ADCY5 (cyclic AMP-generating adenylate cyclase) association with birth weight might be a direct effect of the fetal risk allele on fetal growth via reduced insulin secretion, consistent with the fetal insulin hypothesis. The association with ponderal index, relative to those with birth length and head circumference, was particularly strong for the variant near the cyclin gene CCNL1, which encodes a kinase known to phosphorylate histone H1, suggesting that it might have a greater association with fat mass than with skeletal growth. However, for ADCY5, the birth measures showed more proportionate associations. Birth weight represents a complex phenotype. Beyond the usual gene-environment interactions, the fetal environment may be governed by maternal genes. It is therefore important to clarify whether apparent effects of fetal genes might be proxy markers for maternal genes acting on maternal

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metabolism. In the current study, meta-analysis of associations between birth weight and fetal genotype, conditional on maternal genotype, yielded very similar results to the original associations at both loci, showing that these are direct fetal effects. Secondly, fetal growth seems to be one of the main targets of imprinted genes. Future studies need to explore whether these fetal genes demonstrate parent of origin effects.

New paradigms The genetics of epigenetics

Heritable individual-specific and allele-specific chromatin signatures in humans
McDaniell R, Lee BK, Song L, Liu Z, Boyle AP, Erdos MR, Scott LJ, Morken MA, Kucera KS, Battenhouse A, Keefe D, Collins FS, Willard HF, Lieb JD, Furey TS, Crawford GE, Iyer VR, Birney E Center for Systems and Synthetic Biology, Institute for Cellular and Molecular Biology, Section of Molecular Genetics and Microbiology, University of Texas, Austin, Tex., USA Science 2010;328:235–239
Background: The extent to which variation in chromatin structure and transcription factor binding may influence gene expression, and thus underlie or contribute to variation in phenotype, is currently unknown. Methods: Individual-to-individual variation and differences between homologous chromosomes within the same individual (allele-specific variation) in chromatin structure and transcription factor binding in lymphoblastoid cells derived from individuals of geographically diverse ancestry were catalogued. Differences between chromatin structure were compared between parents and children in order to identify whether chromatin signatures are heritable in humans. Results: Ten percent of active chromatin sites were individual-specific; a similar proportion were allelespecific. Both individual-specific and allele-specific sites were commonly transmitted from parent to child, which suggests that they are heritable features of the human genome. Conclusion: This study shows that heritable chromatin status and transcription factor binding differ as a result of genetic variation and may underlie phenotypic variation in humans.

Variation in chromatin structure can facilitate or restrict the binding of transcription factors to regulatory regions and is therefore a major component in the regulation of gene transcription. While there is much interest in such epigenetic changes as the possible mechanism to explain ‘long-term programming’ responses to specific early exposures, alterations of chromatin structure are in turn also influenced by genetic variation. In order to increase our understanding of this allele-specific gene regulation, the authors catalogued variation in transcription factor binding and chromatin structure in a European and an African family (both parents and one daughter from each) from the ‘1000 Genomes Project’ using deoxyribonuclease I hypersensitive (DNase I) site mapping and chromatin immunoprecipitation (ChIP). This allowed them to identify regulatory DNA elements such as promoters, enhancers, silencers and insulators. The study design enabled the investigators to compare related and unrelated individuals and determine whether chromatin structure is heritable. Comparison of the children’s chromatin signals to that of the parents revealed that chromatin sites were much more similar to their own parents’ than those of the unrelated family, demonstrating its strong heritability. Remarkably, only 10% of active chromatin sites were individual-specific and this indicates that one of the major types of epigenetic variation (i.e. chromatin structure) is itself largely influenced by genetic variation. Future studies should explore the specific genetic regulation of epigenetic marks.

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Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis
Baranzini SE, Mudge J, van Velkinburgh JC, Khankhanian P, Khrebtukova I, Miller NA, Zhang L, Farmer AD, Bell CJ, Kim RW, May GD, Woodward JE, Caillier SJ, McElroy JP, Gomez R, Pando MJ, Clendenen LE, Ganusova EE, Schilkey FD, Ramaraj T, Khan OA, Huntley JJ, Luo S, Kwok PY, Wu TD, Schroth GP, Oksenberg JR, Hauser SL, Kingsmore SF Department of Neurology, University of California at San Francisco, San Francisco, Calif., USA sebaran@cgl.ucsf.edu Nature 2010;464:1351–1356
Background: Monozygotic twins are often studied to quantify the relative contributions of genetics and environment in human diseases. In multiple sclerosis (MS), disease discordance between monozygotic twin pairs has been interpreted to indicate its important environmental pathogenesis. However, both genetic and epigenetic differences between monozygotic twins have been described, challenging the accepted experimental model in disambiguating the effects of nature and nurture. Methods: Genomes of one MS-discordant monozygotic twin pair were sequenced and compared. Messenger RNA transcriptome and epigenome sequences of CD4+ lymphocytes from three MS-discordant monozygotic twin pairs were also determined and evaluated. Results: No reproducible differences were detected between co-twins among approximately 3.6 million single nucleotide polymorphisms (SNPs) or approximately 0.2 million insertion-deletion polymorphisms. Nor were any reproducible differences observed between siblings of the three twin pairs in HLA haplotypes, confirmed MS susceptibility SNPs, copy number variations, mRNA and genomic SNP and insertion-deletion genotypes, or the expression of approximately 19,000 genes in CD4+ T cells. Only 2–176 methylation differences out of approximately 2 million CpG dinucleotides were detected between siblings of the three twin pairs, in contrast to approximately 800 methylation differences between T cells of unrelated individuals and several thousand differences between tissues or between normal and cancerous tissues. Conclusion: In the first systematic effort to estimate sequence variation among monozygotic co-twins, there was no evidence for genetic, epigenetic or transcriptome differences that explained MS discordance. These are the first female, twin and autoimmune disease individual genome sequences reported.

Genetically identical twins discordant for a particular disease are considered a useful tool for studying a possible contribution of epigenetics to disease pathogenesis. In this study, the authors compared genetic and epigenetic differences in monozygotic twins discordant for multiple sclerosis (MS), using CD4+ lymphocytes due to their known involvement in the autoimmune pathophysiology of MS. This study of unprecedented resolution is the first to systematically characterise both genetic and epigenetic contributions to disease discordance in monozygotic twins using an impressive range of sophisticated sequencing technologies. Surprisingly, no reproducible genetic, epigenetic or transcriptome differences were identified to explain the twins discordance in MS. So what lessons can be learnt? Firstly, the lack of genetic differences between monozygotic twins at least reassures us of the validity of the monozygotic-dizygotic twins model to study the heritability of disease risk. Secondly, the further lack of epigenetic or transcriptome differences between monozygotic twins is consistent with the recent findings of McDaniell et al. (described above) in illustrating the predominant ‘genetic regulation of epigenetic marks’. And what could explain the disease discordance? The authors describe that their novel comprehensive approach still had limited coverage by exclusion of low coverage regions and repetitive sequences, by only moderate sensitivity for detection of structural variants of size 50–1,500 nucleotides, and (the most tractable explanation in our opinion) by limited feasibility to detect possible somatic mosaicism in tissues other than the CD4+ lymphocyte.

Population Genetics and Pharmacogenetics

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New paradigms Parent of origin effects in genome-wide association studies

The imprinted DLK1-MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes
Wallace C, Smyth DJ, Maisuria-Armer M, Walker NM, Todd JA, Clayton DG Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK Nat Genet 2010;42:68–71
Background: Genome-wide association (GWA) studies successfully mapped common disease susceptibility loci. To date, over 300 reproducibly associated loci have been reported. However, there is yet no convincing evidence for any susceptibility locus that displays parent-of-origin effects. Methods: Data were combined from three existing GWA studies comprising a total of 7,514 cases and 9,405 controls of European ancestry. Potential novel T1DM loci were tested in additional case-control and family studies. Results: There was robust evidence at rs941576 for paternally inherited risk of T1DM; ratio of allelic effects for paternal versus maternal transmissions = 0.75; 95% CI = 0.71–0.79). This marker is in the imprinted region of chromosome 14q32.2, which contains the functional candidate gene DLK1. Our meta-analysis also provided evidence for a further T1DM locus at chromosome 19p13.2. The highest association was at marker rs2304256 (odds ratio (OR) = 0.86; 95% CI = 0.82–0.90) in the TYK2 gene, which has previously been associated with systemic lupus erythematosus and multiple sclerosis. Conclusion: This study reports two novel T1DM loci, one of which is located in an imprinted gene region and conferred protection against T1DM only when paternally transmitted.

Previous analysis of these data had identified over 40 loci for T1DM [2]. This study took forward three further loci which had not quite reached the p-value thresholds for genome-wide significance (p < 10–8), but had strong ‘suggestive evidence’ for association (p < 10–7) with T1DM in additional case-control and family samples. In an overall test of GWA stage and replication data, two of these loci then reached overall genome-wide significance (p = 4 × 10–9 and p = 1.6 × 10–10). The authors noticed that one of these signals was located in a region characterised by several imprinted genes. They therefore tested the hypothesis that this association could show parent of origin effects, which they indeed showed by analysis of informative parent-offspring trios from family-based studies. As is typical of imprinted regions, the imprinted region of chromosome 14q32.2 contains several imprinted genes, some of which are only maternally expressed (BEGAIN, MEG3, MEG8 and DIO3OS), and others only paternally expressed (DLK1, RTL1 and DIO3). Notably, they found that the overall protective effect was paternally (and not maternally) inherited, and this then narrowed the list of potentially causative genes. The best candidate, DLK1, is paternally expressed, with high levels seen in human heart, pancreatic islet cells, pituitary tissue, ovaries, placenta and testes. DLK1 encodes a membrane-bound protein that is cleaved to form fetal antigen-1, which is involved in the differentiation of many cell types, including pancreatic cells and B lymphocytes, and promotes B-cell proliferation in human peripheral blood. Thus, there are a number of ways in which variation in DLK1 expression could alter susceptibility to T1DM.

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each harbouring a cluster of imprinted genes. Steinthorsdottir V. Intriguingly. Sulem P. In the debate over the yet ‘missing heritability’ of common diseases. genotype association with disease risk because its influence on increased risk if T2DM when paternally inherited was balanced by a protective effect when maternally transmitted. Jonsson T. SNP rs2334499 at 11p15 was identified as a novel locus for type 2 diabetes. this variant showed little traditional. or overall. Thorsteinsdottir U. Gudbjartsson DF. Conclusions: Genome-wide association studies have so far yielded variants that explain only a small fraction of the heritability of the traits studied. Parental origin of the alleles was determined using a combination of genealogy and long-range phasing. Ferguson-Smith AC. Besenbacher S. Jonasdottir A. Kristinsson KT. Olason PI. in genome-wide association studies to date. Sigurdsson A. Sverrisson S. this study claims to open new avenues for the discovery of further disease loci. This paper. Jonasdottir A. Hreidarsson AB.462:868–874 Background: Effects of susceptibility variants may depend on from which parent they are inherited. Sigurdsson H. Benediktsdottir KR. Iceland kong@decode. Results: Of the 7 SNPs analysed. the impact of parental origin has largely been ignored. (above). here the allele that conferred increased risk when paternally inherited was protective when maternally transmitted. These variants are located in two genomic regions. Some of the remainder may be hidden in more complex relations between variants and disease risk. the national genealogy database was used to identify even distant family relationships with other study participants (their examples even included third cousins. rs2334499 demonstrated correlation with methylation levels at a novel differentially methylated CTCF-binding site at 11p15. Novel mathematical approaches were developed to take advantage of this uniquely characterised population. and 3 with type 2 diabetes). Population Genetics and Pharmacogenetics 181 . The strategy was remarkably successful in that 5 of the 7 SNPs analysed did indeed show evidence of parental origin effects. it is a path that will require a new generation of large and well-characterised family-based studies. This inference of parent of origin was tested in a subset of direct parent-offspring trios and was found to be 99. Sigurdsson G. Gylfason A. Stacey SN. 5 showed parent-of-origin specific associations (1 with breast cancer. those independent SNPs (n = 7) located within 500 kilobases of a known imprinted gene were selected. Frigge ML. Stefansson K deCODE genetics. twice removed). Benediktsson R. 1 with basal-cell carcinoma. Johannsson OT. Sigurgeirsson B. Reykjavik. Masson G. whereby in the absence of direct genotype information on parents. However. They identified a novel T2DM variant at KCNQ1. which is one of the known loci for methylation defects in Beckwith-Wiedemann syndrome.is Nature 2009. Their disease associations were re-examined in 38. However. published only 1 month prior to Wallace et al. took a unique systematic approach to identify SNP-disease associations that differ according to whether the allele is inherited from your mother or father. 11p15 and 7q32.8% accurate.Parental origin of sequence variants associated with complex diseases Kong A.167 Icelanders with existing GWA data. Thorleifsson G. Methods: From a public database of all disease-associated SNPs identified by GWA studies. Olafsson JH. Gudjonsson SA.

Hindorff LA. Goldstein DB.nih. low frequency and structural variants. Cho JH. McCarroll SA. to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment. and the remaining or ‘missing’ heritability should be seen as the opportunity for future genetic discoveries! The authors present several suggestions. Mardis E. and the HapMap database on which they are based. low-frequency variants have alleles in the 0. and the low proportion of heritability that they explain. to investigate the potential contributions of gene-gene and gene-environment interactions and to make the most of existing and future genome-wide association studies. Slatkin M. Collins FS. The hype over the high profile results of genome-wide association studies has been countered by criticisms about the weak effect sizes and poor individual predictive ability of common variants. Ong/Cathy Elks . Gibson G. and explain only a small proportion of familial clustering.5–5% frequency range. Whittemore AS. USA manoliot@mail. Eichler EE. Kruglyak L. Distinct from rare deleterious mutations that cause mendelian disorders. Boehnke M. GWA studies have been enormously successful. Haines JL. Visscher PM National Human Genome Research Institute. The debate over the nature of the genetic contribution to individual susceptibility to multigenic diseases goes on. and have provided valuable insights into their genetic architecture. the hope was that they would find at least some’. Md.gov Nature 2009. The authors argue that ‘few investigators expected GWA studies immediately to find all of the variants associated with common diseases. In that regard. and rare variants with relatively large effects are the likely major contributors to genetic susceptibility. or even most of them.Food for thought ‘Missing heritability’ Finding the missing heritability of complex diseases Manolio TA. Genetic variants with appreciable frequency in the general population but relatively weak effects. Hunter DJ. Much attention is also currently focused on the role of low frequency variants with potentially relatively large effect sizes. Currently. Chakravarti A. Kong A.461:747–753 Background: Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits. including and extending beyond current genome-wide association approaches. McCarthy MI. Results: Strategies were identified to explore the contribution of rare. GWA chips. the current 40 loci for adult height together explain only around 5% of its heritability. Systematic discovery of these variants is rapidly progressing through the ‘1000 Genomes Project’ and this information is already being applied in new genotyping study designs for obesity. Rotimi CN. ‘missing’ heritability will be explained. Valle D. Clark AG. Guttmacher AE. poorly represent variants with minor allele frequencies <5%. Cox NJ. type 2 diabetes and cardiovascular disease. Most variants confer relatively small increments in risk. Mackay TF. ‘mega’ or greatly expanded GWA studies for several traits are in progress and the results of these more powerful GWA analyses will likely be published in the coming months. Most imminently. Cardon LR. leaving the question how the remaining. Ramos EM. For example. Methods: These authors examined potential sources of missing heritability and propose research strategies.. Conclusion: The search for missing heritability provides a potentially valuable path towards future discoveries. and the corresponding figure for the 18 loci for type 2 diabetes is only 6%. Bethesda. 182 Ken K.

Butler JL. They found that the European obesity-associated intronic variant rs9939609 in FTO showed no association at all with obesity risk in African-derived populations. did show strong associations in African-derived populations. Wilks R. This is because African-ancestry populations show less linkage disequilibrium. Results: Most of the variants. or greater genetic heterogeneity. The 40-plus adult height loci identified in previous GWA studies contained surprisingly few genes implicated in traditional hormone pathways [4]. Keck School of Medicine and Norris Comprehensive Cancer Center. which considerably limits the resolution of fine mapping. many common variants are tightly correlated. variation at the FTO locus and body mass index (BMI) was explored. Methods: In populations of predominantly African ancestry. For example.7% in Caucasians. which explains why those European studies had insufficient power to detect its effects. Zhu X. showed strong evidence of association (p = 2. such as RPGRIP1L. Tayo B. Los Angeles. While in Europeans the ‘FTO-association signal’ arguably extended to covered neighbouring genes. These authors argue for the study of African-ancestry populations. Henderson B. and have been proposed to be useful in fine-mapping studies. Sarpong DF. Jr.. i. In addition to simple confirmation of ‘European’ GWA hits in African populations. The vast majority of GWA studies have been performed in studies of White-European populations. Single nucleotide polymorphisms that are correlated with the signal of association in individuals of European ancestry but that have varying degrees of correlation in Africanderived individuals were genotyped. the more precise location of the underlying causal gene or causal variant.881 Africanancestry individuals. the setting of ‘discovery’ phase studies in non-Europeans may identify new genes or loci for common disease. Waters K. Second.19:2907–2916 Background: Genome-wide association studies have typically been performed in individuals of recent European ancestry. Hirschhorn JN Department of Preventive Medicine. Calif. Le ML. However. Kolonel LN. two FTO variants.e. Akylbekova EL. Population Genetics and Pharmacogenetics 183 . a recent GWA study in 19. firstly to test whether the loci identified in European studies are also relevant in individuals of African ancestry. rs3751812 and rs9941349. including one previously proposed as being functionally important. However. Forrester T. Nguyen TT.61 × 10–6) in a meta-analysis of 9.633 Japanese individuals identified IGF-1 as a major locus for adult height [3]. ruling this out as the causal variant. Haiman CA. rs3751812 and rs9941349.58 × 10–6 and 3. Conclusions: This study both strongly replicated the FTO-BMI association in African-ancestry populations and narrowed the list of potentially causal variants to those that are correlated with rs3751812 and rs9941349 in African-derived populations. The minor allele frequency for the height lowering at IGF-1 was 26% in Japanese subjects compared to only 1. USA Hum Mol Genet 2010. Lyon HN. Liu J. the current study clearly localises FTO as the underlying gene in this locus in African populations. Stram DO. studies of African-ancestry populations may be more efficient for ‘fine-mapping’ studies. In these populations. Cooper R. University of Southern California. McKenzie C.Associations revisited in non-European populations Fine mapping of the association with obesity at the FTO locus in African-derived populations Hassanein MT. than European populations. Taylor HA. showed no significant association with BMI. Populations with recent African ancestry often have less extensive and/or different patterns of linkage disequilibrium (LD). This study illustrates the potential of using populations with different LD patterns to fine map genetic associations and supports the rationale for genetically guided functional studies at the FTO locus. Lettre G. two further FTO variants.

the obesity-susceptibility SNP rs17782313 is located 188 kb downstream of its nearest gene MC4R [5]. inter-chromosomal interactions were detected.. the chromatin conformation is consistent with a fractal globule. This study demonstrates a further possible mechanism of long-range DNA interaction due to genome folding. Although this global arrangement allows insights into chromatin folding principles. Telling A. the ‘average intra-chromosomal contact probability’ for pairs of loci decreased monotonically with increasing genomic distance between the loci. intra-chromosomal contact probabilities were higher than the contact probabilities between different chromosomes. Ong/Cathy Elks . At the megabase scale. Stamatoyannopoulos J. Results: Spatial proximity maps confirm the presence of chromosome territories and the spatial proximity of small. In general. Sabo PJ. 20. which could bring into close approximation distant genes and regulatory sites. 21. Lander ES. Spatial proximity maps of the human genome were constructed at a resolution of 1 megabase. An additional level of genome organization was identified. 17. even beyond distances of 200 Mb. gene-rich chromosomes. gene activity. but commonly re-occurring feature of GWA studies is that variants that are highly robustly associated with disease risks can be located very far away from genes or gene regions. and 22). Gnirke A. Williams L. Cambridge. van Berkum NL. Dorschner MO. Such loci are beyond the traditional range for binding sites of activators or regulators of gene expression. Furthermore. the human genome is roughly 2 m long. For example. Important questions are ‘How does the linear order of basepairs relate to their spatial arrangement?’ and ‘How are genes regulated by distant elements?’ A surprising. Dekker J Broad Institute of Harvard and Massachusetts Institute of Technology. Bender MA. 18. the 9p21 locus is incontrovertibly linked to risk of cardiovascular disease. Lajoie BR. Groudine M. characterized by the spatial segregation of open and closed chromatin to form two genome-wide compartments. Amit I. However. Bernstein B. Conclusions: This study demonstrates the power of the novel Hi-C method to map the dynamic conformations of whole genomes. at this point it is not yet clear whether spatial proximity of two loci necessarily means that there is a functional relationship. a knot-free. methods have explored interactions between target loci. Previously. Mirny LA. which paves the way for exploration of gene-gene interactions. Imakaev M. and the functional state of the cell. and blocks could be identified with either enriched or deleted interactions. Mass.326:289–293 Background: Understanding how chromosomes fold can provide insight into the complex relationships between chromatin structure.New mechanisms: Long-range DNA interactions Comprehensive mapping of long-range interactions reveals folding principles of the human genome Lieberman-Aiden E. Furthermore. yet is in an ‘intergenic’ region devoid of protein-coding genes [6]. Sandstrom R. although it is possible that such regions might encode functional non-coding RNAs or copy-number variants. Ragoczy T. 19. polymer conformation that enables maximally dense packing while preserving the ability to easily fold and unfold any genomic locus. particularly between small gene-rich chromosomes (16. USA Science 2009. In its stretched out form. 184 Ken K. Methods: Hi-C is a novel method that probes the three-dimensional architecture of whole genomes by coupling proximity-based ligation with massively parallel sequencing.

with the presence of both H3 lysine-4 and H3 lysine-27 methylation. but also behaviour. As in the mouse. and mothers’ genes favour small size). Stanier P. whereas a lack of paternally derived growthenhancing GRB10 in brain could explain the weaning phenotype associated with poor suckling. expressed. human GRB10 gene was paternally expressed in brain. The authors suggest that this more complex model of imprinting of GRB10 might have evolved to allow multiple actions of GRB10 to be manifested. an essential part of the placenta involved in nutrient transfer. Hence promoters of fetal growth tend to be paternally expressed. Remarkably. while growth suppressors are maternally expressed [7]. University College London.18:3066–3074 Background: Genomic imprinting may have evolved not only to regulate fetal growth and development. Results: As in mice. The brain-specific paternal expression from the ICR also shows mechanistic similarities with the mouse. GRB10 has long been a candidate to explain further cases of the Silver-Russell syndrome (SRS) of low birth weight and postnatal growth failure.net Hum Mol Genet 2009. In addition to methylation defects in the imprinted H19-IGF2 region.New concepts Reciprocal imprinting in humans Reciprocal imprinting of human GRB10 in placental trophoblast and brain: evolutionary conservation of reversed allelic expression Monk D. contrary to the conflict model (that fathers’ genes favour large offspring size. Hills FA. where this potent growth inhibitor is paternally. UK dmonk@iconcologia. It has been suggested that imprinting evolved to allow the expression of parent-specific considerations regarding the balance of fetal survival to cost or risk to the parent. as the authors point out maternal uniparental disomy (mUPD7) and small duplications of 7p12 encompassing GRB10 have been reported in ~10% of cases of SRS. Arnaud P. Grb10 is a potent growth inhibitor. This conserved CpG island is DNA-methylated on the maternal allele and is marked on the paternal allele by developmentally regulated bivalent chromatin. Moore GE Clinical and Molecular Genetics Unit. Feil R. Institute of Child Health. overexpression of maternally derived GRB10 in trophoblast would limit fetal growth. Population Genetics and Pharmacogenetics 185 . The murine growth factor receptor-binding protein 10. Frost J. Indeed. London. They further suggest that chromatin defects at the GRB10 DMR leading to lack of paternal GRB10 expression in brain could potentially result in other cases of non-syndromic postnatal growth restriction. rather than maternally. from a promoter region at which we find no allelic chromatin differences. Maternal allele-specific expression was seen only in placental villous trophoblasts. Conclusions: The strong conservation of the opposite allelic expression in placenta versus brain supports the hypothesis that GRB10 imprinting evolved to mediate diverse roles in mammalian growth and behaviour. Its gene displays reciprocal imprinting in mice. This study now finds that GRB10 is indeed exclusively maternally expressed. Hence. in human brain GRB10 shows the opposite pattern of exclusive paternal expression. as in the mouse model. we explored its conservation in humans. and specifically in the placental cells responsible for nutrient transfer. resulting in IUGR. GRB10 shows biallelic expression in most tissues except brain. However. the maternal transcripts originate from several kilobases upstream of the imprinting control region (ICR) of the domain. All other fetal tissues tested showed equal expression from both alleles. Methods: To assess the biological relevance of this reciprocal pattern of imprinting.

-thalassaemia.ac. UK mrs@sanger. Positively selected haplotypes of EGLN1 and PPARA were significantly associated with the decreased hemoglobin phenotype that is unique to this highland population. Witherspoon DJ. Wellcome Trust Sanger Institute. Methods: 31 unrelated Tibetans were genotyped for 1 million single nucleotide polymorphisms (SNPs) using the Affymetrix Genome-Wide Human SNP 6. but their genetic basis remains unknown. and hemoglobin C persist by protecting against malaria mortality.Food for thought Genetic adaptation to altitude Genetic evidence for high-altitude adaptation in Tibet Simonson TS. This is purportedly due to more efficient oxygen transport systems. this study identified evidence for evolutionary selection of several genes with a priori functional roles in hypoxia response. Futreal PA Cancer Genome Project. USA Science 2010. Epub ahead of print Background: Tibetans have lived at very high altitudes for thousands of years. Further studies of these genes may lead to new approaches for the treatment of hypoxia-related diseases. Yang Y. By comparison of genome-wide SNP frequencies in Tibetans to those in neighbouring lowland populations. Xing J.458:719–724 Background: All cancers arise as a result of changes that have occurred in the DNA sequence of the genomes of cancer cells.uk Nature 2009. Qin G. Salt Lake City. Prchal JT. Over the past quarter of a century much has been learnt about these mutations 186 Ken K. Campbell PJ. Utah. Cambridge. Jorde LB. however the specific mechanisms and the genetic basis have been elusive. In contrast to other nonadapted populations who increase haemoglobin levels and maintain oxygen saturation in response to hypoxia (with often adverse consequences). Since the beginning of the Himalayan climbing era. and they have a distinctive suite of physiological traits that enable them to tolerate environmental hypoxia. Bai Z. the cross-population extended haplotype homozygosity (XP-EHH) statistic was used to compare highland Tibetans to the combined HapMap Chinese (CHB) and Japanese (JPT) lowland populations. New paradigms The other genomes we carry The cancer genome Stratton MR. high-altitude Tibetans show profound arterial hypoxia yet they maintain normal aerobic metabolism. Ge R Eccles Institute of Human Genetics. To pinpoint loci under positive selection. Remarkably. University of Utah School of Medicine. There are yet few specific examples of genetic adaptation. Huff CD. Yun H. These authors describe that the Tibetan highlands are one of the most extreme environments inhabited by humans. These phenotypes are clearly the result of adaptation to this environment. while G6PD deficiency. which is consistent with the previously suggested mechanism of adaptation. the anecdotal extraordinary physical performance at high altitude of Sherpas has intrigued climbers. Hinxton.7 g/dl reduction in haemoglobin concentration. Genetic variants that confer lactase persistence are thought to have evolved with the expansion of agricultural societies. Results: There was evidence for positive selection in several regions that contain genes whose products are likely involved in high-altitude adaptation. Lorenzo FR.0 Array. Ong/Cathy Elks . each additional copy of an advantageous haplotype at either EGLN1 (a suppressor of HIF target genes and recently implicated in growth plate processes) or PPARA (known to play a role in lipid metabolism) was associated with a massive 1. Conclusions: Identification of these genes provides support for previously hypothesized mechanisms of high-altitude adaptation and illuminates the complexity of hypoxia response pathways in humans.

Ouwehand WH. Barrett JC.6%) of the 22. Intricate DNA repair mechanisms usually reduce the impact of somatic mutations. Hum Mol Genet 2010. Erlich HA. Hunter DJ. Kamatani Y. Cooper JD. Wheeler E. De S. Jarvelin MR. Palmer CN. Weedon MN. Doney AS. Ring SM. Groop L. Bergmann S. Scheet P. Wareham NJ. Vollenweider P. Papadakis K. Daigo Y. Illig T. Kubo M.41:703–707. Over the next few years several hundred million more will be revealed by large-scale. McArdle WL. Loos RJ. Scherag A. Ong KK. Dominiczak A. Johnson T. Labrune Y. Sims MA. Kraft P.000 protein-coding genes in the human genome have been reported to show recurrent somatic mutations in cancer with strong evidence that these contribute to cancer development. Deloukas P. Hunt SE. Vaxillaire M. Conclusions: These studies will provide us with a detailed and comprehensive perspective on how individual cancers have developed and will provide new directions for the treatment of cancer. 4. complete sequencing of cancer genomes.e. Palmer CN.000 to 100. ranging from the microbiomes in body cavities to somatic genomes in our cells. Barroso I. Nica AC. Smyth DJ. Herrera B. These authors now describe that with the recent advent of whole-genome sequencing of DNA from cancer cells it is now recognised that cancer genomes may carry between 1. Morris AD. References 1. Neville MJ. Clayton DG. Sandhu MS. Freathy RM. Nat Gen 2009. Morris AD. Stevens S. Recent studies indicate that there may be as many as 20 driver mutations in individual cancers. Bennett AJ. DNA rearrangements. Bouatia-Naji N. moving into an era in which it will be possible to obtain the complete DNA sequence of large numbers of cancer genomes. Chanock SJ. Pouta A. and ‘passenger’ mutations without any growth advantage. Sladek R. Timpson NJ. Prokopenko I. Ridderstrale M. Hattersley AT. Diabetes 2009. Elliott P. Froguel P: Genetic variant in HK1 is associated with a proanemic state and A1C but not other glycemic control-related traits. Wichmann HE. Cooper C. Wiesner S. Zeggini E. Heid IM. Takahashi A. Zhao JH. Levy-Marchal C.e. Strachan DP. Tobias JH. Dina C. Rayner NW. Ohmiya H. Hankinson SE. Munroe PB. Matsuda K. Furthermore. Meyre D. Marre M. Rich SS: Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Waterworth DM. Bonnefond A. Mohlke KL. detection and monitoring. Khaw KT. We are now. Samani NJ. In addition to our ‘own’ germ-line genome (i. Waterworth DM. Plagnol V. drug response and chemotherapy resistance. Frayling TM. Jacobs KB. Chevre JC. Ness AR. Hall AS. Stevens H. Cauchi S. Abecasis GR. Somatic mutations may be classified into two groups: ‘driver’ mutations that confer a growth advantage on the cancer cell. Mangino M. Pedersen O. Hebebrand J. Horber F.58:2687–2697. Sadaf Farooqi I. Inouye M.and the abnormal genes that operate in human cancers. Mooser V. Walker NM. Froguel P. and copy number increases and reductions. Balkau B. however. and germ-line mutations in these housekeeping genes explain the heritability of cancer susceptibility. Akolkar B. Frayling TM: Genome-wide association analysis identifies 20 loci that influence adult height. Kaakinen M. Meitinger T. Sanna S. Weedon MN. Yamamoto K. McCarthy MI. Dina C. Todd JA. 5. Song K. Soranzo N.000 mutations. Jackson AU. Ghori J. Smith GD. considerably more than the 5–7 previously predicted. Li S. Hadley D. At least 350 (1. Li S. cancer genomes may have incorporated exogenous viral DNA. insertions or deletions of small or large segments of DNA.19:2303–2312. Uda M. Dermitzakis ET. Luben RN. Nagaraja R. Evans DM. Methods: This paper reviews the history and recent rapid progress in this field and gives comments on its future directions. Beckmann JS. Schuilenburg H. Yuan X. Bergmann S. Voight BF.000 somatic mutations from cancer genomes have been reported in the quarter of a century since the first somatic mutation was found in HRAS. Collins FS. Lecoeur C. Hercberg S. Kamatani N: A genome-wide association study in 19 633 Japanese subjects identified LHX3-QSOX2 and IGF-1 as adult height loci. Attwood AP. Lyon HN. One of the most famous somatic genetic disruptions (i. Wheeler E. Karpe F. Ouwehand WH. that inherited from our parents). Bingham SA. Mangino M. Connell JM. Loos RJ. Johnson T. Owen KR. McGinnis R. Sandhu MS. Berndt SI. Lango H. Nerup J. there is increasing evidence of the potential disease impacts of the ‘other genomes’ that we carry. Hattersley AT. Cauchi S. These somatic mutations range from single basepair substitutions. Albai G. Lamina C.40:575– 583. Caulfield MJ. Nierras C. Okada Y. Czernichow S. Munroe PB. Gieger C. Brown M. Nat Genet 2008. Lindgren CM. prognosis. Hall AS. Concannon P. O’Rahilly S. Ganz Vogel CI. Gallois Y. Morahan G. Bochud M. Speliotes EK. Potter S. Keniry A. Freathy RM. Zhao JH. Wallace C. Evans DM. Inouye M. Groves CJ. Nakamura Y. Gwilliam R. Syddall HE. Tuomilehto J. Hirschhorn JN. Meyre D. Wallace C. Jolley JD. Population Genetics and Pharmacogenetics 187 . Hayes RB. acquired post-meiosis) in cancer etiology is the ‘Philadelphia translocation’ between chromosomes 9 and 22 in chronic myeloid leukaemia. Shields B. Lindgren CM. Day I. Beckmann JS. Charpentier G. Prokopenko I. Riveline JP. Samani NJ. Pociot F. Schlessinger D. Results: Approximately 100. Wraight VL. Willer CJ. The authors describe that these studies will generate new insights into specific disease phenotypes. Elliott P. and will also have acquired epigenetic changes. Randall JC. Marchini J. Jarvelin MR. Hadjadj S. Hinney A. 3. Hu FB. Caulfield M. Hosono N. Elliott KS. Boehnke M. Soranzo N. Tichet J. Farrall M. Qi L. Julier C. 2. Perry JR. Teichmann SA.

