Research into Spinal Deformities 8 [1 ed.] 9781614990673, 9781614990666

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RESEARCH INTO SPINAL DEFORMITIES 8

Research into Spinal Deformities 8, IOS Press, Incorporated, 2012. ProQuest Ebook Central,

Studies in Health Technology and Informatics This book series was started in 1990 to promote research conducted under the auspices of the EC programmes’ Advanced Informatics in Medicine (AIM) and Biomedical and Health Research (BHR) bioengineering branch. A driving aspect of international health informatics is that telecommunication technology, rehabilitative technology, intelligent home technology and many other components are moving together and form one integrated world of information and communication media. The series has been accepted by MEDLINE/PubMed, SciVerse Scopus, EMCare, Book Citation Index – Science and Thomson Reuters’ Conference Proceedings Citation Index. Series Editors: Dr. O. Bodenreider, Dr. J.P. Christensen, Prof. G. de Moor, Prof. A. Famili, Dr. U. Fors, Prof. A. Hasman, Prof. E.J.S. Hovenga, Prof. L. Hunter, Dr. I. Iakovidis, Dr. Z. Kolitsi, Mr. O. Le Dour, Dr. A. Lymberis, Prof. J. Mantas, Prof. M.A. Musen, Prof. P.F. Niederer, Prof. A. Pedotti, Prof. O. Rienhoff, Prof. F.H. Roger France, Dr. N. Rossing, Prof. N. Saranummi, Dr. E.R. Siegel, Prof. T. Solomonides and Dr. P. Wilson

Volume 176

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Recently published in this series Vol. 175. S. Gesing, T. Glatard, J. Krüger, S.D. Olabarriaga, T. Solomonides, J.C. Silverstein, J. Montagnat, A. Gaignard and D. Krefting (Eds.), HealthGrid Applications and Technologies Meet Science Gateways for Life Sciences Vol. 174. B. Blobel, R. Engelbrecht and M.A. Shifrin – Large Scale Projects in eHealth – Partnership in Modernization – Proceedings of the EFMI Special Topic Conference 18–20 April 2012 Moscow, Russia Vol. 173. J.D. Westwood, S.W. Westwood, L. Felländer-Tsai, R.S. Haluck, R.A. Robb, S. Senger and K.G. Vosburgh (Eds.), Medicine Meets Virtual Reality 19 – NextMed Vol. 171. P.B. Cerrito, Data Mining to Determine Risk in Medical Decisions Vol. 170. G.J.E. De Moor (Ed.), Transatlantic Cooperation Surrounding Health Related Information and Communication Technology Vol. 169. A. Moen, S.K. Andersen, J. Aarts and P. Hurlen (Eds.), User Centred Networked Health Care – Proceedings of MIE 2011 Vol. 168. D.P. Hansen, A.J. Maeder and L.K. Schaper (Eds.), Health Informatics: The Transformative Power of Innovation – Selected Papers from the 19th Australian National Health Informatics Conference (HIC 2011) Vol. 167. B.K. Wiederhold, S. Bouchard and G. Riva (Eds.), Annual Review of Cybertherapy and Telemedicine 2011 – Advanced Technologies in Behavioral, Social and Neurosciences

ISSN 0926-9630 (print) ISSN 1879-8365 (online)

Research into Spinal Deformities 8, IOS Press, Incorporated, 2012. ProQuest Ebook Central,

Research into Spinal Deformities 8

Edited by

Tomasz Kotwicki Spine Disorders Unit, Department of Pediatric Orthopedics University of Medical Sciences, Poznan, Poland

and

Theodoros B. Grivas

Copyright © 2012. IOS Press, Incorporated. All rights reserved.