35:226–232 188 Ken K. weight and risk of obesity. Deloukas P. Am J Reprod Immunol 1996. Barroso I: Common variants near MC4R are associated with fat mass. McCarthy MI. Ong/Cathy Elks . Waeber G. Wareham NJ. Mooser V. Nat Genet 2008. Haig D: Altercation of generations: genetic conflicts of pregnancy.362:1736–1737 7. McPherson R: Chromosome 9p21 and coronary artery disease.Vollenweider P. N Engl J Med 2010.40:768–775 6.

and clear evidencebased guidance for our endocrine investigation protocols. however only the treatment study limb which showed a significant elevation in all treatment periods was continuously 8 µg/kg/day (p < 0.05 vs. Quero J. After 14 days. UK This year’s evidence-based medicine chapter is different yet again in flavor from last year [1]. Maria Fareri Children’s Hospital at Westchester Medical Center.. >7 µg/dl (90 nM/l. Ares S. Over 2. Kok JH. The incidence of necrotizing enterocolitis was higher in the combined 8 µg/kg/day arms (p < 0. Retinopathy of prematurity was significantly lower in all the four thyroid hormone treatment arms compared with the combined placebo and iodine arms (p < 0. and were entered into a masked randomized trial <24 h of birth to one of six study arms (n = 20–27 per arm): placebo (vehicle: 5% dextrose). 1 µg/kg/day of T3 was added during the first 14 postnatal days to the T4 and was infused with 1 mg/ml albumin to prevent adherence to plastic tubing. Methods: Eligible subjects had gestational ages between 24 and 28 weeks. USA Edmund_lagamma@nymc.124:e258–268 Background: Transiently low levels of thyroid hormones have been shown to be associated with higher rates of cerebral palsy and cognitive impairment in approximately 50% of neonates born 24–28 weeks’ gestation. other arms). Valhalla. TT4 remained elevated in the first 7 days in all hormone-treated subjects (p < 0. definite evidence for the efficacy of insulin pumps and school-based obesity interventions. New York Medical College.002 vs. Mechanism of the year Treatment of hypothyroidism in preterm infants Phase 1 trial of four thyroid hormone regimens for transient hypothyroxinemia in neonates of <28 weeks’ gestation La Gamma EF. Paneth N Department of Neonatal-Perinatal Medicine. .edu Pediatrics 2009. Together with large population studies and more RCTs of long-term GH treatment reporting at final height. Hong T.002 vs. This study aimed to identify whether any of four thyroid hormone supplementation regimens could raise TT4 and FT4 levels and improve neurodevelopmental outcome without suppressing TSH (biochemical euthyroidism).Y. Golombek SG.05 vs. Regional Neonatal Center. all other groups). placebo or iodine arms). p < 0. yet warnings about GH use in others. van Wassenaer AG. Rahbar MH.04). Results: FT4 levels were high in the first 7 days in all hormone-treated subjects. We see the benefits of GH on the cardiovascular system in some groups of children.05 vs. Unexpectedly the duration of mechanical ventilation was significantly lower in the continuous 4 µg/kg/day T4 arm and in the bolus 8 µg/kg/day T4 arm (p < 0. we have important new evidence in the treatment of preterm infants with thyroxine. de Escobar GM. Butler University College London Hospital and UCL Institute of Child Health. remaining arms).Evidence-Based Medicine in Pediatric Endocrinology Gary E. both 8 µg/kg/day arms as well as the continuous 4 µg/kg/day arm produced a sustained elevation of the mean and median TT4. Fisher DA. The selection was based on searching under the terms pediatric endocrinology and again under clinical trials. placebo).000 journal articles were identified from which this selection has been made with the needs of you the clinician in mind. The lowest suppression of TSH occurred during the continuous infusion of 4 µg/kg/day T4 arm. N. potassium iodide (30 µg/kg/day) and continuous or bolus daily infusions of either 4 or 8 µg/ kg/day of T4 for 42 days.

for TT4 concentration as 77 nmol/l.0 ± 0. p = 0. The study protocol evaluated changes in dual-emission x-ray absorptiometry. pelvic ultrasound.39 vs.03).13 ± 0. Tanner staging. and lipids in Turner syndrome (TS) as the optimal route of estrogen delivery is unknown. This trial accomplished the goal of elevating thyroid hormone blood levels in extremely premature neonates to exceed a predefined target threshold without completely suppressing TSH.. 190 Gary E. Riley Hospital for Children. IGF-1.12 ± 0.2 ± 4. This was most successfully achieved by using continuous 4 µg/kg/day T4 as replacement therapy. 66% of subjects in the TD group had a mature uterus compared with 0% in the oral group. 1. Perkins SM. indicating overtreatment and suggesting that T3 supplementation is unnecessary.1 vs.04. as thyroid hormone effects on vascular and retinal development in both animals and humans have been described. This was associated with several improved clinical parameters suggesting that T4 was of benefit.0 ± 4. Indianapolis. 5. and for TT3 concentration as 0.4 ml. Z-score 0. pubertal development. Future trials will be needed to evaluate the long-term neurodevelopmental effects of such supplementation. 0.94:2009–2014 Background: This study aimed to compare conjugated oral versus transdermal estrogen (TD E2) on bone accrual. meriting future investigation. bone mineral density 0. This study was an elegantly designed masked randomized trial investigating two T4 dosage schedules in different delivery modes (bolus or continuous). a statistically significant reduction in retinopathy of prematurity was found compared with the iodine/placebo arms.8 ± 0.39 cm. uterine growth.9 vs.edu J Clin Endocrinol Metab 2009. Ind. with or without initial T3 co-supplementation and designed to avoid overtreatment which has also been reported as harmful. Butler . 4. TD E2 also produced better uterine growth than the oral group at 1 year (length 4.01 g/cm2. Supplementation of the prohormone T4 with the active hormone T3 for the first 14 postnatal days raised the TT3 blood level but was depressed by TSH values to or below the assay’s level of detection. IGF-1. growth velocity.8 nmol/l.003. Furthermore. p = 0. p = 0.0 ± 1.7 ± 0. 0. No other significant differences were seen.06 ± 0. The authors describe this as intriguing. Dimeglio LA. The goal for a minimum threshold for FT4 concentration was identified as 19 pmol/l.7 years were randomized to conjugated oral estrogen or TD E2. After 12 months.01 vs. The authors’ view is that biochemical euthyroidism is the minimum thyroid hormone threshold associated with a reduced risk of neonatal illness or better long-term neurodevelopment.02). New paradigms Patches versus pills Conjugated oral versus transdermal estrogen replacement in girls with Turner syndrome: a pilot comparative study Nabhan ZM. Results: TD E2 therapy resulted in a significantly greater change in spine bone accrual parameters at 12 months compared with conjugated oral estrogen (bone mineral content 9.9 g.3 ± 0.98 ± 0. Eugster EA Section of Pediatric Endocrinology/Diabetology. and lipid profile at 6 monthly intervals over 1 year. and in any case does not give any guidance in the need for T4 replacement in the transient hypothyroidism of prematurity. Qi R. p = 0. Conclusion: Because extremely preterm low-birthweight infants frequently suffer severe systemic illness and experience changing biological requirements during a period of critical brain development. p = 0.4 vs.Continuous supplement of low-dose thyroid hormone (4 µg/kg/day) for 42 days caused elevation of TT4 with only a modest suppression of TSH. the 8% mortality rate in the two 4 µg/kg/day arms was half that of the placebo or iodine arms (16%) and also less than half that of higher dosage arms (22%). Indiana University School of Medicine.004. USA znabhan@iupui.1. Methods: Twelve prepubertal GH-treated girls aged 14. using hormone values based either healthy fetal levels or levels observed in term neonates to determine thyroid status is probably inappropriate. In addition. volume 22.

625 mg every day for the second 6 months. Monash University. Quality of life measures suggest that CSII is preferred over MI. Study investigators were contacted to obtain missing information. but no differences in height velocity.CD005103 Background: This review aimed to assess the effects of continuous subcutaneous insulin infusion (CSII) compared to multiple insulin injections (MI) in people with type 1 diabetes mellitus. Shaw J Australasian Cochrane Centre. the authors discuss publications which cite a lack of evidence for a difference on bone mineralization between the different oral preparations.. Clayton. but that TD E2 had improved bone mineral density in young adult patients. Conjugated oral estrogen was administered at a dose of 0.3 mg every day for the first 6 months followed by 0. Page M. long-term studies. The significant apparent benefit of TD E2 on more rapid uterine maturation and bone accrual could be as a result of incorrect assumptions as to the bioequivalent of each estrogen preparation. It is recognized that synthetic estrogens (ethinyl estradiol) are also frequently used for the induction of puberty in TS. EMBASE and CINAHL. Monash Institute of Health Services Research. These doses were chosen based on published equivalences. New hope Do we now have the evidence base for insulin pumps? Continuous subcutaneous insulin infusion (CSII) versus multiple insulin injections for type 1 diabetes mellitus Misso ML. whereas the TD E2 group was treated with a 0. IGF-1. Methods: Electronic searches were made of The Cochrane Library. The authors acknowledge that this is a small-scale pilot study.0375-mg patch twice a week for the second 6 months. O’Connor D. MEDLINE. Studies were included if they were randomized controlled trials comparing CSII with three or more insulin injections per day (MI) in people with type 1 diabetes mellitus. There was a statistically significant difference in glycosylated hemoglobin A1c (HbA1c) favoring CSII (weighted mean difference –0.3 mg alternating with 0. morbidity and costs. Evidence-Based Medicine in Pediatric Endocrinology 191 .Conclusion: In girls with TS. Egberts KJ. There were no obvious differences between the interventions for non-severe hypoglycemia. The onset of type 1 diabetes mellitus may occur at any age and it is one of the commonest chronic diseases of childhood and adolescence. no information is available on mortality. but severe hypoglycemia appeared to be reduced in those using CSII. This pilot study provides a good evidence base and platform for larger scale research programs to confirm that TD E2 appears to be a significantly better modality for estrogen replacement in TS and potentially other hypogonadal girls. it is vital that effective treatment regimes are available. Still much controversy surrounds the choice of estrogen preparation to induce puberty in girls with TS and by inference in chromosomally normal hypogonadal girls. They were subsequently assessed by two authors who independently evaluated the risk of bias and extracted characteristics of selected studies. this pilot study showed that TD E2 resulted in faster bone accrual in the spine and increased uterine growth compared with conjugated oral estrogen.1 to –0.025-mg patch twice a week for 6 months followed by a 0. Australia Cochrane Database Syst Rev 2010. This preliminary information for optimizing estrogen replacement in this population may inform further large-scale. Since there are currently no known interventions to prevent onset. Results: 23 studies randomized 976 participants with type 1 diabetes to either intervention. Adverse events were not well reported. Generic inverse variance meta-analyses using a random-effects model were performed. No significant difference was found for weight. Vic.4). but the reason for inclusion here is that it is the first prospective randomized controlled trial comparing conjugated oral versus TD E2 for pubertal induction to be performed.3% (95% CI interval –0. lipid parameters or degree of breast development attained between the two groups were reported.

thyroid ultrasonography and a 99mTc thyroid scintiscan were performed. Czarnywojtek A. free thyroxine (FT4). Cost-effectiveness data are also needed to support choice and for healthcare budgeting purposes. Pietz L. The remaining archival 3 cases were diagnosed with the use of 131I scintiscan pre. Szaflarski W.and post-TSH stimulation. The Health Technology Assessment report and the National Institute for Clinical Excellence (NICE) guidelines on the use of CSII are methodologically rigorous.2–0. Moczko J. This may be as a result of the long-lasting TSH overstimulation. Szczepanek E. Given the limitations of these previous systematic reviews. large-scale and methodologically rigorous studies are needed to determine the effect of CSII and MI on outcomes such as hypoglycemia. This paper provides a long-term outlook in patients with a rare abnormality of the thyroid gland. There may be benefit in using CSII over MI for improving glycaemic control and improving health-related quality of life in people with type 1 diabetes. Zabel M. reductions of diabetes late complications. a higher incidence of functional. Non-severe hypoglycemic events do not appear to be reduced with CSII. with a higher FT3/FT4 ratio in comparison with the controls. Methods: Serum TSH. There is insufficient evidence regarding adverse events. this review has considered these factors and used specific methodology and criteria outlined by the Cochrane Collaboration in their intent to present a comprehensive systematic review to assess the effects of CSII compared to MI. mortality and cost which are all vital in deciding which treatment regimen to choose. Metabolism and Internal Medicine. The aim of the study is to provide the first controlled systematic analysis of 40 patients with THA in comparison with 80 subjects with a fully developed thyroid gland out of 2. and autoimmune thyroid disorders was seen in THA patients compared controls (p < 0. Conclusion: This study showed that individuals with THA are more likely to develop thyroid pathology. free triiodothyronine (FT3). Meta-analyses were performed where possible and feasible. Of the 40 patients. mortality. clinical significance.05).159 participants from a cross-sectional population-based thyroid screening program. Niedziela M. and thyroid autoantibodies were measured in all subjects. with 7:1 female-to-male ratio. however the most up-to-date search strategies were conducted in 2007 and therefore do not include recent randomized controlled trials [2]. Non-severe hypoglycemic events do not appear to be different between either treatment methodology. using validated scales. New concerns Increased risk of thyroid pathology in patients with thyroid hemiagenesis: results of a large cohort case-control study Ruchala M. Nowicki M. Poznan.162:153–160 Background: Thyroid hemiagenesis (THA) is an anomaly resulting from the developmental failure of one lobe of the thyroid. Although conducted in a moderately iodine- 192 Gary E. firm recommendations as to whether CSII is superior in the management of people with type 1 diabetes are not possible. morbidity and costs. and management of patients in whom THA is identified are still unclear. In 37 of the THA patients. Until evidence is available for these outcomes. Poland mruchala@ump. Butler . Patients with THA were usually clinically euthyroid but levels of TSH and FT3 were significantly higher. University of Medical Sciences. The diagnosis of THA should be followed by systematic observation and adequate levothyroxine treatment in patients with elevated TSH level.edu. Sowinski J Department of Endocrinology.pl Eur J Endocrinol 2010. morphological. followed by fine-needle aspiration biopsy if indicated. It is important to note that there is insufficient evidence regarding adverse events. mortality. The prevalence of THA is estimated to be 0. Results: In this study. a considerable prevalence of women with THA was noted. Kohrle J. Long-term.Conclusion: There is some evidence to suggest that CSII may be better than MI for glycemic control in people with type 1 diabetes. diabetes late complications and other adverse effects.025%. 35 had left-sided agenesis. Furthermore. The etiology.

NHANES III. Skakkebaek NE. Variation in reproductive hormones and in BMI did not explain these marked changes.hosp. Department of Growth and Reproduction. from the pediatric perspective. Petersen JH.095 girls aged 5. luteinizing hormone. Other factors yet to be identified may be involved. even though 6 proceeded to surgery due to uncertainties on the initial biopsy or goitre size. Age at entering pubertal breast stages 2–5. Results: The onset of puberty (Tanner breast stage 2+) occurred significantly earlier in the 2006 cohort (estimated mean age 9. Older patients were more likely to have autoimmune disease and compensatory hypertrophy. Serum FSH and LH did not differ between the two cohorts at any age interval.0 years were studied in 1991–1993 (1991 cohort.and sex-matched control group. as in this study via a population screening program. and menarche was documented for the two cohorts. thus excluding obesity as a variable. n = 1. This difference remained significant after adjustment for BMI. so. the younger patients (<25 years) were less likely to have compensatory hypertrophy of the residual thyroid lobe and a lower incidence of autoimmune disease compatible with the congenital etiology. This study presents new European data systematically collected from the same region and by the same research group at the beginning over a 15-year period up to the present. secular trend analyses are often limited by poor comparability between studies over different time periods and counties. The study looked at patients between 12 and 79 years of age. even in familial cases ongoing follow-up is indicated in these patients.dk Pediatrics 2009. has been controversial. Juul A Rigshospitalet. However. Evidence-Based Medicine in Pediatric Endocrinology 193 . THA was more frequently associated with hyperthyroidism and higher TSH levels and thus indicating levothyroxine replacement. and measurement of height and weight. no malignancies were found.42 and 13. and folliclestimulating hormone was done. n = 995). However.88 years). this study was of a prospective design with an age.86 years) compared with the 1991 cohort (estimated mean age 10. is able to give us an idea of long-term prognosis if THA is identified.13 years in the 1991 and 2006 cohorts. Denmark lise.aksglaede@rh. In the 22 patients who had fine-needle aspiration biopsy of suspicious lesions on ultrasound scan. Sorensen K. Conclusion: This study demonstrated significantly earlier breast development but less of a reduction in the age at menarche among a recent population of girls compared with a similar one 15 years earlier. Estimated ages at menarche were 13. Puberty was staged by palpation of glandular breast tissue. The debate also continues as to the upper normal level for plasma TSH and whether earlier levothyroxine substitution may alter outcome in some patients with this condition.6–20. Copenhagen.deficient area of Poland. Methods: 2. pubic hair stages 2–5.to 10-year-old girls from the 2006 cohort in comparison with girls of the same age from the 1991 cohort.123:e932–939 Background: Data published showing an earlier onset of breast development in American girls. all controls being recruited from the screening program. In 17/40 the anomaly was detected by screening or incidentally.100) and 2006–2008 (2006 cohort. and blood sampling for estradiol. respectively. However. In the absence of a clear genetic cause for THA. estradiol levels were significantly lower in 8. Concepts revised The age of adolescence Recent decline in age at breast development: the Copenhagen Puberty Study Aksglaede L.

Conclusion: Estimated mean age at the onset of puberty has declined significantly over the past 15 years.025.9 years were studied in 1991–1993 (1991 cohort. Significantly higher LH levels were found in the 11. p < 0.66 years (95% CO 11. n = 824) and 2006–2008 (2006 cohort. Butler . 11. Although a series of publications from the USA and other European countries had suggested a lowering of the age of the onset of puberty.361) in 2006–2008. testosterone and estradiol levels were lower at maturity in the recent compared with the historical cohorts. the BMI effect cancels itself out in girls when controlled for. The relationship between reproductive hormones and clinical pubertal changes is important to mention as the earlier physical changes were not matched by rises in gonadotrophins or sex hormones. Blood samples were analyzed for LH.001.3 years whereas age at B2 is 1 year earlier.Recent changes in pubertal timing in healthy Danish boys: associations with body mass index Sorensen K.020). no conclusions could be made about the age of the onset of puberty due to the lack of comparable data. Copenhagen. Results: The mean age of the onset of puberty (attainment of testicular volume >3 ml) of 11. However. Thus the latter 20% of boys entering puberty do not seem to show this secular trend.8–19. identified possible secular trends in male puberty in the 1990s. 194 Gary E. Paradoxically. This study aimed to evaluate secular trends in pubertal onset during the recent 15 years and their relation to body mass index (BMI) in boys. whereas earlier pubertal development in boys is limited to those beginning before age 12. paradoxically. boys going into puberty later are the ones where BMI rises. Contrary to popular myth.95:263–270 Background: The American population-based study. The age of B2 is shifted to the left across the whole age spectrum. FSH.290 (0.regionh.08). but this was not found with testosterone. NHANES III.5 years. Knowledge about the timing of sexual development in children and adolescents and the causes and consequences is fundamentally important not only for the practice of medicine but in society as well. Copenhagen University Hospital. Clearly there is much need for further exploration and research. there is a consistent finding that the tempo or transit time through the pubertal process is not necessarily accelerating at the same pace [3]. The BMI Z-score increased significantly from 0. testosterone. p = 0. and there is no secular trend here as discussed above.92 years (11.82) occurred significantly earlier in 2006–2008 than in the 1991–1993 cohort.49–11.044 (–0.528 boys aged 5. The picture is clearly more complicated than was expected. Interestingly. This decline was associated with the coincident increase in BMI. Petersen JH. n = 704) at a tertiary centre for pediatric endocrinology. Methods: This was a cross-sectional study in 1991–1993 and a combined cross-sectional and longitudinal study in 2006–2008 (The Copenhagen Puberty Study).104) in 1991–1993 to 0. Aksglaede L. Juul A Department of Growth and Reproduction. but the value of this study is its carefully designed methodology and attempt to find the evidence base upon which we can improve our knowledge of childhood and develop our clinical practice.to 16-yearold boys from 2006–2008 compared with 1991–1993 (p = 0.dk J Clin Endocrinol Metab 2010. Genital and pubic hair stages as well as testicular volume using an orchidometer were evaluated. and SHBG.Soerensen@rh.016 to 0. This is evident in this study at least in girls with a reduction in the age at menarche by only 0. and the early developers in boys are not the ones showing a rise in BMI. There are different tempo patterns emerging between boys and girls too. Denmark kaspar.219–0. pubertal onset and LH levels did not differ significantly between study periods after adjustment for BMI. 1.76–12. obesity does not appear to be implicated in these trends.

Diagnostic criteria based on the cut-offs identified by ROC analysis were combined. Calcagno A. Italy J Clin Endocrinol Metab 2009. Methods: 48 children (median age 4. Istituto di Ricovero e Cura a Carattere Scientifico G Gaslini Institute. 48 of the subjects had isolated GHD or one additional pituitary defect and normal MRI or anterior pituitary hypoplasia (low likelihood GHD group). However. di Iorgi N.636. Giannina Gaslini Institute. Median GH peak after glucagon was similar between patients with multiple pituitary hormone deficiency and those with isolated GHD and between subjects with and without structural hypothalamic-pituitary abnormalities.Important for clinical practice Growth in our knowledge of tests The glucagon test in the diagnosis of growth hormone deficiency in children with short stature younger than 6 years Secco A. and IGF-1 were evaluated as single or combined tests in 79 subjects with childhood-onset GHD (median age. Calandra E. area under the curve (AUC) = 0. Casini MR. and structural hypothalamic-pituitary abnormalities in 17. The 2007 Consensus Statement had suggested a peak GH to the ITT of <6 µg/l as being the diagnostic cutoff for permanent GHD. Lorini R. and IGF-1 in the diagnosis of permanent GH deficiency (GHD) in young adults with childhood-onset GHD. Calandra E. Methods: ITT.7 and 3. Genova. although further validation was recommended.92). specificity 94%. Results: The median GH peak response to glucagon (13. University of Genova. Parodi S. was to evaluate the accuracy of the insulin tolerance test (ITT). Frassinetti C. There was a negative correlation between age at diagnosis and the magnitude of the GH peak after glucagon (r = –0. Loche S.0 years).0001). University of Genova. Genova. 12-h SNGH. specificity Evidence-Based Medicine in Pediatric Endocrinology 195 . Instituto di Ricovero e Cura a Carattere Scientifico. Ghezzi M. Lorini R. Napoli F.e. Maghnie M.0 SD score) with GHD confirmed by a peak GH to ITT and arginine <10 and (median 4. 20 subjects (group 1) had a GH peak after glucagon which was <10 µg/l and 28 subjects (group 2) had peak GH levels of >10 µg/l without significant clinical or biochemical differences between the two groups. p < 0.94:4195–4204 Background: The aim of this study. mean 12-h spontaneous nocturnal GH (SNGH). Frassinetti C. mean 12-h SNGH of 1. Ghezzi M. Radetti G Department of Pediatrics. conducted in two pediatric endocrinology centers. Maghnie M Department of Pediatrics.0001). considering as positive a subject who was positive on each test) and in parallel (i. both in series (i.94:4251–4257 Background: The aim of this study. Results: Receiver operating characteristic curve analysis showed the most accurate parameters for the diagnosis of GHD was a peak GH in the ITT of 5. Italy J Clin Endocrinol Metab 2009. Fratangeli N. Leitner Y. Benassai M.e.5 µg/l) was significantly higher than that observed after ITT and arginine (p < 0. performed in two pediatric endocrinology centers. and 31 subjects had structural hypothalamic-pituitary abnormalities or multiple pituitary hormone deficiencies (high likelihood GHD). 18.6 µg/l or lower (sensitivity 77%. Magnetic resonance imaging had showed normal hypothalamic-pituitary anatomy in 24 children. isolated anterior pituitary hypoplasia in 7. di Iorgi N.20 µg/l or lower (sensitivity 90%. Gastaldi R. Parodi S. Reassessment of the growth hormone status in young adults with childhood-onset growth hormone deficiency: reappraisal of insulin tolerance testing Secco A. was to investigate the diagnostic value of the glucagon test as an alternative to insulin tolerance test (ITT) and arginine test in children younger than 6 years with GHD as few studies have addressed the diagnostic role of the glucagon test in children when GH deficiency (GHD) is suspected. the differing results between GH levels and those following ITT and arginine in this study suggest that normative data for this test in young children need to be established. Napoli F. considering as positive a subject who was positive on at least one test). Conclusion: Glucagon can effectively release GH and can be used to evaluate somatotroph function in young children with short stature.4 µg/l respectively) subsequently underwent a glucagon stimulation test.2 years and median height –3.

AUC = 0. demonstrating that ITT is a reliable test for evaluation of GH secretion and confirming that the GH peak adopted by the 2007 Consensus is adequate for the definition of permanent GHD in young adults [5].93).8 SDS with 96% specificity. Butler . In the absence of normative data for GH responses to pharmacological stimuli in this age group.8 SD score or lower (sensitivity 81%. suggesting that a single IGF-1 evaluation may have a role in the definition of GH status. Paris. p = 0. the mean GH response to glucagon was higher than that observed after ITT or arginine. In this study.3 vs. together with two or more pituitary hormone deficiencies. Trivin C. Despite decades of reliance on GH stimulation tests.0001). Among the various GH stimulation tests. Breart G. but that normal IGF-1 concentrations do not exclude GHD in approximately 20% of young adult patients.6 µg/l performs well as an accurate diagnostic strategy for determining persistent GHD in young adults with childhood-onset GHD. In contrast.6 µg/l or lower and to arginine of 3. and IGF-1 of –2. 15 (35. Charkaluk ML. but the results are normal in more than 80% of cases and it is stressful and expensive. Overnight measurement of spontaneous GH secretion was not determined to be cost-effective. Therefore. so the aim was to identify clinical and plasma predictors of LO-CAH among patients presenting with PP. this reinforces the caution to exert in the interpretation of GH stimulation tests. In addition. One limitation of these analyses is that GH assay used in many previous studies is now obsolete.6 µg/l with an AUC of 0. The presence of anatomical abnormalities on MRI. and thus. this predictive accuracy could be overestimated because it was based on observations of a cut-off point derived from retrospective data. Measurement of IGF-I provides useful information in direct parallel to the degree of GHD. However. by standard criteria. whereas ROC analysis applied to GH peaks obtained during childhood showed that a peak GH of about 3 µg/l after at least one stimulation test offered good accuracy for the discrimination of patients with a high likelihood of GHD in adult life from those who might subsequently normalize GH secretion.92. France J Clin Endocrinol Metab 2009. AUC = 0. Specificity of GH peak and IGF-1 levels are similar. The authors did not find that clinical parameters at the time of initial diagnosis during childhood played any role in the prediction of GH status after adult height attainment. the same cut-off levels cannot be adopted. This could suggest that the GH-releasing effect of glucagon in young children with congenital GHD is greater than that of ITT and arginine.1 µg/l or lower at childhood diagnosis can predict a future permanent GHD condition. was taken as the basis for the prediction of diagnostic accuracy. 28 of the patients would have been diagnosed as normal.6 µg/l in the diagnosis of GHD. –0. ROC curve analysis indicated the best diagnostic accuracy for a peak GH to ITT of 5.3%). There was also an association between a very low IGF-1 concentration with a GH peak of <10 µg/l after both ITT and arginine. the glucagon test has been poorly studied in the pediatric population.4%) of whom had abnormal anatomy on MRI scanning and/or MPHD. Careful follow-up is needed for subjects who have discordant ITT and IGF-I results.94:2835–2840 Background: In 5–20% of children presenting with precocious pubarche (PP).90%. Peak GH to ITT of 3. specificity 96%. late-onset congenital adrenal hyperplasia (LO-CAH) is found and an adrenal stimulation test is recommended in the diagnostic schedule. data on re-evaluation of young adults with childhood-onset GHD provides the evidence for a good diagnostic performance for a peak GH cut-off level of <5.7 SD score. Tardy V.93). IGF-1 is a reliable marker providing information about the severity of GHD. ROC analysis of IGF-1 showed the best diagnostic accuracy for an IGF-1 cut-off of –2.6 µg/l. Chalumeau M Université Paris Descartes. Seven patients in the high likelihood GHD group showed a peak GH to ITT >5. Conclusion: Using a cut-off point of a peak GH to ITT <5. Precocious pubarche: distinguishing late-onset congenital adrenal hyperplasia from premature adrenarche Armengaud JB. there was a surprise finding of the GH peak after glucagon being >10 µg/l in 28 of 48 patients (58. their use is highly problematic as discussed in the past and pointed out in this pair of papers [4]. The authors caution that GH responses to glucagon may give false-negative results when the threshold of normal of 10 or 20 µg/l is used. but a median IGF-1 that was significantly lower than that of group low likelihood GHD (–3. either as a diagnostic test or for economic reasons. Brauner R. 196 Gary E. In a systematic study investigating patients already confirmed as GHD on two other stimulation tests.

Hegedus L. p < 0. and thyroid volume (TV) measured by ultrasound. 2. serum insulin-like growth factor-I. Additionally. thyroid hormones.001) as well as other anthropometrical measurements. 3. Association of thyroid gland volume. 7 years.94:4031–4035 Background: This study investigated thyroid gland volume and several hormonal and anthropometric variables in prepubertal children as previous studies had focused on the interrelation between thyroid size. weight. Although a retrospective audit rather than primary research.001).3 ml. TV also showed a positive correlation with family history of thyroid disease and presence of incidental abnormal ultrasound findings (p = 0. 9 years. and IGF-I in adults. Conclusion: Although the three above factors were predictive of LO-CAH.2 ± 1.001). testosterone (0. Basal levels of 17-OHP. Copenhagen. Rigshospitalet. LO-CAH was diagnosed by a post-ACTH 17-hydroxyprogesterone (17-OHP) plasma level >10 ng/ml (30 nmol/l) and confirmed by mutational analysis of the CYP21 gene. autoantibodies. Stimulated 17-OHP levels actually did not add further clarification of the diagnosis which was confirmed in all cases with mutations in the CYP21 gene. but data such as this was lacking in children. 3. Results: TV increased significantly with age (r = 0. 2. determination of TSH. and testosterone plasma levels were significantly higher in the 10 of 238 (4%) patients who had LO-CAH.3 ml. 17-OHP was the most efficient.regionh. we are increasingly being asked to look at efficiency measures in our daily clinical practice. this will allow savings in laboratory and drug costs and be better for the patient as hospital admission and a stimulation test can be avoided. In this time of a global recession.dk J Clin Endocrinol Metab 2009.8 ± 1.025 and 0. respectively). 2. urinary iodine excretion was estimated.022.boas@rh. basal and stimulated hormonal measures for their performance in their ability to predict LO-CAH. Feldt-Rasmussen U. and pubic hair Tanner stage at the time of the first medical examination in patient with LO-CAH and PA. although LO-CAH patients tended to have a higher BMI than those with PP. 8 years. Basal 17-OHP was superior in its discriminating power (area under the ROC curve of 0. and body surface area (p < 0.3 ml.90). Skakkebaek NE.66) for comparison. were the best predictors of TV.99). One important point not discussed in the paper is the timing of basal 17-OHP measurement due to the circadian rhythm of 17-OHP secretion and risk of false negative result if blood is drawn later in the day. Main KM University Department of Growth and Reproduction.5 ± 1.83) and the most discriminatory clinical parameter BMI (0.487. Conclusion: In this study of prepubertal Danish children. If the study is confirmed on a higher number of affected individuals (only 10 here). sex. Methods: 859 prepubertal euthyroid Danish children aged 4–9 years underwent a thorough clinical investigation.013). including anthropometrical measurements. Presentation of clinical features such as age.5 ± 1. Evidence-Based Medicine in Pediatric Endocrinology 197 . A 2 ng/ml (6 nmol/l) threshold for basal 17-OHP plasma levels offered 100% (95% CI 69–100) sensitivity for the diagnosis of LO-CAH and 99% (95% CI 96–100) specificity.001). without the need for a stimulation test or additional hormonal analyses.001). suggesting that it may have a role in the regulation of thyroid growth. this is the largest and most detailed study addressing this common diagnostic conundrum. lean body mass (p < 0. performing significantly better than androstenedione (0. free T4 (p < 0. We found a significant positive association between IGF-1 and TV (p < 0. height. the GH/IGF-1-axis was positively correlated with thyroid size. 3. TV correlated significantly with TSH (p < 0. This paper provides a good evidence base for a re-evaluation of practice. anthropometric measurements. Longitudinal growth data from birth were available.Methods: This was a retrospective cohort study that included all patients seen for PP between 1999 and 2006 (n = 238). All underwent an ACTH test.3 ml. 6 years. Moreover. especially body surface area. 4-androstenedione. 5 years. and anthropometric variables in euthyroid prepubertal children Boas M. Denmark malene.7 ± 1. anthropometric variables. Hilsted L. degree of pubic hair development did not show significant differences.3 ml. Mean TV ± SD for different age groups were as follows: 4 years. Applying a selective approach using a 2-ng/ml (6 nmol/l) basal 17-OHP plasma level cut-off would have safely avoided 99% of the unnecessary ACTH tests in this patient group. in multiple regression analyses. Additionally. The study examined clinical. The diagnosis of LO-CAH can be made confidently with basal 17-OHP level.2 ± 1. Results: No statistically significant difference was observed between the distributions of the age at pubic hair onset.4 ml.

Palladino A. Lo Vecchio A. p < 0. Italy J Clin Endocrinol Metab 2009. all anthropometrical variables were positively associated with thyroid volume SDS. 37.0001 and p = 0.2 ± 0.007) and higher end-systolic stress (49. Naples. Results: Compared with controls.8 ± 2. with a reduction in lean mass and an increase in body fat. but even when controlling for age by using SDS. Federico II University of Naples. and estimated lean body mass. Methods: Echocardiography was performed in 24 GHD children at baseline and at 1 and 2 years after GH therapy and in 24 aged-matched controls with familial short stature. 0. BSA. stress shortening index 0.3 g/m2.9 ± 1.009). There was a significant improvement of cardiac size after 1 year of GH treatment (left ventricular mass/body surface area 67. Of particular interest was that children with BMI >2 SD had significantly higher thyroid volume SDS.1%).5 ± 2. subtle left ventricular dysfunction was revealed by load-dependent and load-independent indices of myocardial contractility. with fractional shortening showing only a slight trend toward impairment (34. Body size was strongly associated with age. p < 0.03 circ/s. Clinical trials of GH At the heart of the matter Subtle alterations of cardiac performance in children with growth hormone deficiency: results of a two-year prospective.9 ± 1.94:3347–3355 Background: Children with GH deficiency (GHD) may have reduced left ventricular (LV) mass. Farina V.05). these abnormalities are likely of little actual clinical significance in childhood because general systolic function is within normal limits. GHD children had a had lower left ventricular mass at baseline (left ventricular mass/body surface area 50. This is the first study to document that children with GHD have mild alterations in myocardial contractility and impairment in cardiac performance. left ventricular mass/height2 38. Lettiero T. p < 0. the authors compared the patients with a group of controls who were younger but height and body surface area matched to better compare cardiac parameters.03 vs.9 g/m2. Salerno M Department of Pediatrics. a similar finding in children exhibiting catch-up growth.19 ± 0. However. The results of the present study demonstrate that GH therapy is able to reverse all these subtle abnormalities. However. weight. respectively) and in myocardial contractility (mean velocity of circumferential fiber shortening 1.0003. p < 0.0 g/cm2. case-control study Capalbo D. p < 0.This large-scale population cohort study was able to define factors associated with thyroid gland growth. p < 0.18 ± 0.02.002.2 ± 1.7 ± 1. p < 0.7 ± 1. and since children with GHD may have abnormal body composition. 60.18 ± 0.6 ± 1. The aim of this study was to evaluate effects of GHD and GH therapy on cardiac function using load-dependent and load-independent indices of myocardial contractility.4 g/m2. There was a lower rate-corrected mean velocity of circumferential fiber shortening in GHD patients compared with controls (1. Conclusion: This study has demonstrated that GH deficiency is associated with abnormalities in morphology and function in not only adults but also in children and further supports the beneficial effect of GH on the heart.4 g/cm2. The findings are also in agreement with studies of cardiac function in adults with GHD showing similar 198 Gary E. BMI. mainly by inference and comparison with other anthropometric variables and serum markers. This large treatise principally on normality and its definitions is a welcome addition to our knowledge and the literature. this has not been documented as impairing cardiac function. This was a case-controlled study.10 ± 0. Lombardi G. and left ventricular mass/ height2 28.2 vs.02.0002.4 vs. General systolic function was normal. Thyroid volume highly significantly correlated with age and anthropometric parameters: height. 1. 1 year of GH treatment caused a significant decrease in wall stress and a consistent increase in cardiac contractility parameters.0 g/m2. In addition to a positive effect on cardiac size.8 vs.02 vs. p = 0.6 ± 1. Spinelli L. Butler .6 ± 1.04 circ/s. These positive correlations are reassuring and reassuring that in normal children the thyroid gland grows as the children themselves grow which predicates the maintenance of a euthyroid state.2 ± 2.5 vs.003) and reduced afterload (end-systolic stress 43.03). 45.0 ± 0. Colao A. Tiano C.0001) and stress shortening index (0. p < 0. 33.

9 ± 8. and ASP levels. The study demonstrated twofold higher ASP levels in young children with PWS. together with blood pressure. but normal triglyceride levels. ASP correlates positively with fat mass and negatively with triglyceride levels. and with the improvement in atherosclerotic parameters provides yet more evidence of the beneficial effect of GH treatment on the cardiovascular system.0 years) participated in the study. and IGF-1 during 12 and 24 months of treatment compared with randomized controls. coinciding with an increased fat mass. Infants and prepubertal children received GH (1 mg/m2/day) or served as controls for 12 and 24 months. However. Cianflone K. Two years of GH treatment significantly decreased homocysteine concentrations and improved lipid profiles with a decrease of total cholesterol and total to HDL cholesterol ratio. Thus. Mean ± SD baseline ASP was 107 ± 45 nmol/l (normal <58 nmol/l) and this correlated with fat mass and TG levels. Rotterdam. as children with partial GHD also have a significant reduction in cardiac size compared with controls. Results: Mean ± SD fat% was 28. ASP stimulates glucose uptake and triglyceride storage in adipose tissue. fasting insulin and glucose levels. BMI. The Netherlands r. GH improved fat% SDS and the HDLc/LDLc ratio (p < 0. whereas blood pressure and glucose homeostasis are normal in most patients with only 5% fulfilling criteria for the diagnosis of metabolic syndrome. compared with both pretreatment and control values. Fat% and high-density lipoprotein cholesterol/low-density lipoprotein cholesterol was improved with GH treatment. Gao Y. ASP levels were not altered by GH. These results suggest that children with untreated GHD may also have subtle abnormalities of their lipid profile that might place them to an increased atherosclerotic or thrombotic risk and on which GH seems to exert a beneficial effect.0001 and p = 0. High ASP levels may prevent complete normalization of fat% SDS during GH treatment but may this effect may help to keep glucose and insulin levels within normal ranges.nl J Clin Endocrinol Metab 2010. Methods: This was a randomized controlled GH trial. Conclusion: A high proportion of children with PWS had dyslipidemia and high ASP levels. This RCT of GH treatment confirms that young children with PWS have a high fat mass and dyslipidemia. was abnormal in 63% of infants and 73% of prepubertal children. defined as hypertension or dyslipidemia. GH reduced fat mass and fat% and increased the HDL/LDL ratio. Hokken-Koelega AC Dutch Growth Research Foundation. but no effect was seen on ASP. At least one cardiovascular risk factor. When atherosclerotic or thrombotic risk factors are considered.effects but are of shorter duration in children. Cardiovascular and metabolic risk profile and acylation-stimulating protein levels in children with Prader-Willi syndrome and effects of growth hormone treatment de Lind van Wijngaarden RF. ASP may contribute to maintaining a high fat%. with 5% of all children having the metabolic syndrome. serum lipids. GH therapy normalizes cardiac size and function in both severe and partial GHD patients. Leunissen RW. 95% of prepubertal children had a fat% SD score (SDS) >2 SDS. 85 children with PWS (mean ± SD age of 4. GH-treated children showed significant improvement of height. In addition. which should signal well for long-term health. myocardial contractility was only slightly impaired and afterload was not significantly increased. Acylation-stimulating protein (ASP) is produced by adipose tissue and stimulates free fatty acid incorporation into adipose tissue by increasing triglyceride synthesis and storage and by inhibiting hormone-sensitive lipase-mediated triglyceride lipolysis.2 in infants and 36.9 ± 3.5 in prepubertal children. GH treatment does not Evidence-Based Medicine in Pediatric Endocrinology 199 . This study shows that children with severe GHD have a greater impairment of systolic function in addition to a more severe reduction of left ventricular mass when compared with children with partial GHD. but GH treatment had no effect on mean ASP levels in this population.delindvanwijngaarden@erasmusmc. GHD was associated with higher serum homocysteine levels compared with controls.4 ± 6. respectively.04). Percentage fat was measured (fat%) with dual-energy x-ray absorptiometry.95:1758–1766 Background: The aim of this study was to investigate the metabolic and cardiovascular risk profile and acylation-stimulating protein (ASP) levels and to investigate the effects of GH treatment in children with Prader-Willi syndrome (PWS).

Brunner-La Rocca HP. Puder JJ Institute of Exercise and Health Sciences. Children in the intervention arm (n = 297) received a multicomponent physical activity program that included structuring the three existing physical education lessons each week and adding two additional lessons a week. Dones V Centre for Allied Health Evidence. between August 2005 and June 2006.kriemler@unibas.74 (95% CI 0. Longer-running programs were more effective than shorter ones.14). daily short activity breaks. there was convincing evidence that schoolbased interventions can be effective in reducing the prevalence of childhood obesity. They were restricted to those in which odds ratios (OR) or standardized mean differences and their 95% CIs were reported or could be calculated from available data. Methods: A comprehensive literature search for papers to be included for the meta-analysis was undertaken for RCTs and clinical controlled trials published between 1995 and 2007 on school-based interventions that addressed childhood obesity. Effect of school-based physical activity program (KISS) on fitness and adiposity in primary schoolchildren: cluster randomized controlled trial Kriemler S. Hebestreit H. This study provides further evidence for the metabolic benefits of GH treatment in this condition and helps to shed further light on the mechanism of fat accumulation. Adelaide. with a weighted mean difference of –0. Conclusion: This meta-analysis showed that in the short term. University of South Australia.ch BMJ 2010. Hartmann T. 200 Gary E.340:c2968 Background: This cluster randomized controlled trial aimed to assess the effectiveness of a school-based physical activity program over one school year on physical and psychological health in young schoolchildren.60. Methods: 28 classes from 15 elementary schools in Switzerland (540 children. of whom 502 consented and presented at baseline) were randomly selected and assigned in a 4:3 ratio to an intervention (n = 16) or control arm (n = 12) after stratification for grade (first and fifth grade).result in complete normalization of fat mass in children with PWS which suggests that GH insufficiency is not the only factor involved in the mechanism leading to abnormal body composition in PWS. the assessors were blinded. For most outcome measures. Switzerland susi. 0. Schindler C. S. Grimmer-Somers K.A. New mechanisms Teaching fat-busting School-based interventions on childhood obesity: a meta-analysis Gonzalez-Suarez C. Australia cgsuarez@mnl. van Mechelen W. interventions were not effective in decreasing BMI compared with control treatments. This meta-analysis set out to evaluate the effectiveness of school-based programs in the prevention and management of childhood obesity. but not on reducing BMI. Zahner L. Children (n = 205) and parents in the control group were not informed of an intervention group. Butler . Programs that were conducted for more than 1 year had a higher OR of decreasing the prevalence of obesity. The study measures included body fat (sum of four skinfolds). Results: The meta-analysis showed that the odds of these school-based intervention programs being significantly protective in the short term for overweight and obese participants was OR = 0..ust. Meyer U. 0. which in turn is strongly linked to chronic lifestyle diseases. Basel.ph Am J Prev Med 2009. and physical activity homework. However.39. University of Basel.37:418–427 Background: Childhood obesity has been recognized as an increasing health problem worldwide and predicts adulthood obesity.edu.62 (95% CI = –1.92) in comparison with the control arm. Worley A.

They concluded that programs with compulsory physical activity components seem to be superior to those based on educational interventions.3) years for first grade.59.03) did not show any significant changes.17. –0. Sas TC. Delemarre-van de Waal HA. Leiden. this was very reassuring. Results: 498 children in total (mean age 6. the inclusion of all children in a class avoided any stigmatization of overweight and unfit children and gave all children an equal chance to benefit from this type of intervention.21. de Muinck Keizer-Schrama SM.1 (0. Jansen M.21 to –0. p = 0. and clustering within classes. Furthermore.03. 95% CI –0. may have reached more children by broadening the levels of the intervention and the spectrum of activities by making them not only fun but also developing their motor skills too.35–1. As 90% of all children and 70% of the teachers liked the program and wished it to continue. and triglycerides). inverted high density lipoprotein cholesterol. Waelkens JJ. Gevers EF. New uses for old hormones Efficacy and safety of oxandrolone in growth hormone-treated girls with Turner syndrome Menke LA.78–1. as did those for moderate-vigorous physical activity in school (1. p = 0. in the intervention arm children showed more negative changes in the Z score of the sum of four skinfolds (–0. 133 patients with TS were split into three age groups: 1 (2–7. Methods: A double-blind. Odink RJ. placebo-controlled. 0. Zandwijken GR.003).99 years).42. presented such an approach in a cluster randomized controlled trial.06) as well as psychological quality of life (0.03). Dejonckere PH. and adiposity and they postulated could thus reduce cardiovascular risk. blood glucose.50. completed the baseline and follow-up assessments.60. van Buuren S. mean blood pressure. p = 0. van Trotsenburg AS. After adjustment for grade.23 to 2. The Netherlands l. p = 0. which included a variety of strategies to enhance physical activity. Westerlaken C.95:1151–1160 Background: Although GH therapy has been shown to increase growth and adult height in Turner syndrome (TS). Given these results. Leiden University Medical Center.63) and physical quality of life (0. as adherence is guaranteed. 11. 2 Evidence-Based Medicine in Pediatric Endocrinology 201 . 0. the authors suggest that school principals and policymakers should consider implementing school-based interventions as long-term strategies for preventing and managing childhood overweight and obesity. dose-response study was performed in 10 centers in The Netherlands. physical activity (accelerometry). Secondary outcome measures included body mass index and cardiovascular risk score (average Z score of waist circumference.21 to 0.nl J Clin Endocrinol Metab 2010. 0.9 (SD 0. Otten BJ. 0. Stokvis-Brantsma WH. and quality of life (questionnaires).44.009) compared with controls. p < 0. Kreimler et al. –1. baseline values. The multicomponent and systemic physical activity approach.04). A multicomponent physical activity intervention delivered during one school year had beneficial effects on physical activity.a. de Ridder MA. It found that combined interventions of physical activity in the classroom curriculum were effective in preventing childhood overweight and obesity. randomized.aerobic fitness (shuttle run test).19.01–0.82. Reeser HM. aerobic fitness. –0. The duration of the intervention however was positively associated with its effectiveness.5) years for fifth grade). Z scores for overall daily physical activity (0. the benefit to risk ratio of adding the weak androgen oxandrolone (Ox) in addition to GH is unclear. The meta-analysis showed that long-running school-based interventions are effective in preventing childhood overweight and obesity.menke@lumc. Hokken-Koelega AC. all-day moderate-vigorous physical activity (0.85 to 2.92. Wit JM Department of Pediatrics. sex. Conclusion: A school-based multicomponent physical activity intervention which included some elements that were compulsory improved physical activity and fitness and reduced adiposity in children.05–0.32. This approach of integration of increased physical activity into the regular school curriculum going in the long term is the challenge for society. Z scores for aerobic fitness increased more favorably (0.001). and total physical activity in school (0.12.

05.4 cm. Breast development could be slightly delayed but not adversely affected. Reviews Prevalence and risk factors of radiation-induced growth hormone deficiency in childhood cancer survivors: a systematic review Mulder RL.06 mg/kg/day) because of its low benefit-to-risk ratio.03.001). two-sided) in first-year height velocity of 2 cm with an assumed SD of 2. This double-blind. Conclusion: In GH-treated girls with TS.02.0 cm. van Dalen EC Department of Paediatric Oncology. with several participants either refusing or stopping conventional dose oxandrolone and the final conclusion advises against this. 7. p = 0. van Trotsenburg AS. combined with placebo (Pl) or Ox in low dosage (0. placebo-controlled. Kremer LC. Schouten-van Meeteren AY. and more girls reported virilization on GH+Ox 0. The Netherlands r. The lessons and boundaries of the use of this additional agent are clearly spelled out by this study.uva. Safety evaluation was a notable feature of this study.2 cm greater on GH+Ox 0. EMBASE and CENTRAL for studies reporting on radiationinduced GHD in childhood cancer survivors.06. Butler . 6.6.03 and 2. Ket JL. the authors discourage the use of the conventional Ox dosage (0.mulder@amc. both on account of a greater virilization effect and also a less good outcome for final height due to acceleration in bone age maturation. adult height gain on GH+Ox 0. Breast development was slower on GH+Ox (GH+Ox 0. Results: Compared with GH+Pl. The girls received GH (1. On account of the accelerated bone maturation (p < 0.03 mg/kg/day) or conventional dosage (0. p = 0.8 cm on GH+Ox 0. Koning CC.(8–11. Growth hormone deficiency (GHD) is usually the first and commonest endocrine problem occurring after cranial radiotherapy (CRT). except for some deceleration of breast development.03 increased adult height gain over GH+Pl in the intentionto-treat analysis by mean 9. The eventual group sizes of 39–48 clearly exceeded this.3).06 mg/kg/day) from the age of 8 years and estrogens were added from the age of 12 years.06. Given the lower cost of oxandrolone compared with GH. When correcting for bone age at starting GH therapy. dose-response study of careful design aimed to assess the risk-to-benefit ratio and effectiveness of low and a conventional dose of the weak anabolic steroid in augmentation of the GH induced GH response in girls with TS. this result could be seen to produce a greater cost-benefit ratio on improving adult height than GH alone.001).05).7 vs. p = 0.06 was not significantly different from that on GH+Pl (8.8 SD 4. Emma Children’s Hospital/Academic Medical Center. adult height gain was 3. Methods: The authors searched MEDLINE.nl Cancer Treat Rev 2009.9 vs.03 mg/kg/day modestly increases adult height gain and has a fairly good safety profile.1 cm greater on GH+Ox 0.l.06 than on GH+Pl (p < 0. Outcome measures included adult height gain (adult height minus predicted adult height) and safety parameters were carefully evaluated.99 years). The addition of Ox 0.7 vs. p = 0.8 SD 4.3 SD 4. A meta-regression analysis was performed on the information about study characteristics.2 SD 4. Amsterdam.05). van Santen HM. Neggers SJ. Statistical pre-analysis estimated that 15 patients per dosage and age group were needed to achieve a power of 80% to detect a difference (p = 0.33 mg/m2/day) from baseline.2 SD 4. GH+Ox 0. the difference in adult height gain compared with GH+placebo was +1. which provides an excellent evidence base for clinical practice. 7.0 cm. randomized. p = 0. prevalence and risk factors abstracted and the quality of each study was assessed. GH+Ox 0.5 SD 4.02). which may in its own right have other safety considerations.02) and per-protocol analysis (9.99 years).35:616–632 Background: The aim of this systematic review was to evaluate the existing evidence of the prevalence and risk factors of radiation-induced GHD in childhood cancer survivors. and avoids the need to consider the more expensive option of higher GH doses. 202 Gary E. In the per-protocol analysis. or 3 (12–15. Caron HN. Intention-to-treat analyses were performed and differences in adult height gain were also assessed by a per-protocol analysis.03 (p = 0.

In these studies the prevalence ranged from 29. with precise and accurate outcome definitions and uniform methods of detection.9%. The Netherlands Horm Res 2009. Follow-up should be long enough and complete.0 ± 2. insulin.1% when selecting only studies with adequate peak GH cut-off limits.6%. Only BMI was proportional to -cell function. 39 TS patients (20. The meta-regression analysis showed that the wide variation in the prevalence of GHD could be explained by differences in maximal CRT dose.0 years. low-density lipoprotein and high-density lipoprotein (HDL) were elevated in comparison with values measured 6 months after stopping GH. several years after GH had been discontinued.7 mg/m2/day). The GH-induced decrease in insulin sensitivity. van der Palen RL.3. evaluates the metabolic consequences after GH treatment in girls with TS in three dosage schedules. The atherogenic index remained constant. with a pooled prevalence of 35. Erasmus MC-Sophia Children’s Hospital. Results: For several years after GH discontinuation.0.8 ± 1. Fasting glucose. Whether this was just the natural history of TS is unclear. but a no-treatment or placebo arm is not included. Nearly 5 years after discontinuation of GH therapy the favorable effect of GH was still noticeable. The authors also recommend that appropriate multivariate analyses are necessary taking into account the separate and joint effects of CRT and other important prognostic risk factors for GHD. Previously.1 years) participated 4. insulin sensitivity remained lower. Serum total cholesterol (TC). Additional well-designed studies are needed to estimate the precise prevalence of GHD and to define the exact CRT threshold dose at which GHD occurs. pancreatic -cell function impaired and fasting insulin levels remained high. Mulder PG. however. did not return to baseline.Results: Most studies had methodological limitations.0 to 39.0 to 39. Conclusion: GH therapy in girls with TS has beneficial effects on serum lipids as well as on growth promotion. the authors hypothesized that the higher insulin levels after GH might Evidence-Based Medicine in Pediatric Endocrinology 203 . and serum lipids were measured. Is this good or bad news? This long-term follow-up study. The main risk factors of GHD identified from studies included in this review were higher CRT dose and longer follow-up times. but also higher HDL levels compared to controls. Conclusion: GHD is a frequent consequence after CRT in childhood cancer survivors. Methods: The original trial had three GH dosage arms (1. Higher CRT dose and longer time from treatment are the main risk factors. The prevalence of radiation-induced GHD was estimated in 33 studies and this varied considerably between 0 and 90.1%. Furthermore.7 ± 2. Division of Endocrinology. the evolution of different risk factors time should be investigated. This systematic review and meta-analysis of factors surrounding the diagnosis of GHD in childhood cancer survivors is helpful if not new. 2. Insulin sensitivity remained low.9 years after finishing GH. but recommends that future studies should prospectively evaluate all children treated with CRT. Rotterdam. Time to ensure your database is up to date. The prevalence of radiation-induced GHD ranged from 29. not returning to baseline levels.71:343–349 Background: This follow-up study of a randomized GH dose-response trial study aimed to investigate the long-term metabolic consequences of childhood GH treatment in young women with Turner syndrome (TS). and 2. but below that of the controls. Only three studies had adequate peak GH cut-off limits (<5 µg/l). so we need to rely on historical data for comparison [6]. de Muinck Keizer-Schrama SM Department of Pediatrics. Food for thought Swings and roundabouts Long-term follow-up of GH-treated girls with Turner syndrome: metabolic consequences Bannink EM. whilst -cell function and fasting insulin levels stayed higher than before treatment. resulting in higher TC. with. The mean GH treatment duration was 8.

AH was –2. However.0 (0.2–5. Odink RJ.3 (0.0) showed an increased mean height SDS at discontinuation of the treatment of –1.1 (0. In 28 cases. Oostdijk W. What is the effect of GH treatment in ISS children when given a boost in prepuberty only? and Does the dose make a difference? This study makes several innova- 204 Gary E. This resulted in a similar adult height compared with the untreated controls.D. respectively). such an effect cannot be ruled out.result from a higher BMI. even though conclusions may be different with contrasting conclusions on height gain. range 1. the persistence of low insulin sensitivity and high -cell function may be explained by the GH therapy administered.) age of 20. this one asking separate questions. Study designs are deliberately different.e. height SDS <–2. as the authors discuss here.6 (0.4 (2. and with higher fasting insulin levels several years after GH therapy. as previous studies had shown a positive correlation between insulin levels and BMI in normal children and adults and would be in agreement with a previous report on the relationship between the effect of GH on adiposity and insulin sensitivity on and after GH treatment in TS [7]. 1. Wit JM Department of Pediatrics. were randomly allocated to receive GH at a dose of 2 mg/m2/day (equivalent to 75 µg/kg/day at the start and 64 µg/kg/day at the finish) until the onset of puberty for at least 2 years (preceded by two 3-month periods of treatment with low or intermediate doses of GH separated by two washout periods of 3 months) or no treatment as a control group.8) SDS in the controls. and an increase in HDL and triglycerides. adult height (AH) was assessed at a mean (S. long-term RCTs of GH treatment are reported as in 2009 there were reports of apparent success [9] and failure [10] of GH treatment in short normal children. This pattern extended at long-term follow-up with lipid profiles similar to those reported in untreated TS women being age and BMI independent [6]. Leiden University Medical Center.162:653–660 Background: This was a randomized-controlled study to assess the long-term effect of high-dose GH treatment on growth in children with idiopathic short stature (ISS) given in the prepubertal period only. Follow-up on YB 2009 papers GH and ISS High-dose GH treatment limited to the prepubertal period in young children with idiopathic short stature does not increase adult height Van Gool SA. Although no association with GH dosage or GH duration is known.3) years. bone maturation accelerated significantly in the GH-treated group compared with the controls (1. outcomes of carefully designed. so the authors believe the findings in this study may just be part of the natural history of TS [8]. LDL and HDL cholesterol increased. Conclusion: High-dose GH treatment given only in the prepubertal period in young ISS children augments height gain during treatment but is associated with an acceleration in bone maturation. Leiden. This effect is similar to that seen in GHD and treated SGA individuals. associated with an earlier onset puberty. and birth length >–2. Treatment was not given during puberty in either group and after 3–12 years. Each year in the Yearbook. Methods: 40 prepubertal children aged 4–8 years (girls) or 4–10 years (boys).7) and –1. Individually they are important.6) in the GH-treated and control groups respectively. results of this study may be limited by small size and dropout over time. resulting in a further decrease in atherogenic index.2) years per year. It is also reported that untreated young TS women have a higher prevalence of insulin resistance and impaired glucose tolerance. de Muinck Keizer-Schrama SM.6 (0. A positive association of BMI with -cell function. Inevitably. Results: The children receiving GH treatment (mean time on high-dose GH 2.0 SDS. During the first 4 years of GH therapy the study found a decrease in total cholesterol. This is a clear message about the long-term follow-up needed for GH treated individuals. Age was a positive predictor of adult height gain.0 SDS. LDL cholesterol. Alternatively. The Netherlands Eur J Endocrinol 2010.8) SDS compared with –2. So what atherogenic improvements are gained on the swings need to be contrasted with losses in insulin sensitivity on the roundabouts. Delemarre-van de Waal HA.3 years. i.4) vs. Kamp GA. Butler . Six months after GH treatment. supports this possible explanation. and atherogenic index.9 (0. total cholesterol.

8. and Endocrine Society of Australia. Hagenas L. Rosenfeld RG. Wooten N. because children treated with a high GH dose at 11 years achieve an AH gain of 1. Rogol AD. The authors postulate that the most likely explanation is that a high GH dose (approximately three times higher than simple replacement) administered to young children not only leads to faster growth but also results in faster bone maturation. 7. Stephen O’Riordan of the Children’s Hospital. Buyukgebiz A. Rubin K. A statement of the GH Research Society in association with the European Society for Pediatric Endocrinology. Ho KK: Consensus guidelines for the diagnosis and treatment of adults with GH deficiency. Karger 2009. Ranke MB. Evidence-Based Medicine in Pediatric Endocrinology 205 . References 1. Butler GE: Assessment of growth and puberty. Hindmarsh PC: A randomised study of the effect of two doses of biosynthetic human growth hormone on final height of children with familial short stature. Leicester Royal Infirmary. Albertsson-Wikland K. Basel. A disappointing result from a carefully crafted study. Caprio S.92:846–852.93:2109–2114. Lawson Wilkins Society. 10. 4. Gustaffson J. They state that the results also imply that there may be an inverse U-shaped relationship between GH dose and AH gain if treatment is started at a young age.tions such as examining acceleration in growth of different body proportions (sitting height growth accelerates much faster in the GH-treated group) and a novel technique for expressing pubertal stage in SDS (correcting for age and gender). 5. Karger 2007. but in young children higher doses may decrease AH gain due to accelerated maturation of the epiphyseal plates and possibly also of the GnRH regulatory centre with the effect on growth having reached a plateau.72:832–836. Ivarsson SA et al: Dose-dependent effect of growth hormone on final height in children with short stature without growth hormone deficiency. Cassorla F. Standard dose GH is positively associated with AH. Diamond M. Hochberg Z (eds): Yearbook of Pediatric Endocrinology. O’Riordan SM. It seems unlikely that the high-dose per se causes the lack of effect. Bondy CA: Reduced abdominal adiposity and improved glucose tolerance in growth hormone-treated girls with Turner syndrome. NICE Technology Appraisal Guidance 151: Continuous subcutaneous insulin infusion for the treatment of diabetes mellitus (review of technology appraisal guidance 57) 2008. 9. Sagi L. Rakover Y. Acknowledgement I would like to thank Dr. Boulware S. II. Bakalov VK. Gawlik A.80:1532–1540. as most other studies started at an average age of 11 years. chapt 2. The authors speculate that the epiphyseal plates of young children could be more sensitive to high doses of GH and/or IGF-1 than at later ages. J Clin Endocrinol Metab 1995.70:89– 92. 2. Reiter EO (eds): Treatment with Recombinant Human Growth Hormone in Children and Adolescence – 20 Years of KIGS. J Clin Endocrinol Metab 2007. et al: Insulin resistance: an early metabolic defect of Turner’s syndrome. Preece MA. et al: Clinical significance of the parental origin of the X chromosome in Turner syndrome. Frasier SD. Dattani MT. Preece MA. Werther GA: Diagnostic controversy: the diagnosis of childhood growth hormone deficiency revisited. Carpenter TO.3 SD. for assistance with the selection of some papers for review. 93:4342–4350. Loriaux DL. Melmed S.org. 6. Price DA. pp 181–197. Underwood LE. but the discussion (as alluded to above) fosters interesting hypotheses as to the relationships between GH and maturation. J Clin Endocrinol Metab 2008. Horm Res 2008. There was a trend but no statistically significant difference between the groups at Tanner stage 2. There are few data on GH treatment of young children with ISS. Japan Endocrine Society. Barton JS. Sherwin RS.157:695– 700. Butler G: Evidence-based medicine in pediatric endocrinology. pp 6–15.uk/TA151/Guidance/pdf/English 3. Lippe BM. in Carel JC. Elder CJ. Ghizzoni L. Aronson AS. Zuckerman-Levin N. Hill S. in Ranke MB. Reiter EO. http://guidance. Hasegawa Y. Hintz RL.nice. Albertsson-Wikland K. Eur J Endocrinol 2007. J Clin Endocrinol Metab 2008. LaFranchi S. Brook CG. J Clin Endocrinol Metab 1991. European Society of Endocrinology. which is slightly more than that would be gained at a low dose. Basel.

at puberty onset. In humans. However. Sabaliauskas N. but the mechanism for this deficit remains unknown. but not in adults or the very young. Certain learning and cognitive processes decline at the onset of puberty. an effect that can be reversed by a stress steroid. Sherpa A. Pubertal mice also failed to learn a hippocampal.. which is widely regarded as the site for learning. Evidence that DHEAS is a neurosteroid. DHEAS has demonstrated effects on mood in humans. shunting the depolarizing current necessary for NMDA receptor activation. which reduces tonic inhibition at puberty. facilitated learning. whereas it impaired learning before puberty via its inhibition of GABA receptors for restricting hippocampal plasticity during puberty. which alters learning after a delay but has no effect acutely. (2) increasing activity of the hippocampus. Smith SS Department of Physiology and Pharmacology. Shen et al. N. As a consequence. Brooklyn. The pubertal process that shapes this developmental decline is unknown but is likely to involve the hippocampus. Aoki C. at puberty. signal transmission was affected and spatial learning reduced. neurosteroid depletion is consistently documented in patients with current depression and may reflect their greater chronic stress. Fenton AA. the stress steroid THP provides a novel means for rapid changes in synaptic plasticity at puberty.Editor’s Choice Jean-Claude Carel and Ze’ev Hochberg Forgetful adolescents A critical role for 4 -GABAA receptors in shaping learning deficits at puberty in mice Shen H. State University of New York (SUNY) Downstate Medical Center.Y. USA Science 2010. impairing induction of long-term potentiation. Stelzer A. Thus.327:1515–1518 Background: The onset of puberty defines a developmental stage when some learning processes are diminished. Shunting inhibition via these receptors reduced N-methyl-D-aspartate receptor activation. . Results: The paper reports that. and (3) promoting synaptogenesis within the cortex. Conclusions: The emergence of 4 -GABARs at puberty impairs learning. and acts at neuron receptor sites. suggests that DHEAS may play an important role in extended brain maturation among humans. found that puberty impaired learning in mice (the time to enter a shock zone) decreased by 70%. GABA receptors were targeted perisynaptically to excitatory synapses. Providing the stress neurosteroid progestative allopregnanolone (THP) completely reversed the learning deficit at puberty. together with the fact that increases in DHEAS parallel patterns of cortical maturation from approximately age 6 years to the mid-20s. At puberty. the stress steroid THP (3-OH-5[ ]-pregnan-20-one). I suggest three ways in which DHEAS may play a role in human brain maturation: (1) increasing activity of the amgydala. THP effects are distinguishable from glucocorticoids. expression of inhibitory 4 -aminobutyric acid type A (GABAA) receptors (GABAR) increases perisynaptic to excitatory synapses in CA1 hippocampus. long-term potentiation-dependent spatial task that was easily acquired by –/– mice.

Lineage tracing to label the glucagon-producing cells before -cell ablation tracked large fractions of regenerated cells as deriving from cells. Altogether. half a mouse lifespan) pancreatic cells transdifferentiate from glucagon-producing cells. Desgraz R. It is not known whether adult mammals can differentiate (regenerate) new cells after extreme. Finding ways to restore the pancreatic -cell mass in patients with type 1 diabetes is a challenging problem that has been addressed by several different approaches. the exact mechanism of regeneration was not known and one limitation of these experiments was that some cells survived to toxic exposure and could have proliferated after the initial destructive event. This results in a 44-fold increase in -cell mass that is capable of maintaining glucose homeostasis.New hope The grail is in the cell Conversion of adult pancreatic cells to cells after extreme -cell loss Thorel F. Results: If given insulin. It has been long known in animal models of diabetes due to exposure to toxic compounds such as streptozotocin that cells could regenerate after a few months of overt diabetes. total -cell loss. Conversely. after a transient step of bihormonal cells (glucagon and insulin). such that in healthy conditions they replicate little during a lifetime. Herrera PL Department of Cell Physiology & Metabolism. 208 Jean-Claude Carel/Ze’ev Hochberg . these results indicate that there is a very significant potential for islet cell regeneration in adults that could convert into methods to restore -cell mass in patients with diabetes [2. they show increased self-duplication after increased metabolic demand or after injury (that is. Avril I. Conclusion: Such inter-endocrine spontaneous adult cell conversion could be harnessed towards methods of producing cells for diabetes therapies. Methods: A transgenic model of diphtheria-toxin-induced acute selective near-total -cell ablation. the authors have engineered a transgenic model for virtually total ablation of pancreatic cells. Nevertheless.464:1149–1154 Background: Pancreatic insulin-producing -cells have a long lifespan. They show that over time (10 months. as in diabetes. leaving intact the remaining endocrine cells. Geneva. either in differentiation settings in vitro or in induced regeneration. -cell loss).e. gene transfection. Kohno K. Nepote V. Depletion of cells by this mechanism caused a neogenesis of cells then converted to cells resulting in a massive increase of -cell mass. Currently. Switzerland Nature 2010. i. revealing a previously disregarded degree of pancreatic cell plasticity. Here. This would indicate differentiation from precursors or another heterologous (non. Chera S. including culture. transplantation of human islets or pancreas is the only approach to replace cells in diabetes and suffers from a lack of high-quality islets in sufficient quantity.-cell) source. 3]. The interplay between and cells was also demonstrated earlier this year in a series of transgenic experiments where overexpression of the transcription factor Pax4 caused the conversion of cells into cells [1]. the lack of such regeneration in patients further demonstrates that -cell destruction in type 1 diabetes is not a one-time event but rather continues after diagnosis and damages new cells that might be formed by the regenerative process. fetal islet amplification. University of Geneva Faculty of Medicine. neogenesis or differentiation from stem cells. However. the mice survived and showed -cell mass augmentation with time.