Orthopaedic and Trauma Department “Tzanio” General Hospital of Piraeus, Piraeus, Greece

Amsterdam • Berlin • Tokyo • Washington, DC

Research into Spinal Deformities 8, IOS Press, Incorporated, 2012. ProQuest Ebook Central,

© 2012 The authors and IOS Press. All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without prior written permission from the publisher. ISBN 978-1-61499-066-6 (print) ISBN 978-1-61499-067-3 (online) Library of Congress Control Number: 2012940567 Cover picture: Poznan Old Market Square by Ewa Kotwicka Publisher IOS Press BV Nieuwe Hemweg 6B 1013 BG Amsterdam Netherlands fax: +31 20 687 0019 e-mail: [email protected]

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Distributor in the USA and Canada IOS Press, Inc. 4502 Rachael Manor Drive Fairfax, VA 22032 USA fax: +1 703 323 3668 e-mail: [email protected]

LEGAL NOTICE The publisher is not responsible for the use which might be made of the following information. PRINTED IN THE NETHERLANDS

Research into Spinal Deformities 8, IOS Press, Incorporated, 2012. ProQuest Ebook Central,

Research into Spinal Deformities 8 T. Kotwicki and T.B. Grivas (Eds.) IOS Press, 2012 © 2012 The authors and IOS Press. All rights reserved.

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Preface

In July 2012 the International Research Society of Spinal Deformities (IRSSD) held its ninth biennial meeting in Poznan, Poland. IRSSD was founded in 1994, but its history starts in Vermont, USA, where a group of researchers first met in 1980 to discuss moiré topography techniques for the assessment of trunk deformity in scoliosis. The inaugural workshops were organized by Drs. Morey Moreland, Malcolm Pope and Gordon Armstrong and focused on instrumentation, school screening, quantification & computerization. Multidisciplinary participation from both public and private sector, and participants from Japan, USA, Canada and European countries, contributed to the debates and discussion. Following the success of this meeting, a series of biennial meetings devoted to Surface Topography and Spinal Deformity were organized. After Vermont, chronologically and geographically, the meetings were held: 1982 in Munster, Germany, hosted by Drs. Burkhard Drerup, Wolfgang Frobin & Eberhard Hieholzer; 1984 in Oxford, UK, organized by Allan Turner-Smith & J. Derek Harris; 1986 in Canada organized by Ian Stokes, James R. Pekelsky & Morey Moreland; and 1990 in Lisbon, Portugal hosted by A. Alberti. This latter meeting was the last that focused on surface topography. A meeting that drew together the fields of Spinal Deformity & Surface Topography and 3-D Scoliotic Deformities was then held in 1992, in Montreal, Canada, at which discussions were held to decide whether a new Society embracing both Spinal Deformity & Surface Topography and 3-D Scoliotic Deformities, should be formally established. Two years later in 1994, in Pescara, Italy, further discussions during the meeting on Three-Dimensional Analysis of Spinal Deformities, hosted by Moreno D’Amico, Aricia Merolli and Giorgio C. Santambrogio led to The International Research Society of Spinal Deformities (IRSSD) being officially founded. The creation of the new society reflected a desire to consolidate the momentum of the preceding meetings and also to broaden their scope. Subsequently, the first IRSSD meeting was held in 1996 in Sweden, hosted by John Sevastik, and included aetiology & pathomechanisms of scoliosis as main topics. The second meeting was held in 1998 in Vermont and was hosted by Ian Stokes, who introduced new topics: molecular biology & regulation of spinal growth. In the years since, the society has continued to cover a broad range of issues related to scoliosis. The third meeting was subsequently held in 2000 in Clermont Ferrand, France, hosted by Alain Tanguy and Bernard Peuchot, the fourth in 2002 in Athens, Greece, organized by Dr. Theodoros B. Grivas, the fifth