BMI or percent fat. percent fat and grip strength.uk Biol Lett 2009. In Western societies.Lesson from other societies Non-universal heightism How universal are human mate choices? Size does not matter when Hadza foragers are choosing a mate Sear R. the Hadza of Tanzania. productivity and overall quality. Marlowe FW Department of Social Policy. weight.5:606–609 Background: It has been argued that size matters on the human mate market: both stated preferences and mate choices have been found to be nonrandom with respect to height and weight. who are a small. weight. and whether there is a male-taller norm. weight is a factor in both stated preferences. The authors conclude wisely that ‘It is time to expand our horizon to a truly cross-cultural view and begin to sort between highly variable and truly universal mate patterns. There is now a large body of research investigating mating patterns within evolutionary studies of human behavior. so that large size may be a better indicator of quality in Western populations.sear@lse. Hadza couples may assort positively for grip strength. no evidence for a male-taller norm and no evidence that number of marriages is associated with our size variables. individuals take height into consideration when weighing up potential mates. But health and productivity may be signaled in alternative ways in the Hadza. body mass index (BMI). where long-term relationships between partners are common. where the costs of maintaining large size during periods of food shortage may be high. mating appears to be random with respect to size in the Hadza. Much less is known about mating behavior in more traditional societies. Such disadvantages will not be seen in food-abundant societies. This study investigated mate choice in a hunter-gatherers society. It tested whether couples assort for height. Similarly. London School of Economics. it tests for an association between anthropometric variables and number of marriages. There may be some disadvantages to large size in a food-limited society. The results suggest that size and strength are not greatly important in this population mating. This lack of size-related mating patterns might appear surprising.’ Editor’s Choice 209 . Methods: This study investigated mate choice by analyzing whether there is any evidence for nonrandom mating with respect to size and strength in a forager community. size appears to matter for both mate preferences and mate choices. UK r. Conclusion: In contrast to post-industrial societies.ac. But how universal are these patterns? Most of the literature on human mating patterns is based on post-industrial societies. particularly so in a species like our own. London. Choosing the right mate is an important component of evolutionary fitness. but grip strength does not affect the number of marriages. the Hadza who live in the central Rift Valley of Tanzania. Finally. Results: Results show no evidence for assortative mating for height. relatively homogeneous population. since size is usually assumed to be an indicator of health.

particularly in the absence of compelling physiological evidence. shorter patients. Conclusions: Referral recommendations that create the pool of candidates for the specialty drug GH are heavily swayed by physician characteristics and consumer preferences. consumer drivers (family concern) and physician attitudes had almost as great an impact – especially for children with less severe growth impairment (p < 0. shorter. physician. little is known about what drives such referrals – especially for large populations such as short. This paper analyzed the determinants of referrals to pediatric endocrinologists based on 4 typical case scenarios designed to vary in 5 factors – child’s age and gender.001). Methods: To quantify the relative impact of patient physiological indicators. Ohio. Only 1 additional referral per US pediatrician would likely increase GH costs by over USD 100 million/year. Silvers JB Department of Pediatrics. Age of the child was not a factor affecting referral. In addition.000 US children eligible for such treatment. University Hospitals Case Medical Center.edu Med Care 2009. older. The decision to refer patients was not only based on the patients clinical characteristics (i. In addition. 210 Jean-Claude Carel/Ze’ev Hochberg . and family concern about the child’s stature. the fastest growing and costliest pharmaceuticals.001). Recent expanded approval of growth hormone (GH) makes more than 585. typically originate with primary care referrals. height in SDS and physician’s general attitude regarding short stature as a problem. USA leona. otherwise normal children (idiopathic short stature). Rainbow Babies and Children’s Hospital.47:858–865 Background: Candidates for specialty drugs. physician characteristics. However. This makes most of children with short stature strikingly susceptible to nonphysiological influences on referrals that render them candidates for this specialty drug. Mercer MB. growth pattern) influenced referrals (p < 0. Physician belief that short stature impairs emotional well-being and physician characteristics (female. a national study of 1. Results: While patient indicators (height. Connors A. Cleveland. Meehan R.268 randomly selected US pediatricians was conducted. potentially costing over USD 11 billion/year. In the vast majority of cases. Second. beliefs about drug company information) increased referrals (p < 0. child’s height and growth pattern. Marinova D. physician’s attitudes towards height and short stature evaluation were surveyed. there is a need for higher quality evidence in our own evaluations of children with short stature [4] since better establishment of our own evaluation scheme will help in communicating it to the wider community and help referring physicians focus on patients who need a specialized evaluation most. family concern and the child’s gender also influenced the decision to refer. based on a full factorial experimental design in a structured survey. we need better evidence-based evaluation of our interventions in order to allow us to better communicate them to the medical and nonmedical community at large. and consumer drivers: referrals for short stature and access to specialty drugs Cuttler L. and consumer preferences on referrals to endocrinologists (and potential access to GH) for short children. First. These data are not fully surprising to us pediatric endocrinolgists but are important for our practice and future directions. falling off the centile curves more likely to be referred than milder cases) but was also very much influenced by physician-dependent factors such as age. gender.001) – independent of growth parameters.03–0.e.Food for thought Heightism in our societies Patient.cuttler@case. evaluation of a short child by a pediatric endocrinologist results from referral by a primary care physician.

The enigma of these cycles is the lack of population growth following the decline phase when the predators have virtually all disappeared and the food supply is ample.1890/09-1108. A predator-induced increase in maternal stress hormone levels resulted in a decline in reproduction. Editor’s Choice 211 . This study of snowshoe hares shows that high levels of predation result in a sharp increase in levels of maternal stress hormones. chronic). The increase in stress hormones in the offspring born to stressed mothers may trade off the decrease in reproduction by increasing their offspring’s antipredator behavior. acute vs. and (3) higher maternal FCM levels at birth are correlated with an increased responsiveness of the HPA axis in their progeny. They propose that the lack of recovery of reproductive rates during the early low phase of the hare cycle may be the result of the impacts of intergenerational. depressing reproduction. and recent results suggest that this may be epigenetically determined at the glucocorticoid receptor level. These levels remain high in the offspring of these stressed animals and persist into adulthood. undernutrition.C. trauma. However. the transmission of stress hormones between mother and offspring may play an important role in these effects. before or just after birth. Adaptations to the effects of environmental stressors are essential for ensuring individual fitness in natural populations. This suggests that the inheritance of stress levels results in a slow recovery of a population of wild mammals. on the organization of target tissues and/or gene-expression patterns that affect function throughout life. These nongenetic phenotypic effects can have a profound influence on offspring and can cause a resemblance not just between a mother and her offspring but also between grandparents and grand-offspring. In mammals.g. disease. etc. Boonstra R University of British Columbia. (2) maternal FCM levels are echoed in their offspring and this occurs at a population wide level. The environment that an individual’s mother experiences affects her offspring’s fitness. maternallyinherited stress hormones caused by high predation risk during the decline phase. These nongenetic maternal effects are referred to as maternal or developmental programming. the relevance of these studies to free-living mammals is unclear. Humans also inherit a stress level from their parents.org/doi/abs/10. postnatal.1890/09-1108 (2010) http://www.).Multigenerational stress The ghosts of predators past: population cycles and the role of maternal programming under fluctuating predation risk Sheriff M.. the nature of the stressor (e. Results: (1) An index of maternal stress (fecal corticosteroid metabolite [FCM] concentrations) fluctuates in synchrony with predator density during the breeding season. Mechanisms responsible for maternal programming may vary among organisms. The 10-year snowshoe hare cycle is intimately linked to fluctuating predation pressure and predation risk.1 Background: Maternal effects may be a major factor influencing the demography of populations. psychological stress. Krebs C. Canada Ecology doi:10. Conclusions: The results are the first to show an intergenerational inheritance of stress hormones in a freeranging population of mammals. Methods: This study examines population and hormone changes over a 4-year period from the increase (2005) to the decline (2008). B. and timing and duration of occurrence (prenatal vs. Glucocorticoids and their receptors play a key organization role by which these lifelong changes are brought about. A programming effect reflects the influence of a specific environmental factor during the developmental period.esajournals. Vancouver. Laboratory studies have shown that stressors during pregnancy and lactation result in lifelong programming of the offspring phenotype.

Hepatic FGF21 has been discussed in our Yearbook in the last 2 years as a key player in metabolic adaptation to starvation. Moses EKb. turns on genes related to activation of brown fat. Australia.95:2476–2485 Background: Chemerin is a new adipokine associated with obesity and the metabolic syndrome. Iglesias R. This year we learn that expression and plasma FGF21 levels are dramatically induced after birth. Australia J Clin Endocrinol Metab 2010. Gonzalez FJ. UK. Catalonia. among others by stunting growth through STAT5 signaling.Concept recentered Suckling keeps us warm Hepatic FGF21 expression is induced at birth via PPAR in response to milk intake and contributes to thermogenic activation of neonatal brown fat Hondares E. Results: The study mimicked the FGF21 postnatal rise by injecting FGF21 into fasting neonates. Melbourne. Goring HHb. FGF21 expression could be quashed by preventing mice from suckling. Barcelona. Cawthorne MAc. Stocker CJc. and initiated by substituting lipids for the mother’s milk. Jowett JBd a Metabolic Research Unit.643. and was also able to activate brown adipocytes in culture. they found. requires lipid intake. 212 Jean-Claude Carel/Ze’ev Hochberg . Cole SAb. FGF21. in contrast to the upregulation occurring in adults. Dyer TDb. Tex. Deakin University. Design: Plasma chemerin levels were measured in subjects from the San Antonio Family Heart Study. Morrison Sa. This induction is initiated by suckling. Brown adipocytes treated with FGF21 exhibited increased expression of thermogenic genes. Gene expression levels of chemerin were elevated in the adipose depots of obese compared with lean animals and was markedly elevated during differentiation of fibroblasts into mature adipocytes. Changes in FGF21 expression due to suckling or nutritional manipulations were associated with circulating free fatty acid and ketone body levels. and enhanced glucose oxidation. a novel adipokine in the regulation of angiogenesis Bozaoglu Ka. White fat development determines hepatic FGF21 expression in response to fasting and FGF21 released by the liver leads to activation of neonatal brown fat thermogenesis. is impaired in PPAR null neonates. and that hepatic FGF21 induction is caused by a PPAR -mediated effect of lipids in the milk. San Antonio. Walder Ka. The net effect is that mom’s milk activates a pathway that turns on brown fat cells – the heat-generating cells in young animals. Konstantopoulos Na. and dBaker IDI Heart and Diabetes Institute. Giralt M. Objective: The objective of the study was to identify factors that affect the regulation and potential function of chemerin using a genetics approach.11:206–212 Background: Plasma FGF21 levels and hepatic FGF21 gene expression increase dramatically after birth in mice. higher total and uncoupled respiration. Carless Mb. A new cytokine More vasculature for more fat Chemerin. Rosell M. Southwest Foundation for Research.354 Mexican-American individuals. Wy14. cClore Laboratory. Institut de Biomedicina de la Universitat de Barcelona and CIBER Fisiopatologia de la Obesidad y Nutricion. and found that this enhanced the expression of genes involved in thermogenesis within brown fat. Buckingham. Blangero Jb. Curran JEb. and increased body temperature. Spain Cell Metab 2010. University of Buckingham. bDepartment of Genetics. Geelong. Segal Da. Neonates exhibit reduced FGF21 expression in response to fasting. Villarroya F Departament de Bioquimica i Biologia Molecular. and is mimicked by treatment with the PPAR activator. a large family-based genetic epidemiological study including 1.. Conclusions: The induction of FGF21 production by the liver mediates direct activation of brown fat thermogenesis during the fetal-to-neonatal transition. Zaibi MSc.

and blood pressure in several independent human populations. including body mass index. The oscillation is phase locked between neurons. prolactin secretion is suppressed by powerful inhibition from hypothalamic tuberoinfundibular dopamine (TIDA) neurons. Broberger C Department of Neuroscience. A genome-wide association analysis using 542.4 × 10–9). Karolinska Institutet.Individuals were randomly sampled without regard to phenotype or disease status. Stockholm.and postsynaptic effects. an effect assumed to take place in the pituitary. The effect of chemerin on angiogenesis was measured using human endothelial cells and interstitial cells in coculture in a specially formulated medium. prolactin. Thyrotropin-releasing hormone (TRH) potently stimulates prolactin release. Chemerin gene expression was significantly elevated in the adipose depots of obese compared with lean animals and was predominantly expressed by adipocytes rather than stromal and vascular cells in adipose tissue. p = 1.se Neuron 2010. The singlenucleotide polymorphism showing strongest evidence of association (rs347344. Of particular interest is a gene that has been previously shown to play a role in angiogenesis. Functional angiogenesis assays in human endothelial cells confirmed that chemerin significantly mediated the formation of blood vessels to a similar extent as vascular endothelial growth factor. Because the expansion of adipose tissue is dependent on the formation of new blood vessels.lyons@ki. In vitro studies have shown that chemerin expression and secretion was markedly up-regulated during differentiation of fibroblasts to mature adipocytes and was approximately 20-fold higher in fully differentiated adipocytes compared with undifferentiated fibroblasts. Results: Serum chemerin levels were found to be highly heritable (h2 = 0.65:217–229 Background: The pituitary hormone. Horjales-Araujo E. This article demonstrates for the first time that variation in plasma chemerin levels is significantly heritable. the electrical behavior of TIDA cells remains unknown.25. Furthermore. In TIDA cells. and a number of polymorphisms in candidate genes that may influence plasma chemerin levels are identified. and while it persists during chemical synaptic transmission blockade. which has a known role in angiogenesis. Editor’s Choice 213 . These novel data indicate a new role for chemerin in the formation of new blood vessels. it is abolished by gap junction antagonists. TRH caused a transition from phasic to tonic firing through combined pre. Under nonlactating conditions. Conclusion: Plasma chemerin levels are significantly heritable and identified a novel role for chemerin as a stimulator of angiogenesis. this group explored the effects of chemerin on angiogenesis and found that recombinant chemerin promoted the formation of new blood vessels.05-Hz oscillation.4 × 10–6) was located within the gene encoding epithelial growth factor-like repeats and discoidin I-like domains 3. and plasma chemerin levels were significantly associated with characteristics of the metabolic syndrome. Concept revised Synchronizing the mothering hormone Synchronized network oscillations in rat tuberoinfundibular dopamine neurons: switch to tonic discharge by thyrotropin-releasing hormone Lyons DJ. Chemerin was reported in 2007 as a new adipokine elevated in states of obesity and the metabolic syndrome. p = 1. and given the significant association already established between chemerin and obesity. and this may be an essential component of adipose tissue expansion. plasma triglycerides. triggers lactation in nursing mothers. Results: This report demonstrates that rat TIDA neurons discharge rhythmically in a robust 0. recombinant chemerin was shown to stimulate 3T3-L1 adipocyte function such as glucose transport. Although a firing pattern has been suggested as integral to neuroendocrine control. Sweden david.944 single-nucleotide polymorphisms in a subset of 523 of the same subjects was undertaken.

USA ubukat@berkeley. since patients. one of which is reduction of sexual libido. has been identified as their cognate receptor. TRH-mediated stimulation of prolactin release occurs at the hypothalamic level by shifting TIDA oscillations to tonic discharge. and children even more. It also directly modulates GnRH neuron firing. this paper identified the GnIH. This is secreted by cells known as ‘TIDA’ neurons in the hypothalamus in the brain. RFRP-1 and RFRP-3. GnIH may regulate gonadotropin secretion by inhibiting GnRH neurons as well as directly acting on gonadotrope cells in the pituitary as was clearly demonstrated in isolated pituitary 214 Jean-Claude Carel/Ze’ev Hochberg . described in birds. but remained elusive in humans. GPR147 in the human hypothalamic pituitary axis Ubuka T.. In terms of basic prolactin physiology. Prolactin also plays a role in reproduction and fertility. It is believed that prolactin is significant for metabolism. it seems reasonable that the functional role of the TIDA oscillation is not to time prolactin surges but to ensure sufficient inhibitory concentrations of DA in the anterior pituitary. Morgan K. The reason that women normally do not produce prolactin is that its release is normally strongly inhibited by dopamine. A neuropeptide named gonadotropin-inhibitory hormone (GnIH) which directly inhibits gonadotropin synthesis and release from the pituitary was recently identified in quail hypothalamus. Immunocytochemistry revealed GnIH-immunoreactive neuronal cell bodies in the dorsomedial region of the hypothalamus with axonal projections to GnRH neurons in the preoptic area as well as to the median eminence.4:e8400 Background: The existence of a hypothalamic gonadotropin-inhibiting system has been elusive. Thus. Tsutsui K. GnIH homologs were isolated from the human hypothalamus by immunoaffinity purification. Bentley GE Department of Integrative Biology and Helen Wills Neuroscience Institute. GPR147. Osugi T. Results: This report identifies GnIH homologs in the human hypothalamus and characterizes their distribution and biological activity. A new neurohormone Blessing blockers Identification of human GnIH homologs. suggesting the regulation of GnRH neurons by GnIH. Conclusions: The identification of two forms of GnIH (RFRP-1 and RFRP-3) in the human hypothalamus which targets human GnRH neurons and gonadotropes and potently inhibit gonadotropin in sheep models provides a new paradigm for the regulation of hypothalamic-pituitary-gonadal axis in man and a novel means for manipulating reproductive functions. Human RFRP-3 has recently been shown to be a potent inhibitor of gonadotropin secretion in cultured sheep pituitary cells by inhibiting Ca++ mobilization. The study has also shown that TRH can interrupt the rhythmical signaling pattern of TIDA cells. In situ hybridization further identified the expression of GPR147 mRNA in luteinizing hormone-producing cells (gonadotropes). University of California. required to function as a strong inhibitor of prolactin release. Pawson AJ. A G-protein-coupled receptor. Berkeley. By testing the human homologs RFRP-1 and -3 to the GnIH peptide. RT-PCR and subsequent DNA sequencing of the PCR products identified human GnIH receptor (GPR147) mRNA expression in the hypothalamus as well as in the pituitary. Millar RP. it is released during an orgasm.edu PLoS One 2009. with discharges every 20 s. Chowdhury VS. A neuropeptide inhibitor of gonadotropin secretion has been postulated for some years. and then identified as human RFRP-1 and RFRP-3 by mass spectrometry.Conclusions: These findings suggest a model for prolactin regulation where a TIDA network switch from oscillations to sustained discharge converts dopamine from an antagonist at high concentrations to a functional agonist as dopamine output from the network decreases. with elevated levels of prolactin become overweight. GnIH neurons were observed in the dorsomedial region of the human hypothalamus in close proximity to GnRH neurons in the preoptic area. Minakata H. Calif. and the cognate receptor. The study has shown that the TIDA cells normally display an extremely rhythmical activity.

scaffolding with accessory effector molecules. The physiologic actions of PTH were thought to be mediated by classic G-protein signaling. and may also have potential as a novel contraceptive. these receptors trigger two pathways that independently transduce signals to the cell: one through heterotrimeric GTP-binding proteins (G proteins) and one through -arrestins.1:1ra1 Background: About 40% of the therapeutic agents in use today exert their effects through seven-transmembrane receptors (7TMRs). -Arrestins.Tyr34)PTH(7–34) (PTH. PTH. which activates -arrestin but not classic G-protein signaling.. In -arrestin2-null mice. Durham. We now learn that the PTH GPCR can trigger signaling mechanisms that are independent from the classic G-protein pathways. Corsino L. PTH stimulation of the PTH receptor promotes translocation of -arrestins 1 and 2 to the plasma membrane. The -arrestin2-dependent pathway contributes primarily to trabecular bone formation and does not stimulate bone resorption. so-called biased agonists can selectively activate these distinct pathways. internalization of receptor. Flannery P. a small family of intracellular proteins initially identified for their role as GPCR desensitizers. the increase in bone mineral density evoked by PTH(1–34) is attenuated and that stimulated by PTH. This paper shows that a selective agonist for -arrestin signaling in the absence of G-protein signaling promotes osteoblastic bone formation without stimulating bone resorption and may have clinical utility as an anabolic agent in the treatment of diseases characterized by insufficient rates of bone formation. Lefkowitz RJ. as does the nonselective agonist PTH(1– 34).-arrestin complexes. USA Sci Transl Med 2009. Duke University Medical Center. Yuan L.arr is ablated.arr). and activation of ERK1/2. Results: In mice. association of the receptor with -arrestins.C.cells in the sheep. act as signal transducers through a distinct mechanism. (D-Trp12. Editor’s Choice 215 . Conclusions: These results show that a biased agonist selective for the -arrestin pathway can elicit a response in vivo distinct from that elicited by nonselective agonists.arr induces anabolic bone formation. When activated by ligands. such as osteoporosis. Spurney R. N. Important mechanism A needed assistant A -arrestin-biased agonist of the parathyroid hormone receptor (PTH1R) promotes bone formation independent of G-protein activation Gesty-Palmer D. Methods: This study investigated selective activation of these pathways through the use of a biased agonist for the type 1 parathyroid hormone (PTH)-PTH-related protein receptor (PTH1R). Ligands with these properties may form the basis for improved 7TMR-directed pharmacologic agents with enhanced therapeutic specificity. GnIH has the potential of an alternative or adjunct therapeutic agent to inhibit gonadotropins and steroid hormones. Thus this endogenous inhibitor of gonadotropin secretion has therapeutic potential in the treatment of hormone-dependent diseases such as precocious puberty. Luttrell LM Department of Medicine. which activates both mechanisms.

indicating that ghrelin affects response threshold. and not to photic schedules. Impressively.106:13582–13587 Background: Increases in arousal and activity in anticipation of a meal. The present studies explore the possibility that ghrelin-secreting cells of the stomach oxyntic glands are FEOs. food anticipatory behavior is diminished.99) for both wild-type and ghrelin receptor knockout animals. which produce a timed ghrelin output signal that acts widely at both brain and peripheral sites. to predict the availability of food. the behavioral manifestation of this timing mechanism is the expression of food anticipatory activity (FAA). USA Proc Natl Acad Sci USA 2009. and the findings provide an avenue for understanding the previous literature on FAA. The results show that stomach oxyntic cells fulfill several essential criteria of an FEO. Rhythmic ghrelin and PER expression are synchronized to prior feeding. This suggests that ghrelin increases the drive to consume food. Ghrelin stimulates both the appetitive (anticipatory locomotor behavior) and the consummatory component (food intake). and ghrelin is rhythmic in light-dark cycles and in constant darkness with ad libitum food and after 48 h of food deprivation. These activate food-seeking behaviors and enable the synthesis and secretion of enzymes necessary for digestion before mealtime. Conclusions: This article concludes that oxyntic gland cells of the stomach contain FEOs. Silver R Department of Psychology. In mice lacking ghrelin receptors..Y. reflected in an increase in activity several hours before the appearance of food. N. In behaviorally arrhythmic-clock mutant mice. whose locations and output signals have long been sought. FAA is significantly reduced. Both ghrelin and clock genes are expressed rhythmically within oxyntic cells. Pfaff DW. there is no evidence of a premeal decrease in oxyntic cell ghrelin. it keeps running until the usual time of food availability. It is known that ghrelin is secreted in anticipation of a regularly scheduled mealtime. Weintraub M. The body uses an endogenous circadian timing system. once an animal begins its daily anticipatory bout. unlike control animals. Hoque N. 216 Jean-Claude Carel/Ze’ev Hochberg . In the absence of ghrelin receptors. New York. ghrelin release timed to previous mealtimes persists after 1–3 days of fasting.In anticipation of food Stomach ghrelin-secreting cells as food-entrainable circadian clocks LeSauter J. termed ‘food anticipatory activity’ (FAA). Barnard College. the cumulative rise of activity before food presentation closely approximates a gaussian function (r = 0. Administration of ghrelin in the absence of food in a nondeprived animal increases activity/ arousal and increases subsequent food intake. Oxyntic cells coexpress ghrelin and the circadian clock proteins PER1 and PER2. in humans. Results: This report shows that ghrelin administration increases locomotor activity in nondeprived animals in the absence of food. Discovery of the brain mechanisms modulating ghrelin effects on activity and eating will further the understanding of this system in the generation of FAA. It is likely that other FEOs also produce humoral signals that modulate FAA. PER2. with the latter having a smaller amplitude. For regularly scheduled daily meals. The phase of this rhythm is controlled by the time of food availability. depend on circadian food-entrainable oscillators (FEOs). For both groups. Although mice cannot be deprived for many days. termed ‘food-entrainable oscillators’ (FEOs). The expression of PER1.

Cesareni G Department of Biology. Moreover. and ovarian failure and infertility are major side effects of chemotherapy in young patients with cancer. modulates the p63 transcriptional output. the options to preserve fertility are still limited and cryopreservation of one ovary is now a common procedure at pediatric cancer centers [5]. treatment of immature mice with imatinib and cisplatin resulted in normal-appearing follicles in adult ovarian tissue and restored fertility. effect on damage induced by other drugs than cisplatin) before we embark on clinical trials.gonfloni@uniroma2. but this first step is really good news. However. Imatinib. in vitro maturation of eggs is an experimental process that has only been successful in animals so far. imatinib might modulate the effects of cisplatin on the target tumor. new approaches to protect gonadal tissues against the effects of chemotherapy are needed.15:1179–1185 Background: Germ cells are sensitive to genotoxins. The use of GnRH agonist in pubertal girls has been discussed but is unlikely to have any effect [6]. Mattei M. through its kinase activity. Candi E. in oocytes. aimed at preserving oocytes of the follicle reserve during chemotherapeutic treatments. Results: The c-Abl-TAp63 pathway is activated by chemotherapeutic DNA-damaging drugs in model human cell lines and in mouse oocytes and plays a role in cell death. Editor’s Choice 217 . Di Bartolomeo C.New hope Preventing infertility after childhood cancer treatment Inhibition of the c-Abl-TAp63 pathway protects mouse oocytes from chemotherapy-induced death Gonfloni S. this breakthrough idea may raise several issues. blocked the immediate appearance of apoptotic oocytes when delivered with cisplatin. there is a need for more experimental data (action on the testis. an inhibitor of c-Abl. and there are some examples where it might increase or decrease the anticancer effect. c-Abl phosphorylates TAp63 on specific tyrosine residues. De Felici M. First imatinib treatment might rescue damaged oocytes with a high risk for miscarriage and birth defects. Caldarola S. The authors have observed that after cisplatin administration. Italy stefania. Second. As nicely discussed in the associated editorial [7]. which. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters.it Nat Med 2009. Cannata SM. Treatment with the c-Abl kinase inhibitor imatinib counteracts these cisplatin-induced effects. Conclusion: The data support a model in which signals initiated by DNA double-strand breaks are detected by c-Abl. Melino G. University of Rome Tor Vergata. cisplatin rapidly promotes TAp63 accumulation and eventually cell death. p63 serves to eliminate the injured germ cells and that the kinase c-Abl is activated. In young patients with cancer. Di Tella L. transplantation of pieces of the cryopreserved ovarian cortex has resulted in the resumption of endocrine function and in live births but the procedure is only possible for those with low risk of preexisting contaminating cancer cells in the ovarian tissue. upon cisplatin treatment. For others. Klinger FG. they suggest a new use for imatinib. Similarly. In cell lines. Rome. Altogether. Moreover. Therefore. the options to use the preserved ovarian tissue are still experimental.

Grote FK. Nature 2010. van Buuren S. glucose surveillance and patient education. This review considers research in the field of type 1 diabetes toward identifying disease mechanisms using genetic approaches. Zaret KS. Pediatrics 2009. Once diagnosed. Rogol A. Gracia C.and B-cell activation. 6. West ER. Ravassard P. et al: The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into and subsequently cells. Woodruff TK: Preserving fertility during cancer treatment. White MF: Diabetes forum: extreme makeover of pancreatic cells. an evaluation of consensus guidelines. Dekker FW. 2.138:449–462. Ghizzoni L. The authors describe current progress. 7. The last decade has seen tremendous advances in elucidating the causes and treatment of the disease based on extensive research both in rodent models of spontaneous diabetes and in humans. timing of disease activation. et al: The diagnostic work up of growth failure in secondary health care. UK john. will be influenced by epigenetic and environmental factors.123:e752–e762.464:1132–1133. BMC Pediatr 2008.ac.53:289–295. 3.32:457–467 Recent genetic mapping and gene-phenotype studies have revealed the genetic architecture of type 1 diabetes. Chang J. Type 1 diabetes is among the most frequent conditions managed by pediatric endocrinologists and still has a very somber long-term prognosis despite advances in insulin delivery.uk Immunity 2010. De Muinck Keizer-Schrama SM. but with limited impact on daily management.todd@cimr.464:1293–1300 Type 1 diabetes is an autoimmune disorder afflicting millions of people worldwide. Liu Z. 5. Cambridge Institute for Medical Research. Billestrup N.8:21. Palmert MR. Herold K. Antoniazzi F. USA jbluest@diabetes.cam.138:424–426. Coutifaris C. 4. They give an updated and comprehensive view on these fields and future research directions with the hope that these advances will improve patient care during the next decade. Nat Med 2009. Sosa-Pineda B. Xu X. Dussaud S. Oostdijk W. pathogenesis and clinical interventions in type 1 diabetes Bluestone JA. At least ten genes so far can be singled out as strong causal candidates. Zelinski MB. including HLA class II and I molecules binding to preproinsulin peptides and T-cell receptors. and T-regulatory and antigen-presenting cell functions. San Francisco. Integrating these advances has led to the recognition that the balance between regulatory and effector T cells determines disease risk. and therefore disease susceptibility. and disease tempo.15:1124–1125. It is also the pediatric endocrine disease on which the highest amount of research money has been spent. These two reviews are very timely and come from authorities in the field of diabetes genetics and immunology. innate pathogenviral responses. San Francisco. Cell 2009. the challenges ahead and the new interventions that are being tested to address the unmet need for preventative or curative therapies. The known functions of these genes indicate the primary etiological pathways of this disease. Collombat P. References 1. Etiology of type 1 diabetes Todd JA Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory. leading to major advances in our understanding of the mechanisms of the disease. University of Cambridge.ucsf. Calif. Pediatr Blood Cancer 2009. Cambridge. Habener JF: Alpha cells beget cells. T. University of California. Department of Medical Genetics. Eisenbarth G Diabetes Center and Department of Medicine. Carel JC. 218 Jean-Claude Carel/Ze’ev Hochberg . et al: Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Cell 2009.edu Nature 2010. Eugster EA. The expression and functions of these pathways.. chemokine and cytokine signaling. Certain inherited immune phenotypes will be early precursors of type 1 diabetes and could be useful in future clinical trials. patients require lifelong insulin treatment and can experience numerous disease-associated complications. van Dommelen P. Kondapalli LA.Reviews Genetics. et al: Preserving female fertility following cancer treatment: current options and future possibilities.

Paris. It confirms that a metabolic disease affecting the brain can be improved by hematopoietic stem cell correction and suggests that similar lentiviral approaches might be ben- . Lefrere F. Quite interestingly. Caccavelli L. cloning the gene and refuting undue claims of dietary manipulation [1–3]. although preliminary. genetically corrected ex vivo with a lentiviral vector encoding wild-type ABCD1. Conclusion: Lentiviral-mediated gene therapy of hematopoietic stem cells can provide clinical benefits in ALD. the favorable effect of allogeneic bone marrow transplantation demonstrated that replacement of deficient bone marrow-derived microglial cells was sufficient to cure the central nervous system involvement but had no effect on the adrenal dysfunction – an interesting observation for further research. ALD progression can be halted by allogeneic hematopoietic cell transplantation (HCT). partial correction of the biochemical alterations and favorable clinical evolution. Kutschera I. Mittelstaedt D. Bellesme C. These results strongly suggested that hematopoietic stem cells were transduced in the patients. France Science 2009. Audit M. polyclonal reconstitution was detected. an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. Autologous CD34+ cells were removed from the patients. which were reinfused after myeloablation. the major impact of this devastating disease is on white matter demyelination. This study is important not only for those affected or involved in the care of adrenoleukodystrophy. Aubourg P INSERM UMR745. l’Homme B. The results.Science and Medicine Ze’ev Hochberg and Jean-Claude Carel New hope Gene therapy for adrenoleukodystrophy Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy Cartier N. Bougneres P. Schmidt M. bone marrow transplantation is a risky procedure and is often impeded by lack of familial or unrelated donor. Bartholomae CC. but also for the field of gene therapy which has been slowed down by several setbacks [4]. Fischer A. Payen E. Hacein-Bey-Abina S. no preferential clonal expansion was observed as compared to previously observed integration-related mutagenesis and leukemogenesis with retroviral vectors. Vidaud M. are quite striking since they show long-term engraftment of transduced cells. Approximately 50% of affected males present in mid-childhood with progressive demyelinating disease leading to death in adolescence. More importantly. Cavazzana-Calvo M. and T and B lymphocytes expressing the ALD protein. and then reinfused into the patients after they had received myeloablative treatment. monocytes. Mahlaoui N. Abel U. Lahlou N. University Paris-Descartes. Although adrenoleukodystrophy often presents as an endocrine disorder with adrenal insufficiency and to a lesser extent Leydig cell insufficiency. However. Dal-Cortivo L. with 9–14% of granulocytes. basic scientists and clinical hematologists concurred to construct HIV-derived lentiviral vectors and transduce CD34+ hematopoietic stem cells from 2 patients. Von Kalle C. Leboulch P. Beginning 14–16 months after infusion of the genetically corrected cells. The group of Patrick Aubourg has been essential along the years in delineating the disease through establishment of allogeneic bone marrow transplantation as an efficient therapy. Results: Over a span of 24–30 months of follow-up. Methods: The authors performed a gene therapy trial in 2 ALD patients for whom there were no matched donors.326:818–823 Background: X-linked adrenoleukodystrophy (ALD) is a severe brain demyelinating disease in boys that is caused by a deficiency in ALD protein. Kiermer V. A large collaborative group of pediatric neurologists and endocrinologists. Veres G. Blanche S. progressive cerebral demyelination in the 2 patients stopped – a clinical outcome comparable to that achieved by allogeneic HCT.

by correlation with known trait-associated single nucleotide polymorphisms (SNPs). Osaka. and approximately 8% of the human genome is made up of these elements. type 1 diabetes and type 2 diabetes. none has been found as DNA in the germline of animals. Retrotransposition has duplicated and inserted some coding and non-coding DNA segments randomly around the genome. they identified 30 loci with CNVs that are candidates for influencing disease susceptibility. Ikuta K. Wei J. are known to generate DNA forms of their own genomes during replication. are unique among RNA viruses in that they establish persistent infection in the cell nucleus. there are now around 30 genetic variants known to influence susceptibility to the disease.000 patients – 2. Campbell P. Furthermore. Daito T. Macdonald JR. Oshida T. Valsesia A. Origins and functional impact of copy number variation in the human genome Conrad DF. and none of the three CNV loci is believed to contribute to disease.464:704–712 Structural variations of DNA >1 kb in size account for most bases that vary among human genomes. Pang AW. for example. Conclusions: Having assessed the completeness of this map and the patterns of linkage disequilibrium between CNVs and SNPs. a genus of non-segmented. This study analyzed common CNVs in DNA samples from 3. either through particular CNVs having a strong effect or through a large number of CNVs each contributing a small effect. Redon R. Suzuki Y. Gokcumen O. Gojobori T. rodents and elephants. the heritability void left by genome-wide association studies will not be accounted for by common CNVs. African or East-Asian ancestry. Coffin JM. UK Nature 2010. they generated reference genotypes from 450 individuals of European. It seems unlikely that common CNVs play a major role in the genetic basis of these or other common complex diseases. Feuk L. Osaka University. Stirrups K. Results: Here they show that elements homologous to the nucleoprotein (N) gene of bornavirus exist in the genomes of several mammalian species. More importantly. Lee C. For 4.000 each with bipolar disorder. Honda T. including non-retroviral RNA viruses. to generate a comprehensive map of 11.463:84–87 Retroviruses are the only group of viruses known to have left a fossil record. Endogenous non-retroviral RNA virus elements in mammalian genomes Horie M.700 copy number variations (CNVs) >443 bp. Robson S. Tyler-Smith C. Carter NP. Fitzgerald T. Tomonaga K Department of Virology.eficial to other genetic diseases. Zhang Y. coronary artery disease. comprising 42 million probes. and all three had been identified previously by searching for SNPs. this report concludes that. Onyiah I. Walter K. Kobayashi Y. Bornaviruses. Yet. breast cancer. it shows that persistence in clinical and basic study of a single disease can lead to major advances in medicine. but are still relatively under-ascertained. Research Institute for Microbial Diseases (BIKEN). They identified and confirmed three loci with commonly occurring CNV. Cambridge.000 healthy volunteers and compared them to 16. for complex traits. Crohn’s disease. Context: For type 2 diabetes. in the form of endogenous proviruses. Kristiansson K.978 of these CNVs. of which most (8. Wellcome Trust Genome Campus. several studies of diabetes and other complex diseases found that commonly occurring CNV are unlikely to play a major role in such diseases. hypertension. Macarthur DG. Aerts J. Hu M. Results: The predominant mutational mechanisms differ among CNV size classes. non-human primates. negative-sense RNA virus. Scherer SW. Jern P. Barnes C. One theory for this so-called ‘missing heritability’ was that it may have been caused by copy number variations (CNVs). rheumatoid arthritis.599) have been validated independently. Japan Nature 2010. Hurles ME The Wellcome Trust Sanger Institute. Pinto D. Methods: This study use tiling oligonucleotide microarrays. Some of the primate EBLNs contain an intact open reading frame and are expressed as mRNA. Although many other viruses. These sequences have been designated endogenous Borna-like N (EBLN) elements. Andrews TD. including humans. Phylogenetic analyses showed that EBLNs seem to have been generated by different insertional events in each specific Context: 220 Ze’ev Hochberg/Jean-Claude Carel . but these only account for about 10% of the known inherited risk of developing these conditions. Ihm CH.

DNA methylation and gene expression differences in children conceived in vitro or in vivo Katari S. Phylogenetic analyses demonstrate that the oldest primate gene of bornavirus must have appeared in an ancestor of primates at least 40 million years. these differences or changes may affect long-term patterns of gene expression. Alternatively. can form EBLN-like elements in the genomes of persistently infected cultured cells. Furthermore. Borna disease virus. These epigenetic differences have the potential to affect embryonic development and fetal growth. This report provides evidence of endogenous sequences derived from a non-retroviral RNA virus in mammalian species. In either case. like some endogenous retroviruses. This report analyzed DNA methylation at a large number of CpG sites in placenta and cord blood. as a group. Coutifaris C. The authors suggest that there is also a possibility that these changes could pass to the children of IVF babies and spread through the human gene pool. and rare disorders involving imprinted genes. Philadelphia. whereas those in primates must have been formed more than 40 million years ago.. suggesting that epigenetic changes may be associated with assisted reproduction. The paper also raises the possibility that. Foster M. USA Hum Mol Genet 2009. Sapienza C Fels Institute for Cancer Research and Molecular Biology. The range of inter-individual variation in gene expression of the in vitro and in vivo groups overlaps substantially but some individuals from the in vitro group differ from the in vivo group mean by more than two standard deviations.536 CpG sites) in placenta and cord blood and measured gene expression levels of a subset of genes that differed in methylation levels between children conceived in vitro versus in vivo. They observed an overall lower level of specific CpG site methylation in placenta and higher level in cord blood. the Bornal genes may have some function in their host species – us. Bibikova M. do not differ significantly from their control counterparts. IVF children. It is likely that these are processed pseudogenes derived from ancient bornavirus infections. such as obesity and type 2 diabetes. Conclusions: These findings suggest that there may be epigenetic differences in the gametes or early embryos derived from couples undergoing treatment for infertility. Gaughan JP. except for having an increased incidence of low birth-weight and being slightly taller. It also finds that in vitro conception-associated DNA methylation differences are associated with gene expression differences at both imprinted and non-imprinted genes.animal family. Despite replication during tens of millions of years as exogenous viruses. Context: IVF now accounts for at least 1–2% of all live births in the Western world. the EBLN of a ground squirrel was formed by a recent integration event. They also show that the N mRNA of a current mammalian bornavirus. Chalian R. Science and Medicine 221 . but also into a role of bornavirus as a source of genetic novelty in its host. it may suggest differences in the way ‘outer’ and ‘inner’ blastomeres of pre-implantation embryos respond to in vitro culture. Conclusions: These results provide the first evidence for endogenization of non-retroviral virus-derived elements in mammalian genomes and give novel insights not only into generation of endogenous elements. Methods: This study examined DNA methylation at more than 700 genes (1. as well as to influence the long-term patterns of gene expression associated with the increased risk of many human diseases. Several of the genes whose expression differs between the two groups have been implicated in chronic metabolic disorders.and postnatal development are measured. providing a new source of genetic innovation in their hosts. Temple University School of Medicine. the amino acid sequences of current Borna disease virus proteins seem surprisingly conserved. Pa. Although the overall rate of congenital anomalies in children conceived by IVF is low (4–6%).18:3769–3778 Epidemiological data indicate that children conceived in vitro have a greater relative risk of low birth-weight. major and minor birth defects. If these differences are characteristic of differences in embryonic versus extraembryonic tissues. comparing children conceived by IVF with a control group. assisted reproduction technology may have an effect on global patterns of DNA methylation and gene expression. When indices of pre. Turan N. Results: The results suggest that in vitro conception is associated with lower mean methylation at CpG sites in placenta and higher mean methylation at CpG sites in cord blood. Erinle O. this rate still represents a significant increase over the background rate of major malformations (3%).

and develop as the testicle ages. Taylor IBa. Results: Screening of 30 spermatocytic seminomas for oncogenic mutations in 17 genes identified 2 mutations in FGFR3 (both 1948A>G. University of Oxford. Picard C. Cant AJ. Barcenas-Morales G. mucocutaneous candidiasis and neonatal tolerance Autoantibodies against IL-17A. Doffinger R. Massively parallel sequencing of sperm DNA showed that levels of the FGFR3 mutation increase with paternal age and that the mutation spectrum at the Lys650 codon is similar to that observed in bladder cancer. Paris. autism and schizophrenia. Copenhagen University Hospital. and eDepartment of Statistics. Toulon A. Chrabieh M. raising the risk to older fathers of having affected children. Al-Muhsen S. Cobat A.puel@inserm. d Computational Biology Research Group. Fischer A. Here we unify these processes to a single cellular event for mutations arising in male germ cells that show a paternal age effect. Arkwright PD. encoding K650E. Necker Branch. IL-17F. Departments of bGrowth & Reproduction and cPathology. Polak M. But other diseases seem to be more frequent in the offspring of older fathers. U550.fr J Exp Med 2010. to a mutational event likely happening in the same cell. Al-Owain M. The authors call them ‘selfish’ because the mutations benefit the germ cell but are harmful to offspring. McVean GAe. Copenhagen. Costigan C. UK. Wilkie AOa a Weatherall Institute of Molecular Medicine.Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors Goriely Aa. John Radcliffe Hospital. McGowan SJd. the authors suggest that mutations might contribute to these diseases. Natividad A. Lilic D. including breast cancer. Pfeifer SPe. Context: This article offers a link between achondroplasia and Apert. France anne. Nahum A. congenital syndromes and cancer predisposition. but the causative germline and somatic mutations occur in separate cells at different times of an organism’s life. Bougneres PF. FGFR3 and HRAS mutations induce gain of function. Hence. Casanova JL Laboratory of Human Genetics of Infectious Diseases. leading to diverse phenotypes in the next generation including fetal lethality. Marodi L. the number of sperm carrying this mutation increases as men get older. Institut National de la Santé et de la Recherche Médicale (INSERM). which causes thanatophoric dysplasia in the germline) and 5 mutations in HRAS.207:291–207 Background: Most patients with autoimmune polyendocrine syndrome type I (APS-I) display chronic mucocutaneous candidiasis. Conclusions: This article proposes that paternal age-effect mutations activate a common ‘selfish’ pathway supporting proliferation in the testis. The findings link the processes of mutation in the soma (causing neoplasia) and germline (causing heritable disorders in the next generation). Abinun M. Olesen IAb. Kumararatne D. and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I Puel A. 222 Ze’ev Hochberg/Jean-Claude Carel . Bodemer C. Noonan and Costello syndromes and seminomas of older men: they all may arise from germ cell defects. Denmark. Hansen RMa. Jacobsen GKc. University of Oxford. UK Nat Genet 2009. Abel L. New mechanisms All in the Aire – cytokine antibodies. McConnell V. Oxford. Oxford. Bustamante J. Blanche S. and encourage the mutant cells to divide and multiply with copies of the mutation to each daughter cell.41:1247–1252 Genes mutated in congenital malformation syndromes are frequently implicated in oncogenesis. Most spermatocytic seminomas show increased immunoreactivity for FGFR3 and/or HRAS. Roifman C. Meyts ERb. Oxford. which normally occur in different cells. Ouachee-Chardin M.

IL-10. as shown by Western blotting. Autoimmune polyendocrine syndrome type I (APS-I) is a rare and severe monogenic disorder due to loss of function of the Aire gene. Similar data were presented in an accompanying paper [7]. Mathis D Section on Immunology and Immunogenetics. it could not easily provide a basis for the unique susceptibility to candidiasis. This susceptibility to candidiasis is quite unique and is not associated with risk of infection with other pathogens. Boston. IL-26. In addition to providing a mechanistic basis for candidiasis. The lymphopenic state present in neonates was a factor in this dichotomy because inducing lymphopenia during Aire turnoff in adults recreated the disease. including endocrine (parathyroid. but also challenges to. produced by Th17 CD4+ T cells [6]. addresses a fundamental question regarding the immune system of whether the neonatal period is unique as a Science and Medicine 223 .Methods: The authors hypothesized that this chronic mucocutaneous candidiasis might result from autoimmunity to interleukin (IL)-17 cytokines. Here it is shown that antibodies to IL-17 cytokines. Methods: Doxycycline-regulated transgene to target Aire expression to the thymic epithelium. The display of self antigens by thymic epithelial cells is key to inducing tolerance in the T-lymphocyte compartment. None of the patients with APS-I had auto-Abs against cytokines previously shown to cause other welldefined clinical syndromes in other patients (IL-6. Mass. or transforming growth factor. IL-18.. which is often the presenting sign in early childhood and highly prevalent in affected individuals. Results: Aire is essential in the perinatal period to prevent the multiorgan autoimmunity that is typical of Aire deficiency. IL-12. probably explains the candidiasis observed in APS-I patients. The auto-Abs against IL-17A. showing in addition that patients with thymomas. Results: High titers of autoantibodies against IL-17A. …) systems. …) and non-endocrine (liver. Neonatal tolerance revisited: a perinatal window for Aire control of autoimmunity Guerau-de-Arellano M. Complementing this particular aspect of APS-I. the notion that the initial period of the immune system’s development is particularly important for the establishment of tolerance to self. thyroid. adrenals. The auto-Abs against IL-17A were neutralizing as shown by bioassays of IL-17A activity. conversely. interferon. digestive tract. interferon. One of the unique features of the disease is the susceptibility to chronic mucocutaneous candidiasis. Harvard Medical School. The list of autoimmune targets is extremely vast. and IL-22 may cause chronic mucocutaneous candidiasis in patients with APS-I. USA J Exp Med 2009. a process enhanced by the Aire transcription factor. Benoist C. Conclusion: Aire expression during the perinatal period is both necessary and sufficient to induce longlasting tolerance and avoid autoimmunity. could be ameliorated by supplementing neonates with adult lymphocytes. Conclusion: The findings suggest that autoantibodies against IL-17A. a situation of acquired defective central T-cell tolerance similarly have antibodies to Th17 cytokines. as a previously tolerized T-cell pool can buffer newly generated autoreactive T cells that might emerge.. IL-17F.). None of the 37 healthy controls and none of the 103 patients with other autoimmune disorders tested had such autoantibodies.206:1245–1252 Background: There has long been conceptual and experimental support for. The general mechanism for the disease lies in the role of the Aire gene in directing the expression of self antigens in specialized cells of the thymic medulla (medullary thymic epithelial cells) where these self antigens allow for the elimination of highly self-reactive T lymphocytes [5]. bronchi. Although this general mechanism has been demonstrated in human and animal systems. IL-23. and IL-22 were specific in the 5 patients tested. the paper by Guerau-de-Arellano et al. Joslin Diabetes Center.. Aire-controlled mechanisms of central tolerance are largely dispensable in the adult. complementing the Aire knockout in a temporally controlled manner.. and/or IL-22 were found in the sera of all 33 patients tested. Martinic M. islets. with few deleterious consequences. IL-17F. IL-17F. as compared to other involvements. resulting in a failure of central (thymic) tolerance mechanisms and in multiorgan autoimmunity. Aire could be shut down soon thereafter and remain off for long periods. tumor necrosis factor. which. IL-21. or granulocyte/macrophage colonystimulating factor) or against other cytokines (IL-1 . these results give ground to clinical evaluation of immunosuppressive therapies such as ones targeting B cells in patients with APS-I [8]. as detected by multiplex particle-based flow cytometry.

Increased autoimmunity with age could be viewed as an escape from these mechanisms. Conclusion: The results suggest a unique susceptibility of patients with DKA to mucormycosis and provide a foundation for the development of new therapeutic interventions for these deadly infections. polyendocrinopathy. Torrance. The authors have analyzed the pathogenesis of Rhizopus oryzae. Phan QT. Jr. Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center. Infections. the Mathis group used a clever system of inducible Aire transgene in a background of Aire knockout mice. lungs. Altogether. The discovery of Aire and the establishment of its role in central tolerance has greatly enhanced our understanding of immune tolerance. Patients with elevated available serum iron. In this study. Lee AS. In addition. are a hallmark of diabetes and an important cause of morbidity and mortality in diabetic patients. enteropathy. the pathogen involved in mucormycosis.time when the immune system becomes tolerant to any (most?) antigens that it encounters. Angioinvasion is a hallmark of mucormycosis infections and endothelial cell receptor(s) for fungi of the order Mucorales (the fungi that cause mucormycosis) are not determined. Ibrahim AS Division of Infectious Diseases. USA J Clin Invest 2010. Filler SG. which have enhanced susceptibility to mucormycosis. If we ever find a way to cure APS-I. Edwards JE. and brain compared with normal mice. brain. suggesting a role of iron and glucose in regulating the expression of such a receptor. allowing them to control Aire expression throughout development. the most common etiologic species of Mucorales. as exemplified by premature immune aging in young adults thymectomized during early childhood and autoimmune diseases arising in patients with thymomas [9]. Study of neonatal T tolerance in subjects at risk for autoimmune diseases might result in new paradigms for the treatment or prevention of autoimmunity by targeting this specific period of life. in particular fungal. exhibited increased expression of GRP78 in sinus. GRP78-specific immune serum protected mice with DKA from mucormycosis. and failure to establish neonatal tolerance results in catastrophic autoimmune diseases such as APS-I or IPEX (immune dysregulation. Elevated concentrations of glucose and iron. Concepts revised Bugs like sweets – with a little help from GRP78 The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice Liu M. Methods and Results: Glucose-regulated protein 78 (GRP78) was identified as a novel host receptor that mediates invasion and damage of human endothelial cells by Rhizopus oryzae. This paper revisits this concept and shows that such simplistic views should be revised. these results provide important and new understanding of the regulation of autoimmunity in the neonatal period. Fu Y. Calif. It turns out that the thymus continues to play a role throughout life. we will have to diagnose it intrauterinely or in early infancy. are uniquely susceptible to mucormycosis.. whereas transient depletion of lymphocytes in protected adult mice worsened the pathology. whereas expression of Aire during fetal and the first 3 weeks of life almost completely prevented autoimmunity. X-linked). The most generally invoked mechanism for this increased susceptibility is the increased availability of glucose as a metabolic substrate for pathogen growth. but not Candida albicans or Aspergillus fumigatus. infusions of physiologically lymphopenic Aire-deficient neonates with adult T cells partially prevented the autoimmune pathology. They show that a normal endothelial protein with unknown physiological functions serves as receptor for the 224 Ze’ev Hochberg/Jean-Claude Carel . enhanced GRP78 expression and the resulting R. Finally. Spellberg B. consistent with those seen during DKA. Mice with DKA. including those with diabetic ketoacidosis (DKA). oryzae invasion and damage of endothelial cells in a receptor-dependent manner. a deadly fungal infection that can occur in immunocompromised patients and in diabetic ketoacidosis. Expression of Aire during fetal life only had a minimal effect in preventing autoimmunity. or lungs that causes a mortality rate of at least 50% despite first-line therapy.120:1914–1924 Background: Mucormycosis is a fungal infection of the sinuses.

Citation bias. Mass. including an angiogenesis inhibitor. completeness. The author used a very limited research field (the role of -amyloid in inclusion body myositis) and applied social networks techniques to address the question of how citation distortion can create what the author calls ‘unfounded authority’. amplification. the marked expansion of the belief system by papers presenting no data addressing it. Moreover. Six Science and Medicine 225 . authors must consider carefully the selection. Results: The network contained 242 papers and 675 citations addressing the belief. amplification.. is produced by and injures skeletal muscle of patients with inclusion body myositis.org BMJ 2009. and forms of invention such as the conversion of hypothesis into fact through citation alone. Social network theory and graph theory were used to analyze this network. and appropriateness of the articles referenced to ensure adequate and accurate citation as a necessity of scientifically and methodologically sound research. and invention. Extension of this network into text within grants funded by the National Institutes of Health and obtained through the Freedom of Information Act showed the same phenomena present and sometimes used to justify requests for funding. Since most journals allow only a limited number of references. Construction and analysis of a claim-specific citation network may clarify the nature of a published belief system and expose distorted methods of social citation. Food for thought Tell me who you cite. amplification. Although we have all noticed distortions in citations in specific manuscripts. with 220. Brigham and Women’s Hospital. 242 papers generated a network of more than 220. and invention. It has also been reported as a receptor for a variety of ligands. all observed during diabetic ketoacidosis. a synthetic peptide a dengue virus and a Coxsackievirus. and their effects on determining authority were studied. low pH and high iron concentrations. These data demonstrate the plasticity of pathogens which have adapted to mammalian proteins and use them as unwanted receptors or adhesion molecules. Unfounded authority was established by citation bias against papers that refuted or weakened the belief. a protein accumulated in the brain in Alzheimer’s disease. high glucose. Conclusion: The author concludes that citation is an impartial scholarly method and a powerful form of social communication. Harvard Medical School. Last and more importantly. USA sagreenberg@partners.000 citation paths. Citations of peer-reviewed papers constitute one of the bases of medical writing and allow authors to make statements based on ‘current knowledge’ or on previously established facts in the literature. I will tell you who you are How citation distortions create unfounded authority: analysis of a citation network Greenberg SA Children’s Hospital Informatics Program and Department of Neurology. Boston. Distortions in its use including bias. Methods: A complete citation network was constructed from all PubMed indexed English literature papers addressing the belief that -amyloid.553 citation paths supporting it. authors invariably have to make choices in the references they use. concur to increase the expression of the receptor. The aim of the paper was to understand belief in a specific scientific claim by studying the pattern of citations among papers stating it. GRP78 is a member of the HSP70 protein family and functions as a chaperone.339:b2680 Background: During the preparation and writing of manuscripts. We should refrain from simplistic explanations for phenomena we believe to understand.fungus. Ten authoritative papers were all from the same group with only 4 of them containing primary data. can be used to generate information cascades resulting in unfounded authority of claims. this is the first systematic approach to such a phenomenon. an activated proteinase inhibitor. blocking GRP78 with an antibody prevents mucormycosis and might become a useful approach to treat this deadly condition.

Herrin J. Akl EA. and natural frequencies. A relative importance score was calculated by subtracting the VAS for the downsides of taking statins from the VAS score for coronary heart disease.carling@kunnskapssenteret. as well as amplification over time and impact on NIH funding. number needed to treat. Conclusion: Presenting the benefits of taking statins as a relative risk reduction increases the likelihood of people accepting treatment compared to presenting absolute summary statistics. Treweek S. In the field of clinical medicine.6:e1000134 Background: Different ways of presenting treatment effects can affect healthcare decisions but little is known about which presentations best help people make decisions consistent with their own values.no PLoS Med 2009. calling the attention of authors on the fairness of the selection of papers they cite could be one step forward [10]. Oxman AD Norwegian Knowledge Centre for the Health Services. the recognition of such citation biases has led to the development of meta-analyses and systematic reviews where all primary evidence is re-evaluated and weighed appropriately. Important for clinical practice Beware of how you say it Effect of alternative summary statistics for communicating risk reduction on decisions about taking statins: a randomized trial Carling CL. There were no significant differences among the absolute summary statistics in the association between relative importance score and participants’ decisions whether to take statins. or for mechanistic or diagnostic studies. Whether the same is true to other fields of science is not known and more studies like this will be needed in other research areas to establish how widespread the process is. i. 2. for every 5 participants shown the relative risk reduction.e. Communication in modern medical practice is essential since patients are more and more associated with difficult choices offered by several possibilities of contemporary medicine. This corresponds to a number needed to treat of 5.papers with primary data that were critical of the hypothesis were seldom of never cited. reviewers or authors of manuscripts to avoid carrying over inaccurate information from one paper to the next as elegantly demonstrated here. and approaches to present them both to 226 Ze’ev Hochberg/Jean-Claude Carel . tablets needed to take. Citation distortions were noted. Logistic regression was used to determine the association between participants’ relative importance score and their choice. Results: Relative risk reduction resulted in a 21% higher probability of choosing to take statins over all values of relative importance score compared to the absolute summary statistics. Schunemann HJ. The accompanying Editorial calls for systematic reviews included or available for all grant applications. Adult volunteers were recruited who participated through an interactive website. independent of the relative importance they attach to the consequences. Participants rated the relative importance of outcomes using visual analog scales (VAS). Oslo. However.978 participants completed the study. compared to the other summary statistics. based on self-reported preference. this has not been the case for basic science. In addition. event rates. Montori VM. Norway cheryl. They were randomized to one of the six summary statistics and asked to choose whether to take statins based on this information. Methods: Six summary statistics for communicating coronary heart disease (CHD) risk reduction with statins were compared: relative risk reduction and five absolute summary measures – absolute risk reduction. A randomized trial was conducted to determine which presentation would result in choices most consistent with participants’ values. These choices are increasingly complex for physicians in their own field. Natural frequencies may be the most suitable summary statistic for presenting treatment effects. and participants were most satisfied with this information. 1 additional participant chose to take statins. Natural frequencies were best understood (86% reported they understood them well or very well). we should all pay attention to citation distortion as readers. Kristoffersen DT. and confidence in the decision. understanding of and satisfaction with the information. In the meantime.

00–1. 1.530 patients died during the active study period and 4. event rate and natural frequencies. Steensma DP. Piper M. Untch M. Seidenfeld J. Brillant C. Schwarzer G. Individuals in the group that was presented with relative risk reduction selected the treatment in 74% of cases. Although subjectivity is an important part of medical decision-making. Djulbegovic B.healthcare professionals and to patients have been developed. Erythropoiesis-stimulating agents increased mortality during the active study period (combined hazard ratio 1. Moebus V. Egger M. healthcare professionals increasingly share evidence-based medical information with their patients to allow them to participate in medical decisions. the majority of volunteers was above 40 years of age and therefore potentially implicated in similar choices. Schumacher M. 95% CI 1.000 patients showed a 17% increased Science and Medicine 227 . Zwahlen M. and in patients given chemotherapy. communication is never neutral and we know from daily practice that the ways we explain treatment affect patients’ choice. epoetin beta.441 patients on chemotherapy were enrolled in 38 trials. Engert A Institute of Social and Preventive Medicine.12). Schmidlin K. or darbepoetin alfa were obtained and analyzed by independent statisticians using fixed-effects and random-effects meta-analysis.30) and worsened overall survival (1. Tests for interactions were used to identify differences in effects of erythropoiesisstimulating agents on mortality across pre-specified subgroups. Rades D. Machtay M. The combined hazard ratio for mortality during the active study period was 1.98–1. Analyses were by intention to treat. with little heterogeneity between trials.06. A clear limitation of the study is that the recruitment was internet-based. This study shows that this is not enough and that we should pay attention not only to the information we provide but also how we provide it.933 patients with cancer in 53 trials were analyzed.993 overall. absolute risk reduction. Thomas G. 10. Data for patients treated with epoetin alfa.11) for overall survival. tablets needed to treat.04 (0.24). Conclusion: Treatment with erythropoiesis-stimulating agents in patients with cancer increased mortality during active study periods and worsened overall survival. Kluge S. number needed to treat. New concerns EPO and mortality in cancer patients Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomized trials Bohlius J. However. Patients with cancer are often anemic and it has been debated whether erythropoiesis-stimulating agents that increase the comfort and quality of life of patients might increase mortality. as compared with ≈50% in all other groups. irrespective of anticancer treatment. Primary endpoints were mortality during the active study period and overall survival during the longest available follow-up. Clarke M. and 1.10 (0. 53 out of 102 eligible studies were selected and the meta-analysis on more than 14. Weingart O. Ray-Coquard I. Switzerland Lancet 2009. but these drugs might increase mortality.97–1.17. and the volunteering subjects were not really involved in the decision process. The value of this paper is really to illustrate the power of high-quality meta-analyses to elucidate rare or difficult-to-detect events in a complex situation such as the treatment of cancer. Bern. 1. Fey MF. Results: Data from a total of 13. University of Bern.06–1.373:1532–1542 Background: Erythropoiesis-stimulating agents reduce anemia in patients with cancer and could improve their quality of life. Trelle S. However. This study addressed the issue in a systematic way by randomizing volunteers to 6 groups who were presented with the same therapeutic scenario (10-year coronary heart disease of risk of 6% without statins and 30% relative reduction in the risk with statins) using 6 different methods: relative risk reduction. There was little evidence for a difference between trials of patients given different anticancer treatments. Methods: Meta-analysis of randomized controlled trials in which these drugs plus red blood cell transfusions were compared with transfusion alone for prophylaxis or treatment of anemia in patients with cancer. The increased risk of death associated with treatment with these drugs should be balanced against their benefits.

a matter of how the results are communicated. but rather to show how large dataset analyses can increase our knowledge and provide answers to pending questions. Yang X.risk of death during treatment and 6% overall.edu Proc Natl Acad Sci USA 2010. variations in human telomerase gene that are associated with better maintenance of telomere length may confer healthy aging and exceptional longevity in humans. genetic mechanisms responsible for these associations are not known. Results: The study demonstrated that centenarians and their offspring maintain longer telomeres compared with controls with advancing age and that longer telomeres are associated with protection from age-related diseases. or short telomeres reflecting chronologically old age. Bergman A. Schechter CB. Conclusions: Thus. USA gil. Cawthon RM. Govindaraju DR. Telomeres progressively shorten with each cell division in cultured primary human cells until a critically shortened length is achieved.107(suppl 1):1710–1717 Telomere length in humans is emerging as a biomarker of aging because its shortening is associated with aging-related diseases and early mortality.. and lipid profiles of healthy aging. For pediatric endocrinologists. better cognitive function. Wright WE. their offspring. upon which the cells enter replicative senescence. were studied. an indicator of better telomere length maintenance. and lipid profiles of healthy aging. they identified a common hTERT haplotype that is associated with both exceptional longevity and longer telomere length. the inheritance and maintenance of telomere length and variations in two major genes associated with telomerase enzyme activity. Moreover. The practical implications of such answers are then.Y.atzmon@einstein. Barzilai N. They demonstrated that not only centenarians. in a cohort of Ashkenazi Jewish centenarians. the value of the study is not really to discuss whether the use of EPO is warranted during cancer treatment or not. Bronx. Katz M. This study assessed the telomere length in blood leukocytes among subjects with exceptional longevity (centenarians) to investigate if centenarians survived with long telomeres. Context: Telomeres consist of the TTAGGG tandem repeats at the ends of chromosomes and are known to protect these regions from degradation and DNA repair activities. better cognitive function. maintain longer telomeres compared with controls with advancing age and that longer telomeres are associated with protection from age-related diseases. Budagov T. as we just learned in the previous article. Interesting mechanism End of the chromosome and the end of life Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians Atzmon G. but their offspring too.yu. Huffman DM. and offspring-matched controls. Methods: Here. Sequence analysis of hTERT and hTERC showed overrepresentation of synonymous and intronic mutations among centenarians relative to controls. 228 Ze’ev Hochberg/Jean-Claude Carel . N. However. hTERT and hTERC. Albert Einstein College of Medicine. Suh Y Department of Medicine and Genetics. Siegel G. Cho M. They identified a common telomerase gene haplotype that is associated with both exceptional longevity and longer telomere length. Shay JW.

the primates of the Miocene epoch. had a mix of ‘primitive’ traits. University of California. who lived more than a million years before ‘Lucy’.Important to know Know your elder Ardipithecus ramidus and the paleobiology of early hominids White TD. thereby accentuating the derived nature of Australopithecus. Suwa G. Ardi lived in a woodland environment where she climbed on all fours along tree branches but walked. Asfaw B. We keep evolving The following review and the subsequent four articles deal with ongoing evolution of us . bipedality. University of Haifa. The evolution of our lineage after the last common ancestor we shared with chimpanzees has therefore remained unclear. Ar. Ar. Lovejoy CO. This evidence also illuminates the origins of orthogrady. shared with her predecessors.edu Science 2009. Haile-Selassie Y.4 million years ago. feet. Berkeley. More than 110 specimens recovered from 4. ramidus had a reduced canine/ premolar complex and a little-derived cranial morphology and consumed a predominantly C3 plantbased diet (plants using the C3 photosynthetic pathway). limbs. Ar. ramidus lacks any characters typical of suspension.. Methods: Ardipithecus ramidus. and pelvis.326:75–86 Hominid fossils predating the emergence of Australopithecus have been sparse and fragmentary. vertical climbing. and social behavior in earliest Hominidae and helps to define the basal hominid adaptation. and ‘derived’ traits. The investigators described her as a mosaic creature.. recovered in ecologically and temporally resolved contexts in Ethiopia’s Afar Rift. upright. i. hands. on two legs. the ancestor we last shared probably differed substantially from any extant African ape. St. ecology. Calif. Its ecological habitat appears to have been largely woodland-focused. However. who roamed what is now Ethiopia 4. USA.e. Ardi. or knuckle-walking. Israel Rambam Maimonides Med J 2010. now illuminates earlier hominid paleobiology and aspects of extant African ape evolution. Context: A special issue of Science was devoted to describe the eldest hominid. Conclusions: Hominids and extant African apes have each become highly specialized through very different evolutionary pathways. The most complete skeleton of a female was nicknamed ‘Ardi’. Mo. neither chimpanzee nor human. USA timwhite@berkeley. ramidus indicates that despite the genetic similarities of living humans and chimpanzees.4-million-year-old sediments include a partial skeleton with much of the skull. which it shares exclusively with later hominids. Department of Evolutionary and Environmental Biology. WoldeGabriel G Human Evolution Research Center and Department of Integrative Biology. diet. Ardipithecus ramidus. Louis. Results: This hominid combined arboreal palmigrade clambering and careful climbing with a form of terrestrial bipedality more primitive than that of Australopithecus. Washington University. who weighed about 50 kg and stood about 120 cm tall. while on the ground. all organisms adapt to their Science and Medicine 229 .1:e0006 Context: It has been argued that human evolution has stopped because humans now adapt to their environment via cultural evolution and not biological evolution.modern humans Has human evolution stopped? Templeton AR Departments of Biology and Genetics. Beyene Y.

The recent growth in human population size has greatly increased the reservoir of mutational variants in the human gene pool. In particular.000 years. Everything we call culture and civilization we’ve built with the same body and brain. predict future evolutionary change for specific traits with medical significance. they measured the strength of selection. Govindaraju DR. multicohort studies should include input from evolutionary biologists. sometimes with mildly maladaptive consequences. To better understand and predict such changes. Finally. This has been the lesson of the past 10. cultural change can actually spur on adaptive evolution in humans.’ Templeton argues that human evolution has not stopped. The descendants of these women are predicted to be on average slightly shorter and stouter. and our ongoing evolution has many medical and health implications. to have lower total cholesterol levels and systolic blood pressure. to have their first child earlier.000 years. However. The only way to truly stop any biological organism from evolving is extinction. These adaptive responses have important implications for infectious diseases. The increase in human population size coupled with our increased capacity to move across the globe has induced a rapid and ongoing evolutionary shift in how genetic variation is distributed within and among local human populations. and humans are no exception. that trait can still evolve as a correlated response to evolution of another trait. Moreover. mendelian genetic diseases. even when cultural evolution eliminates selection on a trait. This will lead to a loss of most genetic variations through genetic drift and minimize the input of new mutations into the population. thereby enhancing the potential for human evolution. The rationale for the cessation of human evolution is based on the premise that cultural evolution eliminates adaptive evolution via natural selection. long-term. the trait can still evolve due to natural selection on other traits. Lung.environment. Evolution would be slowed by reducing and keeping population size to a small number of individuals. and systemic diseases in current human populations. As long as humans persist as a reproducing population. Even when our cultural innovations do eliminate selection on a trait. and in humans much of our environment is defined by our culture. evolution proceeds by mechanisms other than natural selection. Evidence: Examples are given to illustrate the rapid pace of adaptive evolution in response to cultural innovations. and predicted the response to selection for women in the Framingham Heart Study. but rather are integrated into a functional whole. all organisms adapt to their environment. and is certainly what we can expect to continue for as long as our species persists on the Earth. Results: They found that natural selection is acting to cause slow. our evolutionary potential has never been higher. The distinguished paleontologist Stephen Jay Gould stated: ‘There’s been no biological change in humans in 40. Natural selection in a contemporary human population Byars SG. Our evolution is further driven by a radical change in the balance of genetic drift and gene flow that is rapidly causing a major evolutionary change in the human species in how genetic variation is distributed within and among local populations. Conn.. humans will evolve. and Blood Institute and Boston University that began in 1948. gradual evolutionary change. the design of planned large. and is now so large that the current human gene pool contains an immense reservoir of genetic variation. New Haven. a project of the National Heart. estimated genetic variation and covariation.107(suppl 1):1787–1792 The aims of this study were to demonstrate that natural selection is operating on contemporary humans. Our population size has been increasing over the last 10. Ewbank D. Culture defines much of the human environment. Methods: To do so. USA Proc Natl Acad Sci USA 2010. Conclusions: Selection is tending to lengthen the reproductive period at both ends. so cultural evolution has actually led to adaptive evolution in humans. and show that for some traits we can make short-term predictions about our future evolution. so selection on one trait can cause evolution to occur on another trait. often in a non-adaptive fashion and sometimes in a mildly maladaptive fashion.000 or 50. genetic differences between human populations are rapidly diminishing and individual heterozygosity is increasing. Conclusions: Our traits are not isolated. with beneficial health effects. independent units. Yale University. and to reach menopause later than they would in the absence of evolution.000 years. Hence. Context: 230 Ze’ev Hochberg/Jean-Claude Carel . Stearns SC Department of Ecology and Evolutionary Biology.

1 kg (2. Sweden BMC Evol Biol 2010. Slightly overweight (but not obese) women tended to have more children.10:89 Genes and culture are believed to interact. the ability to continue digesting the milk sugar lactose after childhood. It was suggested that if these trends were to continue with no cultural changes for the next 10 generations. the researchers determined that these characteristics were passed on genetically from mothers to daughters and granddaughters. through which the Stone Age hunter-gatherers’ genes were lost due to some significant advantage associated with the capacity to digest milk. 10 yielded reliable results. have a healthier heart.Natural selection is acting slowly and gradually on traits of medical importance and on life history traits. blood pressure and cholesterol levels and the number of offspring they produced. Both age at first birth and age at menopause appear to be changing so as to lengthen the reproductive period. but from a group that arrived later. replacement of hunter-gatherer populations by sedentary agriculturalists.8 in) shorter. Results: This study investigated the frequency of an allele (−13910*T) associated with lactase persistence in a Neolithic Scandinavian population.2 lb) heavier. facilitating the consumption of raw milk. Holmlund G. Uppsala. The paper suggests two possible explanations for the DNA differences. Uppsala University. and that the frequency is dramatically different from the extant Swedish population (74%). They find that the T allele frequency was very low (5%) in this Middle Neolithic huntergatherer population. Stora J.e. The other is that today’s Scandinavians are not descended from the Stone Age people in question. and less so in African and Far Eastern populations who started farming only some 2. Conclusions: They conclude that this difference in frequency could not have arisen by genetic drift and is either due to selection or.238 postmenopausal women participating in the Framingham Heart Study. Molnar P. but it has been difficult to find direct evidence for the process. weight. Linderholm A. Liden K. This genetic trait is believed to have evolved within a short time period and to be related with the emergence of sedentary agriculture. Context: The ability to drink milk as an adult occurs at a high frequency in present-day Caucasians. But the hunter-gatherers who inhabited Scandinavia 4. Most importantly. High frequency of lactose intolerance in a prehistoric hunter-gatherer population in northern Europe Malmstrom H. Apparently. One possibility is that these differences are evidence of a powerful selection process. Jakobsson M.000 years ago. Gotherstrom A Department of Evolutionary Biology. This capacity is closely associated with the transition from hunter-gatherer to agricultural societies. The study examined the vital statistics of 2. They differed significantly from modern Swedes in terms of the DNA sequence that we generally associate with a capacity to digest lactose into adulthood.000 years. the capacity to consume unprocessed milk into adulthood is regarded as having been of great significance for human prehistory. which is consistent with previous findings. these findings describe a possible scenario where cultural practices could have had a tremendous impact on the genetic composition of human populations. This has been regarded as an adaptive genetic trait exposed to positive selection induced by cultural practices. From the 14 individuals originally examined.000 years ago were lactoseintolerant. Science and Medicine 231 . searching for correlations between women’s height. more likely. as did women with lower blood pressure and cholesterol levels. by 2409 the average Framingham woman would be 2 cm (0. i. One candidate example that has been put forward is lactase persistence in adulthood. have her first child 5 months earlier and enter menopause 10 months later than a woman today. who have been practicing dairying and cattle rearing for 10. Using a sophisticated statistical analysis that controlled for any social or cultural factors that could impact childbearing.

Furthermore. is strongly associated with lactase persistence and appears to have been favored by natural selection. Thomas MG Research Department of Genetics. UK PLoS Comput Biol 2009. Department of Biomedical Genetics. Meijboom JR. One major player in energy homeostasis is the appetite-stimulating hormone neuropeptide Y. This is thought to have helped motivate weaning. a single genetic variant. is rare or absent elsewhere in the world. through at least four parallel evolutions starting several thousand years ago. Since adult consumption of fresh milk was only possible after the domestication of animals. Context: Before the evolution of lactase persistence. Variants in neuropeptide Y receptors 1 and 5 are associated with nutrient-specific food intake and are under recent selection in Europeans Elbers CC.910*T allele frequency and farming arrival dates across Europe. dairying. 2 and 5 (NPY1R. Trynka G. Onland-Moret NC Complex Genetics Section.910*T (derived) allele was very rare or absent in early Neolithic Central Europeans. ancient DNA work has shown that the −13. as previously thought. Wijmenga C.The origins of lactase persistence in Europe Itan Y. London.910*T allele first underwent selection among dairying farmers around 7. University Medical Center Utrecht. Burger J. Methods: The study developed a flexible demic computer simulation model to explore the spread of LP. and farmers in Europe. Utrecht. and not in the northern part of the continent. In Europe. Results: Using data on −13. 232 Ze’ev Hochberg/Jean-Claude Carel . and this has led to a gene-culture co-evolutionary model where LP is only favored in cultures practicing dairying. can only tolerate milk for the first few years of life. Grobbee DE.5:e1000491 Lactase persistence (LP) is common among people of European ancestry. NPY2R and NPY5R). integrating genetic and archaeological data the report shows that lactase persistence/dairying co-evolution began around 7. Using a simulation model of the spread of lactase persistence. although it is not known when lactase persistence first arose in Europe or what factors drove its rapid spread. The transition to new food sources during the agriculture revolution around 11. van Vliet-Ostaptchouk JV. Still today. lactase persistence spread throughout human populations. Conclusions: The results provide a coherent and spatially explicit picture of the co-evolution of LP and dairying in Europe. other subsistence practices and unlinked genetic markers in Europe and Western Asia’s geographic space. It is unlikely that LP would provide a selective advantage without a supply of fresh milk. Evolution and Environment. Furthermore.500 years ago in a region between the Central Balkans and Central Europe. Bauer F. possibly in association with the dissemination of the Neolithic Linearbandkeramik culture over Central Europe. Middle Eastern and Southern Asian groups. but with the exception of some African. the results suggest that natural selection favoring a LP allele was not higher in northern latitudes through an increased requirement for dietary vitamin D. most of the world’s population.910 C/T) indicates that the derived allele is recent in origin and has been subject to strong positive selection. The Netherlands PLoS One 2009. −13. dairying. and these food intake patterns show a strong heritability. and approximate bayesian computation to estimate parameters of interest.500 years ago in the Balkans and Central Europe. in which the stimulatory capacity may be mediated by the neuropeptide Y receptors 1.910*T. including Asians and Africans. University College London. and dairying is more favored in lactase-persistent populations. But. humans typically lost their ability to digest lactose around the age of 5. Powell A. Beaumont MA.000 years ago probably created selective pressure and shaped the genome of modern humans.4:e7070 Context: There is a large variation in caloric intake and macronutrient preference between individuals and between ethnic groups. Lactase gene haplotype conservation around a polymorphism strongly associated with LP in Europeans (−13. they infer that the −13. it is likely that lactase persistence co-evolved with the cultural practice of dairying. de Kovel CG. van der Schouw YT.

We were naive to assume that we all come from Africa during the 100–40. mainly because of a lower consumption of mono. and examines whether genomic regions containing these genes show signatures of recent selection in 270 HapMap individuals (90 Africans. Morwood MJ.argue@anu. inducing particularly carbohydrate intake. Resistance to H. habilis is retained). which started in Europe around 6. Body size reduction in mammals is usually associated with only moderate brain size reduction.9 Ma if the earlier chronology for H. because the brain and sensory organs complete their growth before the rest of the Science and Medicine 233 . The derived allele appears to be under recent selection in the European population. gave a survival advantage in Europeans since the agricultural revolution.edu. Sutikna T. are known to be associated with a lower risk of chronic diseases. and (2) Homo sapiens was the only hominin since the demise of Homo erectus and Homo neanderthalensis. and 90 Caucasians) and in 846 Dutch blood bank controls. is an enormous challenge to paradigms of human evolution. on average. they use cladistic analysis. Until this announcement. The data suggest that a lower carbohydrate intake. mainly because of a lower consumption of mono.000 years ago.66 Ma. The results of this study show that derived alleles in NPY1R and NPY5R are associated with lower relative carbohydrate intake. The appetite-stimulating hormone neuropeptide Y (NPY) evokes through the NPY receptors eating behavior. However. A predicted selective sweep of around 4. habilis. consuming meals with a low GI and GL. and (2) that it is a modern human. a tool that has not.and disaccharides. and/or higher alcohol consumption. and/or higher alcohol consumption gave a survival advantage in Europeans during the agricultural revolution. either a pygmoid form or a pathological individual. and nutrient intake in a cross-sectional. this series of articles conclude that it was indeed a new species. and probably originates from around 4. single-center study of 400 men aged 40–80 years. and debate centers on two sets of competing hypotheses: (1) that it is a primitive hominin.and disaccharides. They also show that carriers of these derived alleles.au J Hum Evol 2009. Injection of NPY in the brain elicits a strong feeding response even in satiated animals. In 2005. and have higher alcohol consumption. consumption of meals with a low GI and GL. the same alleles are associated with increased alcohol consumption. consume meals with a lower glycemic index (GI) and glycemic load (GL). ACT. Canberra. Results: The results show that derived alleles in NPY1R and NPY5R are associated with lower carbohydrate intake. the dominant paradigm stipulated that: (1) only more derived hominins had emerged from Africa. until now. sapiens or a new species. Conclusions: The data suggest that lower carbohydrate intake. a primitive hominin that survived until relatively recent times. consuming meals with a low GI and GL. Saptomo EW Australian National University. Results: The results produce two equally parsimonious phylogenetic trees.000 years ago ‘out of Africa’ migration. Carriers of these derived alleles on average consume meals with a lower glycemic index (GI) and glycemic load (GL). no resolution has been reached. eventually leading to obesity. or after 1. floresiensis branched after H. and/or higher alcohol consumption.000-year ancient hominin in Indonesia with a stature of 1 m and a small skull. This advantage could lie in overall health benefits. Jatmiko.000 years ago fits the theory of adaptation to novel food sources during the agriculture revolution.Methods: The study assesses association between variants in the NPY1R. The second tree indicates H. Despite a range of analytical techniques having been applied to the question. 90 Asians. NPY2R and NPY5R genes. One of these variants shows the hallmark of recent selection in Europe. the Yearbook enthusiastically discussed the finding of a 20. floresiensis is an early hominin that emerged after Homo rudolfensis (1. to establish the phylogenetic position of the species. been applied to the problem.86 Ma) but before Homo habilis (1. Homo floresiensis: a cladistic analysis Argue D. The first suggests that H.000 years ago and was gradually further developed from that point on. Following several years of a debate whether this was a diseased H. Australia debbie. floresiensis has been intense.57:623–639 Context: The announcement of a new species. because lower carbohydrate intake. Homo floresiensis. Methods: Here.

every big marathon like New York. but the modern running shoe was not invented until the 1970s. on the heel (rear-foot strike). The much earlier australopithecine version of bipedalism (as seen in ‘Lucy’. The nature of the proportional change in brain size in insular dwarfism indicates that selective pressures on brain size are potentially independent of those on body size. the so-called insular dwarfism. If the endurance-running hypothesis is correct. 234 Ze’ev Hochberg/Jean-Claude Carel . We generally tend to think that modern life utensils protect us from injuries and provide us with improved performances. Conclusion: Fore-foot. This difference results primarily from a more plantar-flexed foot at landing and more ankle compliance during impact. Concepts revised If injured. resulting in a lessened risk of injury. ‘Modern’ usually shod runners mostly strike the heel first. The authors wondered how runners coped with the impact caused by the foot colliding with the ground before the invention of the modern shoe. Kinematic and kinetic analyses show that even on hard surfaces. floresiensis may teach us otherwise.body during ontogeny. Werbel WA. runners were either barefoot or wore minimal footwear such as sandals or moccasins with smaller heels and little cushioning relative to modern running shoes. this trend has been questioned in the special case of dwarfism of mammals on islands. Nowadays.edu Nature 2010. But the small skull of H. USA danlieb@fas. while unshod runners from Kenya mostly strike the fore-foot first. The authors are evolutionary biologists. but they sometimes land with a flat foot (mid-foot strike) or. Daoud AI.harvard. barefoot runners who fore-foot strike generate smaller collision forces than shod rear-foot strikers. habitually shod runners mostly rear-foot strike. facilitated by the elevated and cushioned heel of the modern running shoe. Australopithecus afarensis) received a major makeover near the Pliocene/Pleistocene boundary about 2 million years ago with longer hind limbs and shorter toes. Indeed. less often.000–40.. and may protect the feet and lower limbs from some of the impact-related injuries now experienced by a high percentage of runners. Harvard University. Many shod modern-day runners develop injuries [13] and new footwear now use barefoot like design and might protect them from repetitive stress injury. Reebok® and consorts. reminds us that human body evolution over millenaries cannot be ‘improved’ in 40 years by designers from Nike®. Methods: Kinematic studies of foot strike in 5 groups of runners habitually shod or unshod. bioengineers and physical medicine specialists and observed foot impact of various groups of runners while shod or unshod.and mid-foot-strike gaits were probably more common when humans ran barefoot or in minimal shoes.463:531–535 Background: Humans have engaged in endurance running for millions of years. For most of human evolutionary history. The findings of the study complement the endurance-running hypothesis for the transformation of the human body plan with the emergence of the genus Homo. This study.000 participants somehow holding an atavistic ceremony commemorating their ancient past. Pitsiladis Y Department of Human Evolutionary Biology. Mang’eni RO. Results: Habitually barefoot endurance runners often land on the fore-foot (fore-foot strike) before bringing down the heel. Venkadesan M. reminiscent of the Noble Savage theory [11]. Mass. Paris or Berlin brings together 30. Cambridge. Davis IS. the evolution of these features are probably linked directly to barefoot running as an integral part of an adaptive strategy for pursuit hunting [12]. decreasing the effective mass of the body that collides with the ground. In contrast. D’Andrea S. The shod heel first pattern resulted in more repetitive high impact forces while unshod running was associated with a more diverse way of running. We might see them leaving their shoes in the locker room before long. run in bare feet Foot strike patterns and collision forces in habitually barefoot versus shod runners Lieberman DE.

Conclusion: miR-33 acts in concert with the SREBP host genes to control cholesterol homeostasis. the authors identified two isoforms of miR-33 that are embedded in introns of SREBP genes 1 & 2. and implicated in Tangier disease. PubMed provides 8. In mouse macrophages. and miR-33 could Science and Medicine 235 . Charney Division of Cardiology and the Marc and Ruti Bell Vascular Biology and Disease Program. Fitzgerald ML. Moore KJ. USA Science 2010. modulates the expression of genes involved in cellular cholesterol transport. They bind to complementary target sites in the 3 untranslated regions of mRNAs. they are now recognized as essential players in gene expression in all tissues. Conversely. The studies demonstrate an impact on macrophages and. Initially identified in the cancer field. Shioda T. a transcriptional regulator of cholesterol synthesis. Background: Results: MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis Najafi-Shoushtari SH.. a regulator of HDL synthesis. Conclusion: miR-33 regulates both HDL biogenesis in the liver and cellular cholesterol efflux. Antisense inhibition of miR-33 in mouse and human cell lines causes up-regulation of ABCA1 expression and increased cholesterol efflux. Using different approaches. miR-33 also targets ABCG1. potentially regulating several genes involved in a physiological pathway. to a lesser extent. N. Mass. an intronic microRNA (miRNA) located within the gene encoding sterol-regulatory element-binding factor-2 (SREBF-2).328:1566–1569 Background: Proper coordination of cholesterol biosynthesis and trafficking is essential to human health. silencing of miR-33 in vivo increases hepatic expression of ABCA1 and plasma HDL levels. on the liver. These two papers further extend the role of microRNAs in metabolic regulation and miR-33 appears as a key regulator of HDL cholesterol metabolism.Y. miR-122 has been previously implicated in cholesterol regulation [16]. Parathath S. Fisher EA. Gerszten RE. thereby attenuating cholesterol efflux to apolipoprotein A1. miR-33 may represent a therapeutic target for ameliorating cardiometabolic diseases. In mouse and human cells. Cohen DE. MicroRNAs are small (22-nt) endogenous double-stranded RNAs that regulate physiological processes at the posttranscriptional level [14. and injection of mice on a Western-type diet with locked nucleic acidantisense oligonucleotides results in elevated plasma HDL. Lentiviral delivery of miR-33 to mice represses ABCA1 expression in the liver. for posttranscriptional repression. ABCA1. Fernandez-Hernando C Department of Medicine. Charlestown. Leon H. Li Y.. encoding sterol regulatory element-binding proteins which in turn regulate the synthesis of fatty acids and cholesterol respectively. Kristo F. They have emerged as essential players in gene regulation. Tamehiro N. miR-33 inhibits the expression of the adenosine triphosphate-binding cassette (ABC) transporter. Suarez Y. 15]. Naar AM Massachusetts General Hospital Cancer Center. reducing cholesterol efflux to nascent high-density lipoprotein (HDL).Mechanism of the year MicroRNA and cholesterol regulation MiR-33 contributes to the regulation of cholesterol homeostasis Rayner KJ.328:1570–1573 Cholesterol metabolism is tightly regulated at the cellular level. which were discovered as late as 2001. Results: MicroRNAs (miR-33a/b) embedded within introns of the SREBP genes target the adenosine triphosphate-binding cassette transporter A1 (ABCA1). Davalos A. an important regulator of high-density lipoprotein (HDL) synthesis and reverse cholesterol transport. miR-33. a condition of plasma HDL deficiency. USA Science 2010. which still constitutes three quarters of microRNA literature. In vivo manipulation of miR-33 levels using lentiviral vectors increased plasma HDL levels by 25% using anti-miR-33 and decreased plasma HDL levels by 22% using miR-33. reducing circulating HDL levels. miR-33 targets ABCA1. New York. Decreased plasma HDL is a key feature of the metabolic syndrome. A single microRNA can have multiple targets. causing translational repression and/or mRNA destabilization [3].186 citations to microRNA. New York University School of Medicine. The sterol regulatory element-binding proteins (SREBPs) are key transcription regulators of genes involved in cholesterol biosynthesis and uptake.

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156. 132 Beckers. P. 76 Andreasen. J. G. I. M. 219 Auger. 175 Arkwright. P. 91. 219 Audit. 179 Bellanné-Chantelot.W.S. D. 179 Barcenas-Morales.R. 175. 156 Biertho. 203 Bannykh. J. 178 Biron.K. 181 Benn.W. 177 Adewale. 117 Bidlingmaier. M. 223 Bentley. L. 79 Balapure. 173 Bamshad. A. 172 Bilo. M. 35 Besenbacher. M. I. 193. E.E. 222 Albrechtsen. 24 Belisle. 139 Ardlie. 221 Bidet.R. M. P. 186 Bainbridge. 7 Altman.L. 108 Bennett. 72 Bamshad. 19 Arnaud. S. S. D. E. 222 Al-Owain. 208 Azuma. A.B. F. C. G. 145 Berlin. S. A. M. 13 Azzi. J. E.J. B. 107. 228 Bastie. P. A. Z.J. N. K. 46 Anderson. 49 Birney. J.A.H. 149 Akl. 144 Bigham.L. 145 Anlag. R. 183 Al-Abdullah. 38 Barlow. L.T. E. S. 219 Below. G.M. Y. G.J. T. K. 222 Abel. 176 Ball.N. 159. M. 181 Beuschlein. C. 131 Adachi.M. 175 Belgardt.H. L. D.Author Index A Abbott. 163 . 220 Andrieux. B. B. 44 Beilby. E. S.A. 229 Ashley.C. S. E. I. M. Y. S. A. 77 Berenson. 109 Armengaud. 175. 207 Arany. 168 Avizov. M. M. M.S. 171 Bakker. C. 219 Abinun.E. P. 117 Bellesme. C. 128 Bertrand. 228 Au. A.A.A. J. U. I. 156. H. S. F. 226 Aksglaede. 174 Altshuler.C. A. 91 Aoki. 94. K. S. 177 Berton. 104 Bindels-de Heus. 67 Barnes. D.D. R. P. Y. 156 Bergmann. G. 33 Abel. 176 Bell. L. 5 Andersson.S.C. 174 Bernstein. R. 222 Arlt. J.K. 178 Bauer. R. S. 176 Bader.J. M.C. R.P. 220 Barroso. 36 Alreja. N. M. J. 232 Baxter. 150 Anderson. 195 Bender. T. 175 Benagiano. 174 Atzmon. 94 Aubourg.L. 124 Ben-Shlomo.F. 145 Andersson. D. C. 117 Bacot. 145 Befroy. 13 Adair. 177 Avbelj. 155. A.E. 61 Beyene. 175. 20 Andersen. 1. L.J. G. J. N. 30 Bannink. G. 177 Bennett. 78 Bai.M. 194 Akylbekova. H. B.J. H.B.N. 228 Bergman. 8 Anderson. 184 Berry. 175 Beri-Dexheimer.D. 37 Becker. 156 Andrews.E.M. W.G. 26 Baranzini. 181 Benediktsson. M. B.C. 66 Bergman. S. R. 127 Al-Muhsen.I. 184 Amory. 166 Bergen 3rd. 55 Beaumont. 94 Avenant. K. M. 37 Avis. 57 Beardsall. M. 176 Alekseev. H. 113 Asfaw. P. 219 Barzilai. A.C. S. 156 Ambresin. 196 Arnaldi.L.R. 77 Avril. A. M. F. 222 Abreu. J. 103 Avis. 128 Beckmann. 79 Balise. 145. 184 Benediktsdottir. 94 Au. M. D. M. E. R. K. 86 Aerts. E.C. 185 Aronin. A. C. 39 Balkau. 165 Ballock.B. L. Z.M. 189 Argue.J. A. G. E. 4 Beck-Peccoz. 113 Ahmed.D. 144 Bistritzer. I. B.L. 162 Benoist. C. A. 91 Andersson. A. 94 Acerini. L. S. C. G. 146 Allen. 91 Bjerre Knudsen. N.P. 172 Bangaru. 214 Bercovich.J. 56 Biebermann. 38 Bizec.D. A. 70 Barnes. H. 147 Baten. C. 46 B Bachelot. 87 Benassai.J. 71 Battenhouse. 229 Bharaj.S. J. M. 222 Barkan.P. M. 156. 163 Aitken. 42 Bielinski. 156 Barter. 70 Aulchenko. 175 Bartholomae. M. 46 Alos. 175 Ares.H. J. 124 Bibikova. M. 49 Balaji. A. C. 233 Ariyurek. Y. 232 Beauvillain. J.M. 159 Bimpaki. M. 175 Andari. 89 Aguiar. J. D. D. B. 90 Antignac. 94 An. 145 Amit. 220 Afrikanova. C.E. 131 Almholt.B.E. 145.

S. J. H.L. E. 175 Brunner-La Rocca. 103 Brown. B.L. 19 Bottcher.A. F. S. 182 Boerwinkle.B. 27 Brown. 67 Carter.G. S.A. 145 Bourque. 23 Blom.A. L. 176 Chase.R. H. 175 Boomsma. 178 Bozaoglu. R. J. M. C.C. K. E.M. M. G. 108 Camacho-Hubner. 156. 99 Charoen. A. 77 Chalumeau. 227 Brinkmeier. M. D. T. 142. G. 177 Bornstein. 175 Bonnycastle. M. 189 Butler.J. P.J. S. S. D. J. D. D. E. 117 Bougneres. I. 217 Chahal. J. 89 Buchanan. 33. 68 Bradfield. 125. J. E. 33 Carré. 52 Bronneke. 176 Borecki. 212 Carling. H. 18 Casanova.I. 156. 179 Calandra.M. S. 37 Chen. I. C.R.N. 177 Charpak. 119 Bucay. 183 Butte. 212 Cerrato. K. 156. J. 195 Calcagno. 217 Cant. F. L.W. 222 Canty. L. 145 Broberger. 208 Chevre.D. A. S. 94 Bonnefond. 202 Carpenter. W. 156. S. 124 Borja.J. 29 Charpentier. 145 Bodemer. 175. K. 145 Bliss.S.A. 145 Bouwens. 175 Bochukova. 148 Chen. 156. 222 Bouligand. 174 Chen. M. 230 C Cabral. 211 Borch-Johnsen. K. 196 Chan. R. 156. 197 Bocca.-C. J. 219 Cawthon. M. 103.P. S. P. 175. D.P. A. 145 Blaumeiser.G. 177 Boon. 176 Cavalcanti-Proenca. M. 59 Boright. 195 Cassou. N.A. T. 29 Caron. 175. K. P.J. P. 94 Carter. 41 Castillo. A. 150 Bush. 145 Caillier. 67 Capalbo. 156.A.L. 145 Carmignac. 124 Bumpstead. 145 Byars. L. W. A. J.P. 232 Buriakovsky. D. K. Y.J. 10 Bohlius.L. 156 Bogan. 68 Bryan. 149 Carvalho. 133 Chassin. 219 Carless. 151 Cartier. 24 Broutin. A. R. M. 207. P. 62 238 Author Index . X. M. 1 Cesareni.I. A.P. J. 49 Bochud. 145 Candi. W. S.A.M.B. G. J. V. 218 Boaretto. F.M. 1 Bouma. Y. M. 156. 182 Chalian. O. O. M. 70 Black. 177 Chen. 172 Budagov. H. F. G. M.Black. N. 219 Bougneres. 41 Carroll. 177 Brailly-Tabard.E. M. N. 66 Brauner. 228 Cawthorne.G. J. S. 222 Butler. 70 Castinetti.C. 212 Bozec. 150 Brugts. S. H. J. 156. 171 Chen. 182 Carel. R. 35.J. C. J.C. Y. 126 Blakemore. 175 Bouatia-Naji. E. C. G. 124 Cao. L. E. 1 Chang. N. 175. 175 Burger. 5 Burton. 156 Buckingham. 217 Cannata. A.R. 196 Brillant. R. 222 Casini. 217 Calebiro.L.J. L. 59 Campbell. T. H. 10 Chan. A. 220 Campbell. J. J. 10 Boute.L. N. 212 Blaszczyk. 222 Blangero. 67 Caccavelli. C. 156. IX. J.J. S. 175 Boesgaard. 175 Borg. 219 Caiazzo. 128 Boyle. 145 Chen. 108 Brown. J. 44 Cheetham.J. 24 Brunner. 71 Bluestone. E. S. K. K. 227 Bolu.L. 37 Calis. 145 Chia. 177 Boudou. C. 18 Campion. 74 Bustamante. M. 228 Buddavarapu. 4 Boonstra. H. N.P. C. L. P. 222 Boehnke.B.A. C. 109 Calmels.W.A. 87 Carrasco. T. 77 Burke. 54 Bruning. L.J. 33. 198 Cardon.J. S.F. 200 Brunton.L. L. E. 196 Charmandari. J. R. 148 Chen. F. 1 Bram. 131 Chatterjee. A. 67 Chanson.R. 220 Carter.C. E.P.R. S. 195 Caldarola.B. F. W. 41 Brown. R. G. A.J. 174 Buxton. 226 Carlsson. H.S. M. S. 1 Charkaluk. 213 Brodesser. M. 156. 221 Chalifa-Caspi. 145 Calton. 105 Carrara. 219. R. 156. 175 Boscaro.J.P. 113 Bull. 29 Castanet. J. P. 113 Boas. 219 Carvalho. 145 Blanche.L.M.S. 156. A. A. S. 18 Brioschi. D. 186 Camper. 89 Bouquillon. P. 176 Cavazzana-Calvo. 18 Cauchi. 196 Breart.C.P. P.C.W. 175 Chera. M. 107 Chakravarti. 24 Broekman. A.

A.M. 227 Dobbelaar.H. L. 94 Crowley. 145. 143 Cox. 175 Crawford. W. 1 De Schutter. M. J. T. 182 Cho. 99. A. E. A.G. 142 Doffinger.J.H. C.A. L. M. 220 Dal-Cortivo.L. P.A. D. 158 Danis. 201. 124. S. S. A. 219 Damron. 175 Dejonckere. C. F. 111 Counil. B. R.A. M. R.L. A.N.A. S. 108 Clarkson. P. 204 De Palma.M. 52 Debono. 75 De Deken.B. D.E. A. 20 Dixon. 66 Chou. 117 Clayton. K. 217 Dimeglio. 199 De Luca. R. 55 Davalos. 113 Choi. 42 de Escobar.E. 94 de Muinck Keizer-Schrama. N. 156. N. 220 Cohen.I.L.D.A. 201.Y.M. 156. 156 Courant. 3 de Geus. 214 Chrabieh.C. F. A. 182 Condon. P. S.S. N. 178 Crawford.R. 201 de Roux. S. A. 113 Daito. 157. 234 Date. L. A. 1 de Jong. 144. 111 Delemarre-van de Waal. F. 178.G. D. 94 Collins. G.F. A. G. E.J. 129 Depinho. 10 Crisponi. L. 117 Coutifaris.M. M.M. G. M. T. 158 Author Index 239 . 175.W. 221 Coutry. 1. K. 175 Crowley Jr. 159 Cutler. A. H.V. 4 de Smith. 58 Cuttler.F. 177 Colao.J.P.J. M. T. A.T. 145 De Waele.K. G. S. 51 Cianflone. 9 Confavreux. W. 146 Coffin. L.J. D. A. F.J. 235 Cohen-Kettenis. C. R. I. 122. J. 29 Desgraz. 2 Cobat. 156. 175 Clarkson. 177 Delplanque. 49. J. 37 Costa. 30 Clarke. 45 di Iorgi. 212 Cole. 222 Coetzee. F. 29 Chrousos. N.C. 85. 74 D’Andrea.A.P. C. J. 177 Coussieu. 122 Daoud. L. 128 Clark. 13. 208 Determann. C. E.W. 180 Clayton-Smith. K. X. 171 Diorio. F. M.S. R. M.E. 145 Deloukas.M.K.R. 110 Dedoussis.K. L. 182 Crawford. V. 145 Cullender. 37 Cho. V. A. 204 Delobel. 175 Corsino. C. C. 122 Day. 89 Clark. 177 Dehghan. 156. L.J. 199 Cirulli. 175.S.G. A. J. C. 184 Deladoëy. 189 De Felici. H. 234 Davis. 203. M. 119 Chiesa. J. 177 David. 145 Davis. S. 175 Cooper. A.H.A.S. 50 de Kovel. A. E. X. F. G. 65 Dewey. J. A. M. C. M. 210 Conrad. 139 Conway-Campbell.M. H. J. J. 175. 175 Dent.M. L. 94 Costigan.M. 174 Cianfarani. 198 Cole. T. 183 Corbetta. J. J. 149 Curran. 4 Daniels. 176 Dinh.A. G. 111. 145 Chines. 37 Cordier.J. 220 Conroe. 22 Cornelis. A. P. J. 70 Cone. F. C. 114 Church. 131 de Ravel. K. C.S. M.F.D. 97 Chowdhury. 29 Cowley. S. 222 Dolan. 139 Denzin. 156 Chipman.J.A. 145 Cordoba-Chacon.H. 156.F. 192 D Dabelea.Chiarelli. M. B. 145 Cleary. W. 94 Cuisset. M. M. 102 Cooney. 46 de Castro.P.S. 157. 79 Connors. 36 Delarue. 124 Clement.F. J. D. 212 Curran.G. J. 114 de Kort. R.W. 232 de la Pena. H. P. G. 90 Cooper. 195 Di Tella. 222 Coudoré. R. 228 Chocron. 121 Dahia. 217 Di Cosmo. 215 Cortinovis. D. S. 71 Dattani. 58. 58 de Lind van Wijngaarden. 175 Chines. M. Y. 150 Djulbegovic. 210 Czarnywojtek. 52 Desarmenien.G. J. 58 Chiumello. C. B. 177 de Guillebon. 175. J.M. 227 Clarke. L.E. P. 234 d’Anglemont de Tassigny. 217 de Gendt. 75 de Seranno. K. N. 100. J. S.E. 174 Di Bartolomeo. S. 41 Couper. 222 Christian. 9 Dateki. 6 Coats. A. 172 Denzer. 179 Clifton. 91 Cousminer. 41 Clendenen. P. C. D. 71 de Ridder. 235 Davey. 94 De Clerck. 4 Clauin. 182 Clark. C. J. 201 Dekker. G. 128 de Wit. P.A. Y. B. 85 Coin. R. T. 13 Dathe. 69 Derr. 174 Chou. 190 Dina. 49. F. 44 Curtis. 56 de Mendonca.B. 156 Cresswell. G. 175 Cooper. 175 de Boer. I.N. 16 Daubas. T. C.

A. 96 Dupuis-Girod. M. 67 F Falchi. N. 148 Franklin. E. 178 Eriksson. S. 128 Flannery. 142 Gagne. 145 Ester. S. 175 Fraser. S. V. 145 Faloia. 103 Engert. 168 Gaillard. T. 53 Fox. G. A. A. 197 Fellmann. A.M. 232 Elefteriou. M.M. 49 Feuk.A. 58 Drop. E. P. M. F. 181 Froguel. J.A. S. C. 156. T. 114 Drucker. E. M. 207 Ferguson-Smith. 156 Fluck. 175 Edwards Jr.V. 220 Fey. J. 128 El-Sayed Moustafa. D. I. J. 19 Furuyashiki. D. S. Y. 145 Fedson. 67 Fenton. 39 Francoeur. 57 Fischer. L.Donahue. 70 Drummond. 186 G Gagel. D.J. J. 175 Fisher. 65 Frassinetti. S.S. 156 Festen. A.A. 195 Frayling. S.S. 121 Firmann. 145 Ferreri. T. 200 Doney. 195 Fratangeli. 175 Durand.L. 137 Ducy. 182 Eisenbarth. 93. 142 Donnelly. S. 181 Fernandes. R. 219.W.M. C. 177 Friberg. 130 Dorschner. 24 Escher. 143 Fishman. M. M. 177 Frohman. D. 145 Galan. 7 Eng. T. E. 59 Filippi. J. 175 240 Author Index . 87 Filler. 94 Dwyer. 36. B. 175 Feil. 156. 155. T. M. 127 Ferrucci. 235 Fitzgerald.J.L. 145. 52 Fantin.R. D.D. 235 Fisher. 183 Forsblom. 221 Fourie. D. 156.A. P. J. 178 Furlani. H. P.T. M. C. S. 41 Epstein. P.A. 14 Esko. 220 Flamez. 145 Firth. 83 Duchen. V. 78 Fukami. P. S.J. D. 235 Ferrannini. Y.G. E. K. T. 185 Feldmann. 163 Dunkel.E. C. 174 Dufour. X. D. T. 4 Eugster. R.J.A. 13 Furey. P. A. K. 179 Farooqi. R. 224 Fine. C. S. E. 22 Frost. E. 66 Ewbank. 41 Feldt-Rasmussen. W.D.E. 175 Franzosi. M.F. A. 18 Elmquist. 198 Farmer. 222 Fischer-Posovszky. E. 92 Forouhi. 103 Eizirik.S. 103 Eicher. L. 175 Frackelton. M. P. S. F. T. 59 Enriori. D. 175 Forrester.G.D. 139 Fischer-Rosinsky. 46 Drummer. M. J.L. 44 Dufrane. 156. 2. 175. R. U. C. R.R. 79 Dudley. 128 Duhamel.J. F. L.W. P. A. 88 Fraser. 130 Du.J.M. G. D.F.R. 95. L.L. D. W. D. 103 Fernandez-Fuente. 36 Frangioni. 177 Freathy. 224 Fujihara. M. A. 156.M. 39 Evans. M. A. 177 Ellis. 189 Fisher. 145 Feng. 175 Elliott. C. G. D. 156 E Eble. K. 185 Fu. 227 Fierz. M. 29 Fernandez-Hernando. I.S. C. D. C. 94 Dyer. L. 115 Erdos. 191 Egerod. J.S. J. 177 Erinle. T. 89 Eichler. 49. 221 Erler.M. 39 Engel. 173 Drop. 145 Dupuis. J. A. 21 Eisenberger. 142 Fontanaud.C. 175. 176 Dwyer. 171 Elleri. T. 20 Duittoz.A.E.G.S. N. 176.E. 134 Foster. A. 25 Ebrahim. A.G. 7 Dumitrescu. 23 Fisher. L. 90 Eisenhofer. 156. G. 155.C. 29 Elbers. R. 227 Ehrhart-Bornstein. 52 Estrella. 73 Elks.C. E. A. 175 Frants. 230 Eyre. 120 Ferrarini. R. P. J. E. 184 Drmanac. 103 Ernst. 39 Gagen. A. M.A. Y. 78 Futreal. T.M.E.S.L. 175 Dong. M. 33 Fingerlin. T. 145 El Yandouzi. 70 Donaldson. 143 Epaud.M. A. 155.L. 156. A.E. V. 103 Fitzgerald. 171 Farina. P.A. 29 Forman. 162.M. 177 Evans.B. K.A. 131. 143 Evans. 19 Fang.B. J.R. 145. C.L.R. M. N. M. 46 Egger. S. C. 45 Dunger.J. 175 Egberts. 131 Elliott.O. E.D. M.M. P. 39 Dones. 3 Dumalska.B. 212 Ellsworth.K.K. 25 Fong. 156.B. 176. P. 224 Egan.C. C. 44. 218 Eisenberg. 190 Evans. 215 Florez. 125 Francis. G. 227 Engstrom. 59 Frigge. D. O. 175 Franks.

E. A. J. V. 199 Gao. M. M. A. R. 156. 130 Gudbjartsson.A. Y.B. 79 Gerszten. 220 Gokcumen. A. 128. 49 Harjutsalo.J. 175 Halperin. 177 Hauser. 92 Gray. 174 Gonzaga-Jauregui. 132 Govaerts. 35 Guillot. J. 146 Gerry. 175. M. X. 131 Hartikainen.M. 61 Hanukoglu. H. 159. D. 108 Hammond. N.F. U. B. K.A. 26 Guttmacher.A. S. R. 149 Ghamari-Langroudi. 44 Halyday. 186 Gebauer.H. 171 Halsall. 177 Grueters. R. 228.O. 43 Grayson. 1 Gastaldi. B. 175 Goodman. 102 Haile-Selassie. 175. 39 Ghervan. 182 Hainsworth. 182 Gwilliam. 223 Guibourdenche. A.E. 135 Harmon. 24 Han. M. 212 Gonzalez. 177 Hartmann. 13 Hassanali. 175 Gill. A. 156. 184 Godeau. A. N. 169 Hamilton-Shield.L. 145 Glaser. J. R.B.C. A.E. G. S. R. R. A. C. 181 Guerau-de-Arellano. N. 132 Goldenberg. 183 Haines. 175 Glusman. 85 Grallert. 162 Hantel. 173 Goodyer. J.C. Y.J. R.T. 77 Hadjadj. 148 Gupta. 27 Golmard. 97 Hapgood. D. T. 222 Hansen.C.L.L. 128 Goldstein. 231 Gottlieb. 181 Gyllensten.M. A. 175 Hanada. 78 Hansen.D. V. 175. 175 Gloyn. 177 Hassanein. A.C. F. 75 Gardiner.L. 222 Goring. C. 156. 156. S. F. D. 108 Gillerot. 41 Guilmatre. 135 Groudine. C. 20 Graubard. 175.F. 46 Gotherstrom. 177 Grarup.J. 71 Gillman. D. R. X. A. 94 Hallmans. O. 212 Gitelman. 25 Goding.M. Y. 159 Groop. T. D. C. S.J. 171 Gibson. 171 Gemelli. 159 Ganusova. 156 Groop. 175 H Haby. 40 Gonzalez-Suarez. D. M. C. A. 195 Gianello. C. 134. 143 Greely. 217 Gong. 195 Gaughan. J. J. 156. A.J. 175 Guan.E. 200 Hasegawa. N. 130 Gaspert. D. 132 Greenberg.A. L. 182 Gieger.M. 43 Goriely. 179 Gao. 68 Grills. J.J. 145 Hager. 38 Hanyaloglu. A. S.K. G. 142 Gotfredsen.P. J. X. T. M. 220 Goland. 201 Gewirtz. 145 Goldhamer. R.R. 145 Hammond. 183 Hattersley. 148 Gawlik. 143 Groves.R. R. 156.A. J. J. D. K.L. 103 Harada. 175 Gygi. J. 184 Grove. J. 134. 125. S.L. 176 Hadjikhani.R. C.J. P. 182 Goldstein. S. 200 Grobbee.B. D. J. 181 Gudjonsson. R. 176 Hanson. 177 Hall.L. 139 Gutman. Y. 119 Harris. 219 Hadad. 9 Gharib. 128 Gianetti. Z. E. G. 175 Hampel. S. R.I. 117 Golombek.H. 174 Greenbaum. R. L. 177 Glavas. B. 7 Gavrilova. H.S. 145 Guiochon-Mantel.W. 79 Giralt. 171 Guo. N. 2.F.P. 179 Gonfloni. 235 Gesty-Palmer. R. B. 189 Gomez. P. 229 Haiman. 175.L. 88 Haring.J. 79 Gao. 155. G. S. N. L. H. D. C. S. X. L. 173 Gnirke. N. J.A. P. 112 Gershon. 122 Hakonarson. 175 Grant. D. A.L. K. S. 55 Godi. 158 Garcia-Segura. 94 Gibbs. 169 Grimmer-Somers. A. H. 200 Goodarzi. 179 Author Index 241 . C.J. 175 Gojobori. 132 Giusti.C. M. H.E. A. M.L. N. O. 42 Grundy. E. 175 Grattan. 1 Ghezzi. 215 Gevers. 78 Hanada. 8 Gratton. A. R. 146 Goldman. 79 Gupta. L. 143 Glazer. T. M.T. M. L. B. D.G. 85 Gordon.E. A. L. A. 77 Goel.E. C. 145. 173 Gandhi. 52 Govindaraju. 225 Grignon. A. 151 Hacein-Bey-Abina. M.P.T. 156. L. 171 Gonzalez. 175 Graff.A. S. S. A. 221 Gautron. 230 Graessler. 175. J.O. M. P. 130 Gooren. 125. T. 148 Gylfason. 155. 143 Gonzalez-Losada. 106 Gans. A.E.T. M.P. 117 Galas. 7 Gerbin.H. D. 65 Ge. T. E. M. M. M. A. 232 Groenier.E. K. G. 1 Guo. 13. D. 36 Grigoriadis. L.Galand-Portier. 74 Hall. 103 Gehman. 142 Gubler. 177 Gingrich. 212 Gorski.-M.

J. S. 54 Jarvelin. 156.E.N. 156. 175 Herich. 90 Jakobsson. E. 175.A. 167 Johnson. 181 Jonsson. 49 Johannsson. D. 177 Hofmann. 111 Iglesias.J. E. 128 Jansen. G. P. 49 Hopkins. 168 Hoque.W. C.E. T. 77 Hicks. Q. 102 Jonas. 89 Huff. 94 Hayward. 53 Hung. 95. 107 Hokken-Koelega. J.B.J. J. 178 J Jabs.Hausler. M. 219 Hodges.C. E. K. 54 Hofman. 176. P. 143 Jiang.F. D.E. 175. 141 Johnson. 200 Hechenberger. 90 Honda. 71 Henning. 182 Huntley.R. R. 175 Huihjbregts.A. 171 Jira. 222 Jacobsen. A. 175 Johnson. 220 242 Author Index . 175 Hiort. A. 97 Ji.A. 175 Hietala. J. 145 Jaddoe. S. A. V. G.D. 174 Hebestreit. 55 Houdijk. 175 Johnson. C. A. N.R. 4. L. 156.B.H. 184 Ingelsson.L. M. 145 Isomaa. T.W. 231 Jamar. 79 Hosseini. 177 Holmlund.M.D. T. 21 Jetha. V. 40 Hayek. 131 Hovorka. 177 Hekkala. 46 Heino. A. 2. 220 Jessberger. 231 Holter. 145. M. E. IX. 144 Hovorka. 173. 173. O. M.A.A. L.D.C. 186 Jorgensen. 46 Jacobson. 89 Hayes. 145. 165 Ji. S. R.A.M. S. 226 Hershey. J. 177 Jatmiko 233 Jaubert. 97 Hui. 156 Ilonen. J. 142 Jing. 172 Jackson. M.D. 29 Hoefels.M. 201 Janssen. T.M. 173 Hudgins.J. X. T. 50. 96 Herold.L. T. 232 Itoh. J. 136 Iyer. I.M. 175 Jacobsen. 175 Hennig.S. 183 Hivert.N. 134 Hillman. G. A. S.C. J. K. T.W. G.J. V. M. T. 177 Hytinantti.M. W. 85 Hen. 94 Hochberg. T. S. 131 Howard. 124 Hoste.A. 197 Hindorff. N. F. F. R. D. J.C. 65 Heinrich. 181 Hsia.D. 175 He. 40 Hong. E.C. 174 Hodgson-Zingman. F. 49 Hould.M.R. 213 Horvath. 175 Jowett. I. 142 Howell.B. 220 Huang. B. L. 52 Johnson. 163 Hokken-Koelega. F.N. A. 146 Hodson. L. 59 Hembree. J. 171 Isidor. A.E. 175 Hu. 55 Hermanns. C. 36 Hermesz. 145 Holly. 183 Henneman.E. J. V. H. P. 185 Hilsted. 212 Ihm. A. P. M. F. C. 77 Hay. 228 Hughes. N. E. 168 Hu. 212 I Ibrahim. 179 Hurles. 123 Hellstrom. B. 145 Herbison. D. L.M. 220 Iliopoulos.R. D. 1 Huisman. 212 Honetschlager. B. 220 Hurt.K. 177.H. 44. 145 Jacquemont. 142 Heath. D. 156.F. 175 Herder. 220 Horjales-Araujo. J. B. J. 97 Jonasdottir. C. M. Z. 175 Hills. T. 220 Hondares.M. 123 Imakaev. 42 Hottenga. 156 Hoang. 175 Hunter. A. 168 Hwa. 207. 174 Hudson. M. 181 Jonveaux. S. P.S. 71 Hirschhorn.H. 172. P. 189 Hood.I. 156 Hingorani. 173 Hoorweg-Nijman.P. 186 Huffman. 14 Jonsson. 86 Jern. L. 49. H. R. P. H. 182 Hingorani.B. J. 94 Huhtaniemi. A. 140 Hreidarsson. T. H. A. 107 Hefferan. T.U. J. 67 Hu.A. S. 111 Hutten. 76 Ikuta. K. L. 181 John. 175 Itan. 8 Herbrecht. J. M. A. O. A. J. 102 Johnson. 197 Hegelund. 175 Hebert. 145 Jorde. 126 Hershkovitz. 116 Hofland. 218 Herrera. 52. T. 155. 66 Hegedus. 177 Houang. K. 38. M.J. E. 177 Jakob. 88 Honda. C. 224 Ichijo. R. 155. P. E. J. 41 Jefferson. 52 Hypponen. M.J. E. L. P. W. S. 15 Hero. T. T. T. D. 199. 201 Holder-Espinasse. M. L.D. B. A. B. E. T. 79 Henderson.T. 10 Horie. 97 Jian. A. R. 104 Illig. J. A. M. L.D. I.J. 145 Hubley. P. 142 Jiang. S. 46 Jacobsen. 156. 175 Irikat. 208 Herrin. 156. 20 Hercberg.K. S. Y. 216 Horblitt.

H. 135 Kasparov.N. M. 162 Knowles. 78 Klasen. 130 Klein. J. T. 141 Keogh. 143 Kirin. 175 Juntti. L. 121 Lamberg-Allardt. 202 Keuper. T.W. 175 Lamb. 91. 69 Kohno. 159 Klein. 9 Kaido. 177 Kitaoka. B. K. G. A.A. S. 114 Koll. 227 Klugmann. C. 56 Lann. L. 90 Knight. H. C. 78 Kong.Y. S. S. U.J. 163 Kerkhof. K. 208 Kohrle. 135 Lander. 174 Koba. S. S. 156 Kousteni. M.M.J. 177 Korada.F. R. O. E.G. 219 Kuttenn. 211 Kremer Hovinga. C.A. H. 132 Krebs.H. G. M. 142 Kandeel. 78 Kivimaki. O. 94 Kajimura. 123 Lahlou. 139 Khan. E. 29 Lahde. D. 37 Kosaka. B.T. L. 125 Kim. 175 Kaprio. G. 221 Katz.J. 179 Kino. 182 Koning. 175. 8 Kennedy. 79 Klingensmith.L. 75 Kremer. 226 Kristrom. G. 193. I. J.T. 123 Knowler. 156. P. 159 Kim. 16 Keller. 175 Labalme. 177 Kansra. 212 Kooy. 178 Kulaga. N. 148 Laitinen. C. B. A.A. A.C. M. H. 71 Kruglyak. J.C. J. 156. C.W. A. 76 Lajic.W. S. 13 Kirigiti. M. S. 179 Khoury. 149 Knip. C. 143 Keefe.A. 175 Karperien.E. 142 Kemp. 69 Kovacs. 93 Laitinen. 189 Kok. J. F. W. R. K. 33 Kobayashi. K. 200 Krishnan. E.R. H. 222 Kumari. S.J. M. 181. G. D. 76 Lambert-Langlais.T. 145 Koppelman.J. 117 Kuusisto. 220 Kristinsson. E. 159 Landreth. 78 Kim. 156. P. D. Z. 139 Kumar.F. 148 Kucera. 156. 71 Kollman. 145 Kurland. E. N. 71 Kluge. F.M. 184 Lajunen. 54 Lammi. 128 Kutschera. H. D.T. 29 Lachin. F. 106 Kelberman. 30 Kao.D. 97 Lajoie. M.Jula. 217 Kloos.F. 60 Kim. P. 235 Kristoffersen.S. K.B. 33 King. 90 Kriemler.W. 202 Konstantopoulos. 22 Kristiansson. M. A. 175 Kurg. 177 Laitinen. 160 Kubota. Y. S. S. R. G. M. 176.C. G. M. 178 Keil. 156. 179 Kimball.C.A. 90 Kleefstra. 68 Kennedy. 204 Kan. M. 177 Kageyama. R.G. H. 109 Kim. 147 Kuroda. 156. 168 Katari. 219 Lai. 105 Kao. H.J. 127 Kurshan. N. N. E. S. J.S. R. M. J. J.M.O.S. 111 Lamberts.S. 228 Ke. S. K.F. 189 Laakso. 158 Khrebtukova.E. B. 184 Landman.C. J. E. E. 79 Karvonen. C. V. 145 Kerkhof. L. 39 Klopocki. K. B. T. J. S. J. 100. K.W. 219 Kilic.F. S. C.T. 183 Komnenovic. A. 220 Kode. A. 167 Kumararatne.A. 111 Kinoshita. 145 Lacampagne.M.C. 192 Kok. 179 Kyvik. Y. S. 99. 155 Langslet. 175 Klaere. 181 Kristo.H. 177 Langenberg. R. J. N. 7.S. 113 Kingsmore. J. F. 5 Kral. V. 144 Krause-Steinrauf. M. 127 Kanoni.M. S. 121 Klinger. 68 Kelly. R. 131 Kolonel. K.E. 44. 59 Kutlu. I. M. S. G.M. A. 175 L La Gamma. R. 127 Kublaoui. 14 Krohn. 1 Lange. S. 42 Kruger. M. A. W. K. 168 Karpe. 194 K Kaakinen. 156. G. 177 Knight. 177 Kesaniemi. N. 174 Klemenhagen. 156 Krude. 88 Juul. F. 23 Lang-Muritano. 103 Kottgen. 168 Lankester.R. 175. A. 142 Koskinen. S. 124. T. 70 Kenny. 157. T. P. 175 Kotitschke. A. 92. M. 175 Lango. 4 Kastelein. P. W. Y. C. 158 Kineman. S.H. 175 Knight. 175 Karki. T. D. G. 132 Lafont. S. 89 Kaiser. 59 Author Index 243 . C. 175 Krajewski. 175 Kwok. I. 22 King.M. S. B.A. 75 Karsenty. J. 179 Kiermer. M. 182 Ku. 157. 13 Kosinski. 179 Khankhanian. 202 Kress. F. S.R. 175 Ket. 148 Kamp. 159.

L. 52 Louiset. 29 Lee.D.F. Z. 171 Machtay. 16.A. M. 51 Maisuria-Armer. 53 Malan. 231 Mandel. 94 Lombardi. 177.J. K.G. F. 150 Lauritzen.M. 10 McCrindle. 6 Maghnie. B.M. 182 McKenna. 234 Liere. 119 Lorenz-Depiereux. R. Z. 183 McMullen. C. K. 175 Loqman.W. 162 Loos. 156. R.J.J. S. 175 Lecoq. 79 Liu. D. 175 Li. 55 Le Caignec. 165 Lewrick.P. 145 244 Author Index . M. 219 Legay. 1 Lawlor. 183 Leunissen. 145. 59 Lofrano. 219 Leboyer. 186 Lorini. 175. 145 Le. C. 145 Malmstrom. 148 Luo. 195 Losekoot. 15 Main. 20 Lechleiter. E. 183 Lyons. 102 McKenna. A. C. E. 235 Li. 79 Lian. 44 Le Bacquer. R.Y.D. L. M. 29 Lebel. 222 McGrice. R. A. 1 Lonneux. 195 Lochmatter. K. 79 Luan. D. 116 Mailloux. L. 178 Macdermot. 66 Madsen. P. 149 l’Homme. 22 Luton. 175 McDaniell. N. C. 156. P.E. 66 Link. 231 Lindgren. 172. X.K.E. D. 175 McRorie.L. 220 Lefebvre. A. 216 Lescelleur. C.P. L. 175 McCarroll.K.W. M.L. 215 Lefrançois-Martinez. F. 222 Lin. B. H.H. E. J.K. A. E. O. 79 Lo Vecchio.I. 74 Lord. 220 McAteer. 198 Lombes.B. 53 Lovejoy. H. G. 176 Lavoie. S. R. 219 Mahley. 145. R.L. J. 50. 125 Li. R. O. R. C. K. X.T.P. 175 Lunsford. M. M. S. K. R. O. L. 156 Lewanczuk. 175 Linderholm.C. P. 184 Lieberman. D. S.R. 156. H. K.L. 111 Lefrere. A. 178 Liu. 229 Lovell-Badge.F. C. 156. Y. G.J. M. A. 107 Loredana Marcovecchio. P. J.J. J. 107 McPherson. S. A. 224 Lee.M. J. 132 McGowan.S. M. M. E. 177 Macarthur.R.P. N.S. 175. 183 Liu.A. C. 168 McCulloch. L. D. 3 Lightman. 195 Lemaitre. 70 McGee.L. 175 Lazarus. E. M. Y. 67 Makitie. 4 LeSauter. 108 McDonough. 111 Lefkowitz. N. M. B. 156. V. 156 Le. M. G. C. 227 Mackay. 77 Levy-Litan. D. 113 Lerner. W. A. R. 73 Liang. 67 Leitner. B. 46 Maeda. 145 Lenci. V. R. 195 Magi. Y. 113 Lecoeur. 76. 198 Lobbens. X. B. 53 Malan. 144 Leboulch. 175 Mahlaoui.N. M. V. 39 Liu. 182 McConnell. 178 Lee. D. 220 McDonald. 144 Lettiero. C. J. G. G. 175.M.M. 67 Leibbrandt. 59 Leroy. 175 Latronico. 131 Lathrop. A.M.Larsen.J. 157 McCrimmon. D. H. 175 Le Bouc. 35 Luttrell.E. D.M. 215 Lutz. S. 77 Levy-Marchal. 179 Luotoniemi. J. 155. 95 Lupski.M. F. 23 McElroy. 78 Leikin.T. H.B. 143 Liu.A. W. 224 Liu. E. 77 Lorenzo. X.A. 33 LeRoith. T. 197 Maiorana. 180 Maji.C.E. 175 Maier.M. 175. 175 M McArdle. 133 Lyon. M. 111 Louw. S. 73 Li. 213 Lyssenko. 143 Li. 45 Liden. 128 Looker. L. Q. 90 Loyens. W. 198 Lettre. 142 Lind. V. T. 25 Lofqvist. R. 222 Madden. 177 Lindquist. R. M. Y.E.W. 27 Li. M. T. B. C. 27 Liao.C. J. 102 Lilic. J. L. 183 Le Tissier. Z. L. S. 231 Lieb.W. 199 Leventhal. J. 10 McNelis. D. 21 Makareeva. 177 Magnusson. R.R. 182 McCarthy. 178 Lieberman-Aiden. 55 Leheup. J.D.L.O. 143 Li. N. A.J. 145 Lei. M. S. N. B.Z. 219 Li. 8 Liu. A.J. 155. P. 61 Ley. M.P. 145 Macdonald. 96 Malan. C. 171 Luque. 36 McKenzie.S. D. 156. 5 McNay. C. J. 94 Laurie. 156. W.O. 163. 4 Lu.C. J. J. 177. 222 McCoy. M. R. 65 McVean. R. 59 Ley. 142. S. 145 Loche. 150 McGuire. 156. 179 McGee-Lawrence.

223 Matsuoka. A. L. V. 175 Mulder. D. 42 Mukherjee. P. 55 Metspalu.J. 175 Natividad. S. R. J.M. 36. 136 Nagy. 142 Mimata. D. P. D. 163 Muzny. J. A. 210 Marks. 175 Morris. R.M. 44 Mittelstaedt. 100. J. 132 Marlowe. J. 23 Miller. 78 Minakata. 212 Moss. A. 176 Meaney. 156 Moran. 210 Meigs.J.A.R. 6 Navratil. 13 Morken. 145. 77 Mantero. A. M. J. R. 128 Mari. 79 Mannik. 9 Mori. 174 Neggers. 167 Nagata. P.S. N.L.M. 182 Manor. M. F. 175 Melino.D. 44 Muroya. S. T. A. S. E. K.S. 17 Mondal. A. D. 127 Mulligan. 136 Mercer. 39 Molino. M. O. S. G. 177 Martillotti. 117 Mudge. 177 Moore. 175. L. F. H.J.L. 145. D.J. 70 Nelson. 142 Narisu.E. 176 Marsella. 176 Meyts. 175 Navarro. 214 Morgan. A.M.M. 175 Manoli. S. P. M. L. 222 Mhaouty-Kodja. S. 67 Nahum. 28 Metzger.Mang’eni. 105 Marsh.L.C.A.P. F. 9 Napoli. 235 Mooser.B. 234 Mangino. 175.A. A. 191 Mitchell. 139 Mera. 214 Miller. H. 142 Marsh. G. 2 Manolio. E. 156. 6 Moriuchi.J. 13 Murphy. D. 175 Morris. V. 209 Marmot. S.P. 201 Mennessier. 139 Moss. 156. 117 Morgan. P. 60 Mayor. S. 181 Mathieu-Dramard. 175 Manin. M. A.G. I. C.E. S. 9 Murata. 112 Marais. A. 156.A. 89 Montori. 9 Monk. W. D.E. 177 Mølck. H. 3 Miettinen. 13 Mowzowicz. 175 Meneton. T.A. 156 Meijboom.A. 182 Marechal. 214 Miot. T. R. 25 Mundlos. G.G.J. N. 156.K. 84 Mauer. 151 Mook-Kanamori. H. H. 175 Martinic. J. 145 Nelson. K. Z. P. 222 Marre. 200 Meyre. B. S. E. 95 May. 184 Misir. N. 29 Molnar. 26 Melzer. 145 Metz. 175 Mitchell. P.J. 132 Morel. 145 Manning. 210 Merke. D. 71 Murakami. 73 Motomura. M. E.C. A. 23 Nazareth. B. 6 Murgatroyd. 120 Marini. N. 1. 202 Mullen. 235 Nakada. 42 Mirny. N. 222 Naitza. N.B. 144 Marceau. 8 Mullis. 85.S.T. 190 Nader. M. 176 Moodie. M. 156. R. A. 145 Mathis. J.A. 91 Montgomery.F. J. G. 36 Neff. A. 144 Mardis. A. P. 156. S. R. 156. T. 179 Miller. 130 Maury. 226 Montpetit. 29 Mollard. F. 156 Mazur. 149 N Naar. 27 Murphy. 217 Matthews. T. A. A. A.R. 136 Masson. K. L. 178 Morozova. 112 Marinova. 203 Mulder.M. A. 185 Moore. 20 Medhamurthy. J. 233 Moses. V. A.M. M. J. F. P.L. M. 78 Nathan. 85 Meyer. R.D. N. A. 111 Mann. 111 Nader. R.F. 156.L. 217 Melino. V. 156. A. K. 6 Mohlke. 222 Navarro.P.J.W.M. 108 Morrison. 29 Mepani.O.R.P. S. 46 Moses. N. 145 Martinez. I. K.B.H. M. A. M. 111 Martinez-Larrad. R. 175 Menke. E. M. S. 76 Millar. 192 Moebus. K. 168 Misso. 109 Mertens. M. C. T. S. N. 223 Martorell. 179 Mayack. 175 Marodi. J. 168 Marceau. P. 106. 219 Moczko. 46 Moley. M. 85 Maruyama. 202 Nelis.S. M.M. M. 6 Nakazato. 174 Morgan. 67 Mariniello.A.K. 175 Najafi-Shoushtari. M. 195 Nargund.R. K. 235 Nabhan.C. 43 Mori. D. 171 Nebesio. D.M. A.D. 129 Martinet. D. 159 Author Index 245 . 231 Monahan. 185 Monteau. J. 136 Mattei. 227 Mogi. 24 Mauer. K. 7 Morris. 175 Narumiya.O. 168 Melmed. 171 Mwangi. 232 Meisinger. F. M. 99. 212 Morwood. 62 Mester. Y. Y. G. S.J.M. U. M. 79 Meehan.D. M. V. R. D. K.D. Y.R. M. I. 179 Mueller. D.M. D. 142 Meyer 3rd.

E.T. 171 Onland-Moret. 73 Perrin.F. 174 Pedersen. C. 125. J.C. 113 O’Rahilly. R. 155. 177 Penninger.B. 145 Oury. 104 Netchine.M.M. 44 Oxman. R. 75 Poston. S. 142 Pando. K. K. 112 Norris. K.D.A. 204 Oostra. A. 220 Oostdijk. L. 214 Otten. M. M. J. 176 Pooley. 145 Palyha. 175 Pant. M. N. 152 O’Brien. 232 Onyiah. 175 Paul. 226 Ozata. A. A.K. 6 Oksenberg.A. 46 Nowicki. 175 Phan. 224 Philippe. 201. S. M. V. J. 133 Porton. 165 Orru. 78 Perantie. 121 Northcott. 222 Ounap. 25 Pfaff. Q.F. 219 Payne.N. C. 193.D. P. 94 P Pacak. S. D. 156. 131 Noel. M.R. R. B. O. I. K.A. 163. 222 Pichler. 160 Odink. 191 Oden. 173 Paolino.H. 148 Nguyen. 156 Nodale. P.P. 177 Ormond. 194 Petersen. J. 145. D. 150 Obunse. 119 Oshida. M. V. 183 Nickerson. D. K. 150 Pavkov. S. 175 Peden. C. D. H. 172 Nguyen.S. 175 Perren. I. A.E.C. 189 Pang. G. L.A. 94 Nofrate.S. 44 Novosyadlyy. 156. 175 Persani. C.S. R. T. 195 Parvari. 55 Neville.H.J. S. 33 Parodi. 77 Pascoe. 176 Posovszky.Nelson.R.L. 176 Pitsiladis. 124 Niedziela. 78 Pigeyre. P. M. H. 175 Postma. 109 Niklasson. 174 Pawson. 179 Paneth.J. 148 Pacini. A. 208 Nesterova. J. 175 Pietz. S.H.C. D. S. 132 Pessin. 145 Phipps. K. 59 Nilsson. N. 61 Perrien. 163 Peltonen. 46 Nieman. A.R.F.H. 6 Ohta. L. E.D. 145. 201 Ouachee-Chardin. J. 145 O’Reilly. 175 Palmer. 136 Okamura. 234 Pitteloud. 214 Payen. 39 O’Brien.E. F. M. I. D. 120 Nogueira. 227 Pisinger. 24 Palkovits. 175 O Obici. 191 Paik. 79 Owen. C. J.D. 33. P.R. 175 O’Connor. 220 Piper. S. M. 103 Petkovic. G. P. 216 Pfeifer. 67 Peng. 69 Pakyz. 181 Olesen. E. 133 Peng. A. 156. L. E. C. M. 175 Oseid. M. S. S. N. 145 Plummer. L. S.E. 127 Pfeifer.T. L. S. 156. 4 Okamoto.F. 37 Pescovitz. 22 Pennell. T. 88 Ohkura. 175 Pedersen. R.A. B. L. 111 Polak. 84 246 Author Index . 37 Pearson. 37 Paterson. 44 Petersenn. G. M. 126 Perin.R. 88 Ojeda. 105 Posner. 192 Pifl. 156. 55 Perkins. S. 222 Olivo-Marston. M. M. X. L. 13 Ohinata.P. 155 Pinto. R. 41. 220 Osugi.F. 8 Picard. X. 58 Paroder. Y. T. G. 21 Nilsson. 177 Palta. 124 Patisaul. 92 Ong. 35. 172 Nicolae. 1. K. 39 Page. J. 222 Polasek. O. 175 Papa. 78 Plessis. M. 147 Petersen. 192 Nzekwu.J. 176 Peeters. 175. U. T. S.M.B. 177 Postnov.A. A.I. 94 Pohlenz. 235 Park. M.M. 106 O’Connell. 175 Pattou. K. M. 86 Pattaro. 49 Pinhas-Hamiel. 139 Posthuma. D. 204 Ogata. 198 Palmer.K. N.W. J. A. 78 Paolisso. 84 Nepote. 175 Opocher. S. 181 Olason. S.H. F.J. J.D. C. F. 19 Paranjape. 59 Nowak. 36 Pointud. A.J. 156 Passoni. L. C. 177 Pencek. J. 175 Polychronakos. J. A. M. A. 38. P. 175 Newbold. 175 Pal. V. M. O. M. 179 Olafsson. 192 Nielsen. O. F. M. 21 Perry. 145 Pilon.D. 159 Pavlovic. 67 Pangas. 86 Ng.S. 10 Parathath. J. 15 Palladino. E. 156. 175.W. 49. 68 Park. H. J. A. J. M. B. 220 Pang. R. W.J.W.P. L. B. Y. H.E. S. 190 Perola. J. M. D. 94 Plehm. I.W. R. 90 Pankow. S.A. 175 Pearce. J. M.M. D. 222 Pfeiffer. 156.J. I.P. 1. K. L. D. 102 Porter. 156. 49.

E. 156. 156. M. 190 Qin. B. 108 Sadie-Van Gijsen. 49 Rotwein. 177 Powell. 182 Rance. M. 146 Savage. 93 Ralston. D.H.W. 3 Raskin. S.N.L. 17 Rybin.E.J. T. N. N. S. 177 Ringel. 105 Pritchard. J. M. M. 21 Author Index 247 . R. 184 Sangkuhl. 176 Prevot.R. 233 Sarpong. R.T. 21 Rivadeneira. M. 33 Ribault. 65 Ramakrishnan. 156. J. 220 Roby. 192 Ruffman. 183 Sas. 175 Puder. J. 61 Reinehr. 127 Ravindran. 174 Sahlin. M. 128 Salomaa. 69 Rades. L. D. 175 Poulsen. 5 Randall. 129 Sapienza. S. I. 166 Rahman.Potter. B. 94 Quon. A. 119 Robinson. 97 Rainey. A. 222 Purmann.J.T. 177 Province. N.A. 168 Rached. J.T. 175 Rissman. 176 Roden. R.M. P. Y. G. A. K. 44 Sävendahl. H. 201 Refetoff. 155.W.H. M. C. 176 Ruokonen. M. C.Q. M. 189 Quinton. 148 R Raal.M. N.H. 175 Prchal. 128 Rolandsson. M. 52 Robertson. 76 Sabaliauskas.A. 33 Pushkarev. C.B. 74 Prokopenko.M.S. S. 109 Ray-Coquard. 44 Rotimi. 232 Power. T. P. I.C. 177 Rivero-Muller. 175. T. 62 Rowen. 112 Raivio. 8 Quero. 175 Rooman. 44 Rayner. 175 Rydh. R. P. I. 195 Radford. M. 65 Sawaya. T. 1 Salerno. I. 182 Rotter. M. L. S. 97 Rivier. 16 Roach.G. W.C. S. 227 Raymond-Barker. 174 Sanlaville. P. M. T. S.D. 142 Rewers. 207 Sabo.R. D. O.C. 175. 171 Reinalda. 184 Rahbar.S. T. L. 200 Puel. A. 39 Rio.F. L. F. A.A. 175 Sampson. 177 Redon. J. 175 Rodriguez. 175 Richards. D.L. 128 Ropers. 43 Ruivenkamp. D. M. A. 235 Rayner. 42 Rose. 139 Reeser. 175 Raskin.L. 184 Sacchetta. 52 Ross. R. U. K. 78 Qi.A. 201 Sass. A. D. P.C. M. S.J. C. 23 Roberts Jr. 40 Reincke. K. 88 Salenave. H.J.E. 58 Rosell.B. 156. R. 175 Psaty.A. R. 220 Reed. J. I. M. D. A. 14 S Saarnio.J. 189 Rahman. 21 Rivkees.R. V. 156. M. R. T. J. 113 Qu. 103 Saeed. 139 Roccasecca.P. M. K. M. S. 145 Sagreiya. P. H. 111 Saitou. 179 Ramasamy. J. D. 171 Ripatti.S. 29 Robson. 45 Reid. P. V. R. R. 175. H. E. 176 Rice. I. 90 Richards. 108 Rothman. K. 35 Ribel-Madsen.G. 132 Roepke. D. 175. M. 175. 4 Price. 113 Sato. J. 221 Saptomo. W. 177 Pramstaller. S. P.K. I. 110 Price. 173 Robbins. 90 Rigutto. A. C.G. 110 Rossi. 177 Ramos. 175 Sandstrom. M. J. S. R.I. 121 Reyes. 145 Sanna.A. 55 Riek. 174 Quennell. 16.P. 70 Roberson. 175 Rauch. 175 Sant’Angelo. F. L. J. S. 175 Rocheleau.J. 42 Ring. C.H. 43 Rose. 176. 67 Ragoczy. 108 Robinson. 222 Roland. 155. J. 155. 198 Salmon. 34 Rizzoti. S. 30 Ragazzon. D. S. K. D.L. 156. 67. V. C. J.M. E. M. 175 Sandbaek. 227 Radetti. S. 175.R.M. 173 Ruchala. M. G. 111 Raggio. 109. 17 Raff. N. 13 Sattiraju. L. 52 Rung. M. 175 Qi. 132 Rathmann. T. C.L. A. 85 Ramaraj. 174 Rosenfeld. 33 Roifman. 145 Purtell. H. 176 Sandhu. 125 Quake. H.C. 174 Q Qadri.J. 65 Ricort. 186 Qin. F. 212 Rosenbaum. M. C. S. C. Y. H. 25. 145 Reyna-Neyra. 83 Sahut-Barnola. 186 Prentki.H. J. R. 107 Raetzman. 155. 152 Reitman. 156 Sampson. S. 176 Pouta. 156 Rotteveel.J.M. A. 156. 146 Reymond.N.T. G. 40 Riches.M. 176 Rybak. B.D. 21 Riethmacher.

Y. D. 44 Schouten-van Meeteren.B. P.F. A. 156 Sitaraman.N. P. 91. 184 Stanier. S. 94 Serrano-Rios. N. E. 156. J. 181 Sijbrands. 14 Seidenfeld. 129 Sethupathy. 116 Siemensma.S. 144 Smith. G. G. A. 94 Silver. 207 Smyth. 207 Sherwin. 61 Schoenmakers. 9 Shioda. 156. 175 Serre.Sawchenko. P. P. 185 Stankiewicz. 132 Schauss. D. T. 181 Stelzer. 139. M. E.L. 180 Soares. D. L. 175. 22 Söder.L. J. M. 156. 186 Simpson.M. B. 175 Spurney. 175 Schally. 58 Silvers. 4 Simpson. A.P. K. 21 Sirigu. 10 Shi. 142 Shendure.J. D.J. L. 207 Shen. 207 Stenbeck.S. 24 Spranger. N.W. R. M. 158 Shah. 145.B. G. S. G.I. L. 59 Smith. 132 Sladek. 155. 123 Silva. J. E. 156. J. 178 Soon.S. 53 Schutz. 68 248 Author Index . 90 Sekine-Kondo. R. D. 136 Seminara. V. L.C. 27 Slucca. 167 Singleton. M. 219 Schnabel. 21 Sawyer.J. 95 Seth. 179 Schubert.S. 195 Seedorf.E. I. 175 Song. U.R. 120 Sovio. N. 156. S. J. T.J. J. S. 175 Smith. 228 Shearman. C. 109 Sinaiko. 108 Siegel.S. 181 Sigurdsson. 149 Sjostrom.V. 202 Schroor. A. S. 123 Simon. 53 Schutte. 119 Smit. 142 Stearns.P. 175 Schwarzer. 49 Schroth. A. E. 192 Spack. 103 Schatz.T. 88 Shimomura.S. L.D.D. P. S. 175 Sinaii. 193.Y. 21 Schuhmacher. A. 227 Schmidt. 85 Sparso. 71 Segal. 172. 176 Shen. 181 Sigurethsson. 85 Stein. M. M. B. 46 Song. A. H. 175 Siljander. A. 44 Sidhu. 175. 220 Schiavi.A. B. 2. 156. N. J. S. P.J. 52 Schwarz. 149 Stacey. A.E. 90 Schwartz. S. B. R.T. 181 Stein.B. 175 Sigurgeirsson.M. F. H. B.M. 139. 181 Sigurdsson. 177 Shigeta. 102 Stearns. 156. 147 Schwartz. 224 Spiegelman. O. J. P.P. 60 Shah. S. B.C. S. G. R. 175 Shuldiner. 168 Schutte.W. H. M. 178 Seale. A. G. 175 Smith. 39 Schmidlin. N. 175 Shaw. G. A. L. 175 Shulman.K. 77 Schneider. R. T. 235 Shrader. T. S. A. 215 Srinivasan. 150 Skyler. P. 115 Sowinski. M. 1. J. E. C.D. C. G. 228 Scheet. 162 Sigurdsson. 88 Solberg. J. D.V. 177 Steensma. 88 Shah. 148 Spinelli. 176 Slatkin.A. 200 Schlumberger. 20 Siscovick. 20 Shannon. K. E. M.A. G. 181 Stamatoyannopoulos. 145 Skakkebaek. 175 Shields. 6 Steinthorsdottir.B. N. 67 Shields. 120. 24 Schechter. 175 Singru. K. 172. 211 Sherpa.W.P. R.M. S. N. 197 Skeaff. 148 Sear. 212 Sehlin. 173 Shao. 123 Simell. U. 175 Spellberg. S. A. 150 Saxena.A. 156. A. 146 Sievers. 142 Shen. 209 Secco. 175 Silveira.F. D. P. S. A. 155. 173 Sheriff.S. J. 175. L. A.R. 226 Schurr. J. 175 Sorensen. D. 175 Silander. Z. N.J. 210 Simard.P. L. 130 Singh. 191 Shay. P. K.R.J. 173 Smith. 156. 227 Stefansson. 227 Scott. 198 Spohn. D. 193. P.A. M. H. 175 Scherer. A. R. 216 Silverman. B. 116 Schumacher. 230 Steegers. R.D. J. R. E.S. 182 Sleeman. A. 49 Sierra. 171 Stavreva. 175 Sayer. 194 Sosenko. K. R. R. 55 Shadrach. 144 Simell. P. D. E. S. H. 9 Shioda. 156 Sijbrands. 175 Seurin.M. A.S. 156. 140 Silveira. 175 Seemann. T. O. E.A. M. R.A. 156. 179 Schindler.S. 160 Shahrokh. 21 Simonson. E. G. Y. J. 228 Siegrist. S. S. 164 Schubert. G. 91. D. 168 Steiner. 227 Schunemann.L. 156. 177 Sowers. 113 Schilkey. D. Y.E.P. 72 Sharp. 227 Sekido. 43 Skinner. 123 Simell.M. 124 Shen. J. 176 Service. P. 143 Smith. 108 Soranzo. F. Z. 156. 83 Soderborg. 156. L.

G. 175. D. 34 Szczepanek. 175 Swift. 158. M. 13 Takahashi.P. 92 Toulon. S. C. T. 90 Trelle. 174 Thorsteinsdottir. J. A.A. 104. N. K. A. 103 Treweek. 176 Vaaralahti. 94 Tyler-Smith.L. Y. L. 220 Sverrisson. 220 van Berkum. 146 Tews.K. 77 Stumvoll. 111 Urbina.Stewart. R. M. K. M. 157. 181 Thorn. 177 Strack.T. 186 Stribling. S. S. 36 Stora. 220 Stocker. A. 220 Tyrka. W. 85 Taniguchi.V. 130 Stratakis. H.A. 212 Stoffel. 67 Tang. Y. M.M. 3 Trudel. 163 Stiles.G. F. B. G. 168 Szarfman. G. S. Y. H. 175. H. 181 Swift.J.H. 161 Sun. B.A. R. 96 Toledo. 156.L. 196 Taylor. C.S. 40 Thorand. M. P. 222 Taylor Jr. G. E. 90 Uitterlinden. D. V. 90 Treier. A. 196 Tron. C. P. 155.E. 177 Ullmann.P. 177 Timmerman. M.S. J.S. J. C. 183 Tayo. E. K. 122 Tamehiro.R. C. 6 Tsutsui. 142 Stringham. S. 41 Tronche. R. S. 113 Toledo. A. D.L. 145 Trarbach. 156 Stutzmann. 156 Tups. 21 Vahasalo. 124 Sun. R. J.A. 183 Tecott. N. 220 Tong. P.V. 83 Tonjes. A. 94 Stijnen. 1 Tsukamura. 233 Sutor. M. 139 Thakuria. 94 Treier. 227 Urade. 93 Vadodaria.D. 99 van den Pol. 79 Suss. T. 192 Szamosi. 111 Vale. I. 145.P. Y. 9 Tamborlane. A. S.P. T. T. R.E. 155. 19 Todd. B. D. S. 174 Thambundit. G. 136 Tardy. T. J. E. 222 Touraine. 175. A. C.P. 226 Trichereau. 214 Tuomi. 177 Surcel.C. 1 Templeton. A. N. C. 218 Todorov. 175 Taneera.M. 229 Tenenbaum-Rakover. S. I. 130 Sulem. W. 8 Turan.R. 66 Suwa.B. 88 Tolson. H. F. 175 Thorel. 156. 124 Syvanen. W. A. 77 Tirabassi.A. E. 175 Sykiotis. 227 Treszl. J.C. 37 Tusset. 221 Turner. 156. 106 Stratton. 7 Tom. N. 176 Tiesler. 65.J. 79 Suh. 177 Tabor. P. 33. J.O. F. 137 Szaflarski. 79 Tanaka. 228 Suissa. Y. 41 T Taanila. 214 Ueta.C. C. P. 93 Tomonaga. S. Y.F. V. J. 177 Tiosano. M. B. 175 Toppari. K. 42 Untch. 201 Stoppa-Vaucher. 123 Val. N. 184 Tello. 46 Thomas. A. 142 Stram. F. 10 Trynka. Y. F.M.F. S. A. M. 156 Swinburn. A. 232 Thompson. H. E. J. A. 175 Szabadkai. H. U. 78 Takenoya. 181 Thorwarth. D. 78 Trivin. W. 156. 127 Toiviainen-Salo.T. 145 Suarez. 42 Tiano.L.G.M. 168 V Vaag. 27 Valle.R. 21 Valenzuela. 231 Strachan. H.T.E. 117 Touraine. 232 van der Westhuizen.A. 203 van der Schouw. 175 Strom. T. 142 Tangpricha. A. G. A. A. N. 156. 38 Terzic.G. 156. Y. 88 Tanaka. K. Y. 182 Valle. K. 151 Syddall. 2. 171 Tommiska. A. 227 Thomas. L. A. E.J. 192 Szinnai. 105 U Ubuka. I. 61 Sutikna. S. G. 13 Tanaka. 94 Thi. 235 Tan. 79 Telling. 113 Tollkuhn. S. A.H. T. 113 Stirrups. W. 175. T. C. S. K. P. T. 202 van de Sande. A. T.H. A. N. 7 van der Palen. J. 107 Taylor. A. G. 198 Tichet. 175 Tuomilehto. 156 Tang.A.B. 122 Surakka. 156 Valsesia. 156. W. 78 Uhlenhaut. 180. 114 Timpson. 184 van Buuren. 140 Thorleifsson. G. 50 van den Akker. 172 Tajima. 229 Suzuki. 94 Sylvestre.M. 140 Stokvis-Brantsma. 235 Suda.F. 164 Sun.H. 134 Sumner. D. 181 Summanen. 201 van Dalen. J. 183 Strand. 156. A. E. T. 117. 232 Tsiaras. J. 53 Author Index 249 . 208 Thorens. S. 76 Suresh.

37 Wareham. 200 Wray. 72 Wang. K. 78 Von Kalle. M. D.J. 140 Wong. B. 156 Watkins.E. 180 Walley. 202 van Velkinburgh. 136 Waters. K. C. M. J.F. N.S. 175 Wilinska. 201. 216 Weis. 30 Weber. C. E. H. M. 56 Wu.C. 49. 126 Webb. A. M. M. 175 van Doorn.E. 179 Van Vliet. R. J.N. C. K. 201. 184 Wilson. 75 Veijola. 148 Wang.A. M.J. D. 59 Viljakainen. 156 Warrington. K. 49 Vuillard. 167 Weaver. D. A.-P. F. 145. 145 Walter.J. 175 Waelkens. 178 Willemsen. 171 Wheeler.J. 228 Wu. R. C. V.F. S. 88 Walder. 177 Wirtz. E.L. 109 Vidal. 222 Wilkinson. K. 204 van Haelst. 145 Waterworth. 75. W. 49. 132 Wilson. 156 Wickman. K. 75 van Duijn. W. J. R. 123 Veit. 122. H. G. 37 Vijay-Kumar. 156. 219 Vigone. 180 Wallace. 50. S.C. S. 175 Vatin.H. 179 250 Author Index . 166 Wilks. D. 1 Wu. L. 177 Willenberg. 219 Verhoeven. M. 182 Wichmann.L. 70 Wojtaszewski.van Dijk. 107 Wang. 175 Vitart. 177 Washburn. 35 W Wabitsch. 156 von Haeseler.F. M. S. 128 Van Hul. 212 Walenkamp. E. K. 156. H. 175 Walters. M. S. 39 Werbel.H.H. T.R. G. 212 Vincent-Delorme. 52 van Gool. 49 van Mechelen. 7 Wu. 126 White.F. C. R. 175 Walley. 65 Varma. 71 Weil. A. 156 Van Huffel. H. 93 Wei. 37 Weedon.M.H. 53 van Santen. C. 103 Williams. 56.J. S.A.O. A. 3 Verma.M. 60 Waggott. A. D. 15 Whaley-Connell. 92 Visvikis-Siest.A. 156. S. G. J. R.T. J. P. T.M. M. 37 Watanabe. N. 76 Villanueva. 114 Wolfrum. K. Y. 54. 175.B. 145 Walvoord. 6 Wakayama. H. 182 Visvanathan. 67 Wan.D. 175 Williams. S. G. 2. H. J. P. M. 149 Vijayakumar. J. 49 van Rooyen.W. H. 176 Veiga.F. S.M. 232 Wild. M. 45 Wells Jr. 156 Walker. M. 174 Worley. 175 Wheeler. 139 Waeber. J. 68 Wagner. E. C.M.F. A. 56 Walker. G.M.A. 220 Walters. R. 106 Wijga. M. 159 van. 229 Whittemore. K. 145 Vaxillaire. 142 White. W.G. M.C. K. 156 Watarai. S. H.P. 115 Whaley.S. J. M. G.M. A. P. 156.D. 155. G. N. 102 Vreuls. P. S. F.S. 132 White. 124 Woodliff. D. 177 Wijmenga. A. G. 96 Widen. I. 183 Waterworth. 183 Willard. 126 Wu. 67 van Leeuwen. 52. 140 von Schnurbein. 175 Wakabayashi. J. 232 van Wassenaer. 156.A.C.C.J.E. A. F.A.V. M. 175 Wehkalampi. 67 Weiss. 89 Wastell.M. G. A. 102 Wiggs. S. 30 Woodward. 176 WoldeGabriel. M. 36. 150 Venkadesan. 175 Vogelzangs.J.C. 156 van Duijn. E. 229 Wolffenbuttel. 234 Veres. W. L. N. 175 Wawrowsky.T. 201 Wagers. 219 von Meyenn. C.M. A. M. T. 42 van Vliet-Ostaptchouk. 175 Voight. M. H. 79 Vidaud. R. E. 67 Wang. N. 116 Wit. 175 Wojda. 145.P. 28 Wright. S. J. 142 Wang. 202 van Trotsenburg.V. 175 Volat. V. P.M.M. 1 Villarroya. 160 White. 220 Weigel.H.C. J. M. C. C.J. 177 van Duyvenvoorde. 75 Van Gool. 108 Wallace. M. 139 Voss. W. H. 175 Ward Platt. 201 Westphal.M.G.A. 179 Woon. 177 Wiegman. H.M. 145 van Hateren.J. 174 Wherrett. E.E. 88 Wu. C. J. F. G. 39. J. C. K. R. O. T. D. A. T. 145 Visscher. 156.J. A. 26 Weaver. 189 Vanryzin. 168 Wiench. A. 174 Wheeler. 54. A.L.G. 200 van Mil. E. 186 Witteman.J. 73 Ward. C.H. P. 109 van’t Hof. 234 Westerlaken. 58 Wan. D. 131 Wilkie. A. 204 Witherspoon. 227 Weinstein. 124 Wagner.E. J.M. 159 Weingart. 148 Weintraub. 111 Vollenweider. L. 175 van Hoek. J. M.

186 Z Zabel. 163. 143 Yang. 143 Xie. 139 Yebra. V. C. X.W. 146 Ziegler. L. L. 136 Yaszemski. 121 Zethelius. K. M. 67 Wucherpfennig. 20 Zhang. 78 You.O. M. 121 Yokoya. F. 143 Young. 20 Zandwijken. 168 Xu. J. 146 Zinman. 175 Zhai. M. 116 Zung.W. X.G. M. 174 Zdravkovic. 15 Zhou. 177 Zhang. 38 Zwahlen. 175 Zelenika. 220 Zhao. J.J. 183 Zhu. 83 Zhu. O.S. 147 Yamada. 88 Yan. 38 Zahner.Wu. 83 Yancopoulos. 215 Yun. J.T. 156. H. C. Y. 131 Xing. Z. Y. 143 Yuan. 73.D. H. 136. 179 Zhang. 46 Zdunek.R. L. K. X. 23 Xie. X. H. 57. 14 Zeggini. 155. 129 Yin. 129 Wunderlich. 7 Zobel. J. J. L. 186 Yao. G. 103 Zillikens. H. B. 85 Yu. X. A. Y. G. 228 Yang. 175 Zadik. 79 Yamada. 26 Zhu. L. A. D. W. 61 Author Index 251 . 27 Zhao. C. 201 Zaranek. T. 24 X Xiao. X. L. 89 Yi. 67 Zhao. 175 Zhao. S. D. M. Y. A.M. 136 Yamanaka.J. B. Y. A. 13 Yoshikawa. 113 Yarnell. 212 Zalla. 156. 130 Zinn. B. 103 Yount. W. T. 175 Yasunami. L. H. 142 Yu.M. 1 Young. 146 Yamaguchi. 27 Yang. Z. G. T. 69 Yoshimatsu. 133 Zhang. 186 Xu. 83. M. G. L. L. G. 175 Zerbe.C. F. 175 Zhang. 200 Zaibi. E.Q. K. C. M. J. 171 Zhang. J.K. 143 Yu. 27 Xing. E. 175 Zingman. A. X. 66 Ye.J. 177 Zhao. 192 Zabena. J. 69 Y Yadav.V.R. S.W. X. 227 Zwermann. H.W. 62 Young. 171 Yang. 9 Yamamoto. 10 Zhu. J.J.H. Y.Y. M.

see Angiotensin-converting enzyme inhibitors ACTH. 140 Adrenal tumor neuropeptide hormone receptors 103. 21 Autoimmune polyendocrine syndrome type I (APS-I). 74 Acylation-stimulating protein (ASP). Zfp423 transcriptional control of preadipocyte determination 139. see also Cushing’s disease curcumin effects on corticotrophs 30. 22 Androgen receptor (AR) conditional inactivation 3 male sexual and territorial behavior role 88 Angiotensin-converting enzyme (ACE) inhibitors. adrenal regulation 111. 87 BMPs. 229 Aromatase estrogen aromatization and male sexual behavior 2. 137 rituximab and preservation of function 132. neonatal exposure effects in rat reproduction 86. 96 vertebral morphology in male idiopathic short stature or constitutional delay of puberty 96 ASP. 223 Autosomal-recessive hypophosphatemic rickets. 104 DNA microarray analysis of adrenocortical tumors 108 TASK1 expression 112. see High-altitude adaptation Amyloid fibril. 137 APS-I. 113 Adrenocorticotropic hormone (ACTH). see Autoimmune polyendocrine syndrome type I AR. oxytocin for social behavior promotion in autism 20. 220 ACE inhibitors. 133 Bisphenol-A (BPA). 117 Aging child abuse and stress induction 105. 224 AKR1B7. interleukin autoantibodies 222. chondrocyte proliferation and differentiation regulation 73. gene therapy with lentiviral vector for X-linked adrenoleukodystrophy 219. MiR-33 and cholesterol homeostasis regulation 235 ABCD1. 76 cognitive effects in prepubertal boys 95. Prader-Willi syndrome levels and growth hormone therapy effects 199 ADCY5. 145 BAT. 129 HMGB1 role in early loss of transplanted islets in mice 136. 113 Alpha cell. pituitary secretory granules and peptide hormone storage 21.Subject Index A ABCA1. enalapril and losartan effects on kidney and retina 136. 106 telomerase variants in Ashkenazi centenarians 228 Aire. see Brown adipose tissue Beta cell alpha cell conversion after extreme beta cell loss 208 FXYD2 a as biomarker 128. see Adrenocorticotropic hormone Activating transcription factor 4 (Atf4). see Acylation-stimulating protein Atf4. American-Indian youths 159 ALD. see X-linked adrenoleukodystrophy Aldo-keto reductase 1B7 (AKR1B7). see Androgen receptor Arcuate nucleus discovery of neurokinin B neurons 5 kisspeptin neurons in pulsatile gonadotropinreleasing hormone secretion 6 Ardipithecus ramidus. see Cyclic AMP-generating adenylate cyclase Adipocyte. see Aldo-keto reductase 1B7 Albuminuria. 112 Aldosterone metabolic syndrome and resistant hypertension 115. see Rickets B Bariatric surgery laparoscopic gastric banding in severely obese adolescents 150. 120 Autism. 31 work overcommitment studies 116. 151 maternal intergenerational transmission of obesity 144. hominid paleobiology 228. beta cell conversion after extreme beta cell loss 208 Altitude. see Activating transcription factor 4 ATP-sensitive potassium channel energy expenditure control and body weight determination 146. 116 TASK1 role in production 112. perinatal window for control of autoimmunity 223. 3 inhibitors bone effects 75. 147 glucagon response role during glucose deprivation 119. see Bone morphogenetic proteins Body mass index (BMI) mate selection in Hadza foragers 209 puberty timing in boys 194 .

109 Copy number variation (CNV). 226 CLOCK/BMAL glucocorticoid receptor regulation 99 hypothalamic-pituitaryadrenal axis interactions 100. 42 Breast development. see Cyclins C/EBP. 73 Chromatin. distortions and unfounded authority 225. 101 CNV. see Comparative genomic hybridization Charcot-Marie-Tooth disease. germ cell specification signaling 88 Bone remodeling. heritable signatures 178 Citations. angiogenesis stimulation 211.. see also specific cancers erythropoiesis-stimulating agents and mortality 227. 47 Calorie restriction. CCNL1 variant effects on fetal growth and birth weight 177. 68 BPA. 110 replacement strategies 110 serum steroid profiling with liquid chromatographymass spectrometry 108. osteogenesis imperfecta human deficiency studies 67 knockout mice 66 CypB. see Copy number variation Colesevelam hydrochloride. 75 thyroid hormone effects in growth plate 72. see Bisphenol-A Brachydactyly. transforming growth factorrole 67. 117 Curcumin. receptor subtype-3 agonists for obesity management 142 Bone morphogenetic proteins (BMPs). glucagon-like peptide-1 receptor agonist activation of thyroid C-cells 46. pathway inhibition in oocyte chemotherapy protection 217 CAH. 187 growth hormone deficiency induction by radiation in cancer survivors 202.Bombesin receptor. 178 Cyclophilin B (CypB). 149 C c-Abl. 227 Comparative genomic hybridization (CGH). 203 insulin-like growth factor-1 receptor immunoliposomes for treatment 61. 149 CGH. 212 Child abuse. ghrelin O-acyltransferase in growth hormone mediation of calorie-restricted mouse survival 27 Cancer. NKX2-1 mutations 41. familial hypercholesterolemia management 168. 31 desmopressin test for differential diagnosis from pseudo-Cushing state 19 quality of life one year after cure 106 Cyclic AMP-generating adenylate cyclase (ADCY5). origins and functional impact 220 Cortisol fetal corticosteroid metabolite concentrations and maternal effects 211 work overcommitment studies 116. Cushing’s disease management rationale 30.activation and neutrophil superoxide generation 107 254 Subject Index . stress and aging induction 105. see Cyclophilin B Cytochrome b5. alternative summary statistics for communicating risk reduction with statins 226. protein kinase C. see Congenital adrenal hyperplasia Calcitonin. findings in congenital hypothyroidism and thyroid dysgenesis 42. 160 CCNL1. see Desmopressin test Dehydroepiandrosterone sulfate (DHEAS). 197 fertility in women with 21-hydroxylase deficiency 117 hydrocortisone therapy pharmacology study 109. 62 metformin and mortality reduction 159. 228 FGFR3 and HRAS activating mutations in congenital disorders and testicular tumors 222 genomics 186. parathyroid hormone-related protein gene mutations in brachydactyly type E 71 Brain-lung-thyroid syndrome. 106 Chondrocyte Atf4 regulation of proliferation and differentiation 73.20-lyase deficiency 114 D DDAV test. 31 Cushing’s disease curcumin management rationale 30. 43 Congenital adrenal hyperplasia (CAH) differential diagnosis of late-onset congenital adrenal hyperplasia from premature adrenarche 196. variant effects on fetal growth and birth weight 177. 169 Communications. 178 Cyclins. transcriptional regulation of myoblast to brown fat switch 148. 74 NKCC1 mediation of volume increase in growth plate 74. age decline 193 Brown adipose tissue (BAT) FGF21 in thermogenic activation 212 Gs deficiency effects 148 transcriptional regulation of myoblast to brown fat switch 148. whole-genome sequencing 171. 172 Chemerin. mutation in 17.

5-Diiodothyropropionic acid DMPA. serum lipid response 166 Desmopressin (DDAV) test. 176 glucagon-like peptide-1 receptor alleles 156 low birth weight as risk factor 155. 132 continuous subcutaneous insulin infusion versus multiple injections 191. 137 autoantibodies and human leukocyte antigenconferred disease susceptibility 123. 161 3. 192 etiology 218 FXYD2 a as beta cell biomarker 128. 136 proliferative retinopathy risks 134. 3 estradiol-kisspeptin positive feedback mechanism in puberty onset 4. 121 rituximab and preservation of beta cell function 132. DUOX2 mutation in transient congenital hypothyroidism 42 DUOX. therapy and cancer mortality 227. 123 mitochondria dysfunction 137 pramlintide and glucose excursion lowering 133. 221 Endothelial cell. human genome 220. see Depot medroxyprogesterone acetate DNA methylation insulin gene methylation 127. 126 height growth velocity and risks 121. 135 angiotensin-converting enzyme inhibitor effects on kidney and retina 136. 5 gas chromatography-mass spectrometry 91. 122 hippocampal volume 126. 129 genome-wide association studies glycemic control locus 124. 127 HMGB1 role in early loss of transplanted islets in mice 136. see Mitogen-activated protein kinase Erythropoietin. 128 patterns for in vitro fertilization 221 DNA microarray. 124 closed-loop insulin delivery system 131. 156 metformin and cancer mortality reduction 159. see Embryonic stem cell Estrogen aromatization and male sexual behavior 2. see Endogenous Borna-like N elements Ectonucleotide pyrophosphate/phosphodiesterase (ENPP1). 214 Dual oxidase (DUOX). 128 intensive therapy and retinopathy outcomes 122. tanycyte plasticity role in median eminence with estrogen 4 ENPP1.5-Diiodothyropropionic acid (DITPA). 125 in silico replication 125. 137 imprinted DLK-MEG3 gene region and susceptibility 180 insulin gene methylation 127. generalized arterial calcification of infancy and rickets mutations 77 Embryonic stem (ES) cell. 92 tanycyte plasticity role in median eminence 4 Turner syndrome replacement therapy 190. 50 DITPA. 134 progression mechanisms and mode of onset 120. Cushing's disease differential diagnosis from pseudoCushing state 19 DHEAS. see Dehydroepiandrosterone sulfate Diabetes type 1 age of onset parent age of onset and offspring risk 135. Mct8 transport studies 49. see 3. 160 parental origin of sequence variants 181 screening in obesity 160. see Ectonucleotide pyrophosphate/phosphodiesterase ERK. 177 atherosclerotic vascular changes in adolescents and young adults 158 genetic loci in fasting glucose homeostasis 175. adrenocortical tumor analysis 108 Dopamine D2 receptor role in addiction and compulsive eating in obese rats 141. see Angiotensinconverting enzyme inhibitors Endogenous Borna-like N (EBLN) elements. germ cell derivation 89 Enalapril. 133 self peptide presentation 129. 130 Diabetes type 2 albuminuria in AmericanIndian youths 159 alleles near insulin receptor substrate-1 gene 176. 228 ES cell. 191 Subject Index 255 . 9 neurokinin B and dynorphin A in arcuate nucleus kisspeptin neurons regulation of gonadotropin-releasing hormone pulsatile secretion 6 E E2F1.Depot medroxyprogesterone acetate (DMPA). 142 oxytocin interactions in maternal behavior 20 thyrotropin-releasing hormone and tuberoinfundibular dopamine neuron effects 213. see Dual oxidase Dynorphin A leptin regulation of neuron function 8. pituitary tumor transforming gene induction in pituitary tumors 26 EBLN elements.

stomach ghrelinsecreting cells 216 Foot strike patterns. 199 diagnosis glucagon test 195 insulin tolerance test 195. 197 estrogen replacement in Turner syndrome 190. see Growth hormonereleasing hormone Giucagon ATP-sensitive potassium channel role in response during glucose deprivation 119. 173 family-based sequencing 173 Germ cell derivation from embryonic stem cells 89 signaling in specification 88 GH. 191 growth hormone deficiency cardiac function 198. see Fibroblast growth factor Fibroblast growth factor (FGF) FGF21 in thermogenic activation of neonatal brown fat 212 FGFR3 activating mutations in congenital disorders and testicular tumors 222 Food-entrainable oscillator (FEO). and anthropometric variables in euthyroid prepubertal children 197. 120 testing for growth hormone deficiency 195 ventromedial hypothalamus insulin and pancreatic glucagon secretion regulation 10 GLP-1. 198 thyroid hemiagenesis and thyroid pathology risks 192.Evidence-based medicine breast development age decline 193 differential diagnosis of late-onset congenital adrenal hyperplasia from premature adrenarche 196. 92 Gastric inhibitory peptide. bone effects 75. osteoblast effects 69. see Natural selection Exemestane. glucocorticoid receptor repression 111 Gas chromatography-mass spectrometry. 203 Prader-Willi syndrome growth hormone therapy 199. insulin-like growth factor-1. see -Aminobutyric acid GACI. sex steroid level determination 91. beta cell biomarker 128. 196 induction by radiation in cancer survivors 202. 129 Fyn. 76 Exome sequencing. maternal effects on concentration 211 FGF. see Glucagon-like peptide-1 Glucagon-like peptide-1 (GLP-1). stomach ghrelinsecreting cells as food-entrainable circadian clocks 216 GHRH. see Food-entrainable oscillator Fetal corticosteroid metabolites (FCM). 201 thyroid gland volume. barefoot versus shod runners 233.-GABAA receptor in puberty-associated learning deficits 207 GABA. see Growth hormone Ghrelin O-acyltransferase (GOAT). 4. somatic sex reprogramming of ovaries to testes by ablation 90. 70 FTO. see Glucagon-like peptide-1 Generalized arterial calcification of infancy (GACI). meta-analysis 200. advantages in mendelian disorders 172. 157 Glucocorticoid receptor (GR) CLOCK/BMAL regulation 99 256 Subject Index . receptor agonist activation of thyroid C-cells 46. 47 alleles in glucose and insulin response 156. 202 Evolution. locus studies of obesity in African-derived populations 183 FXYD2 a. 148 G -Aminobutyric acid (GABA). 91 FoxO1. 234 Foxa2. 173 F Familial hypercholesterolemia colesevelam hydrochloride therapy 168. 141 Foxl2. growth hormone mediation of calorierestricted mouse survival 27 Ghrelin. see Generalized arterial calcification of infancy Gas5. 172 clinical assessment incorporating personal genome 174 exome sequencing advantages 172. 204 oxandrolone efficacy and safety 201. 169 rosuvastin therapy 168 FCM. 190 Turner syndrome growth hormone therapy metabolic consequences 203. see Fetal corticosteroid metabolites FEO. 193 thyroid hormone regimens for transient hypothyroxinemia in neonates 189. energy expenditure control and body weight determination 147. adaptive behavior regulation during fasting 140. 200 pubertal timing in boys and body mass index 194 school-based interventions in obesity. ectonucleotide pyrophosphate/phosphodiesterase mutations 77 Genome sequencing Charcot-Marie-Tooth disease 171.

122 heritability of childhood weight gain and adult metabolic disease risk 163 prolonged juvenile state relationship to cardiovascular and metabolic risk profile 163. 164 Growth hormone (GH) cell in vivo imaging of pituitary microcirculation and somatotrope function 29. 69 systemic signals in niche regulation 60. see G protein-coupled receptor GPR147. functional rescue by intermolecular cooperation 97 GR. RFRP-1/3 homologs and GPR147 distribution in hypothalamus 214. 220 osteoclast differentiation 68. 71 Hi-C. 203 Growth hormone-releasing hormone (GHRH) growth hormone deficiency and dominant-negative growth hormone isoform induction 25. see Glucocorticoid receptor GRB10. 95 neuron origin studies with mutant mice 28. 202 Growth hormone deficiency cardiac function and growth hormone therapy effects 198. physician. mutation in idiopathic hypogonadotropic hypogonadism 1. 196 radiation induction in cancer survivors 202. distribution in hypothalamus 214. 104 GPCR. reciprocal imprinting 185 Growth first-year rapid growth relationship to cardiovascular and metabolic risk profile in early adulthood 163. 26 receptor hyperactivation and somatotrope hyperplasia suppression 22. 225 GnIH. genetics 186 Subject Index 257 . 104 crosstalk with glucocorticoid receptor 103. see also Growth hormone deficiency mate selection in Hadza foragers 209 specialty drug drivers in short stature 210 Hematopoietic stem cell (HSC) gene therapy with lentiviral vector for X-linked adrenoleukodystrophy 219. pituitary development regulation 17 HESX1. 30 ghrelin O-acyltransferase in growth hormone mediation of calorierestricted mouse survival 27 insulin-like growth factor-1 promoter chromatin organization in hormoneinduced activation 62. 204 oxandrolone efficacy and safety 201. estimation of insulin resistance in obese prepubertal children 165 Glucose-regulated protein 78 (GRP78). 29 receptor adrenal tumor expression 103. 164 height growth velocity and diabetes type 1 risks 121. see Gonadotropinreleasing hormone GOAT. transcription factor interactions in pituitary development 18 Hibernation. 215 G protein-coupled receptor (GPCR). see Gonadotropininhibitory hormone GnRH.Gas5 repression 111 gonadotropin-releasing hormone receptor crosstalk 103. 205 inhaled versus subcutaneous administration 58 patient. 8 neurokinin B and dynorphin A in arcuate nucleus kisspeptin neurons regulation of pulsatile secretion 6 neurokinin B mutation and release 94. 63 therapy. 26 glucagon test 195 growth hormone therapy adult height outcomes after high-dose therapy in prepubertal period 204. 215 Gonadotropin-releasing hormone (GnRH) GnRH1. bone loss prevention in bears 70. see Glucose-regulated protein 78 H Height. murcomycosis pathogenesis role in diabetic mice 224. see also Growth hormone deficiency Prader-Willi syndrome cardiovascular and metabolic risk profile 199 efficacy and safety 40. 61 HES1. 23 GRP78. 2 melanin-concentrating hormone inhibition of neurons and kisspeptin activation 7. 104 ultradian hormone stimulation and gene transcription pulses 102 Glucose breath test. and consumer drivers 210 insulin tolerance test 195. 199 dominant-negative growth hormone isoform induction by growth hormone-releasing hormone 25. genome dynamic mapping 184 High-altitude adaptation. see Ghrelin O-acyltransferase Gonadotropin-inhibitory hormone (GnIH). 41 small for gestational age outcomes 51 Turner syndrome metabolic consequences 203.

see Congenital adrenal hyperplasia Hypercholesterolemia. 37 thyroid hormone regimens for transient hypothyroxinemia in neonates 189. insulin-like growth factor1. see Idiopathic hypogonadotropic hypogonadism I B . 60 stem cell niche regulation 60. 55 growth plate chondrocyte effects 72. 127 HMGB1. see Insulin-like growth factor-binding protein-2 IGFBP-3. aldosterone role in resistant hypertension 115.Hippocampus. activating mutations in congenital disorders and testicular tumors 222 HSC. 192 gene methylation 127. 5