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meeting in 2004 in Vancouver, Canada, hosted by Bonita J. Sawatzky and S.J. Tredwell, the sixth meeting in 2006 in Ghent, Belgium, organized by Dirk Uyttendaele, the seventh meeting in 2008 in Liverpool, England, organized by Peter H. Dangerfield, the eighth meeting in 2010 in Montréal, Canada, organized by Carl-Eric Aubin, Ian A.F. Stokes, Hubert Labelle, and Alain Moreau and finally the ninth IRSSD meeting in 2012 in Poznan, Poland, organized by Tomasz Kotwicki. The society promotes a multidisciplinary approach to scoliosis and spinal problems, with a strong emphasis on research in the field of etiology as well as the clinical effectiveness of a wide range of interventions. In one form or another, the IRSSD has been active for three decades, during which time it has encouraged open discussion in all areas related to spinal deformities. Contribution, involvement and interaction among people from all over the world has been a highlight of its activities. As Keith Bagnall said “IRSSD has always been a vehicle to carry the initial, small flicker of the flame. In the past, some of these flames have grown to become forest fires while others have simply died for whatever reason”. This book contains the Proceedings of the 9th IRSSD 2012 meeting: peer-reviewed short papers or abstracts summarizing the 129 papers and posters included in the program. It covers all aspects of spinal deformity research, including etiology, genetics, biology, growth, metabolism, biomechanics, imaging technologies, innovations in treatment, and treatment outcomes. These scientific proceedings provide the opportunity for readers to learn more about the latest development in this field that will be presented and discussed during the meeting. We would like to thank all the participants: the authors for sharing their work with us, as well as the members of the scientific committee, chaired by Dr. Theodoros B. Grivas, MD, PhD. The members of the scientific committee, who deserve a particular acknowledgment, divided into groups to review the various topics of the meeting program, namely for Biomechanics, Movement, Posture: Jim Raso, Carl-Éric Aubin, Moreno D’Amico, Yvan Petit, Nachi Chockalingam, Rene M. Castelein, Konstantinos Sultanis, Aleksander Kabsch; for Genetics and Etiology: Alain Moreau, Keith Bagnall, Peter Dangerfield, Nelson Tang; for Growth and Metabolism: Florina Moldovan, Isabelle Villemure, Ian Stokes, Nathalie Alos, Wlodzimierz Samborski; for Imaging and Measurements: Winnie Chu, Tomasz Kotwicki, Delphine Perie, Farida Cheriet; for Treatment: Theodoros B. Grivas, Hans-Rudolf Weiss, Jack Cheng, Hubert Labelle, Jean-Marc Mac-Thiong, Francisco Javier Sanchez Perez-Grueso, Tiziana Greggi, Jacek Durmala, Seung Woo Suh; and finally, for Quality of Life: Lorenzo Aulisa, Jose Maria Climent, Juan Bago, Maciej Glowacki and Nobumasa Suzuki. We do hope that this book, representing the state of the art in scoliosis research in 2012, will stimulate further studies which will lead us closer to an understanding of idiopathic scoliosis, which remains a fascinating and enigmatic disease. We hope that this meeting will be a unique opportunity to meet in Poznan, Poland, in order to discuss the topics related to spinal deformities, and to advance the study and research into spinal deformities for the benefit of patients. Tomasz Kotwicki and Theodoros B. Grivas Poznan, April 30th 2012

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Acknowledgements The honorary patronage of the 9th Biennial IRSSD Meeting was attributed by: President of the City of Poznan President of the University of Medical Sciences of Poznan Polish Society of Spine Surgery Polish Orthopedic and Traumatologic Society Polish Rehabilitation Society Polish Physiotherapy Society The meeting and this publication received valuable support from several companies involved in the management of spinal deformities. This support made it possible to enhance the quality of the meeting with number of activities and programs. Strategic partners: Medtronic Diers Alteris Implants

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Main partners: Stryker Rehasport Exhibitors: Vigo CHM Samodzielny Publiczny Zaklad Zaopatrzenia Ortopedycznego Protoma Media patronage: Ortopedia Polska: www.ortopediapolska.pl Rynek Zdrowia: www.rynekzdrowia.pl Medycyna Praktyczna The Organizing Committee members deserve thanks for their work. Special thanks go to Piotr Janusz, Agnieszka Zygmunt and Michał Karlik. Tomasz Kotwicki Poznan, April 2012

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Presidents of the International Research Society of Spinal Deformities Location

President

1996 1998 2000 2002 2004 2006 2008 2010 2012

Stockholm Burlington Clermont-Ferrand Athens Vancouver Ghent Liverpool Montreal Poznan

Morey Moreland Dirk Uyttendaele Stig Willner (*)/Dirk Uyttendaele Nobumasa Suzuki Hubert Labelle Ian Stokes Keith Bagnall Theo Grivas Carl-Eric Aubin

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Yrs.

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Contents Preface Tomasz Kotwicki and Theodoros B. Grivas Acknowledgements

v vii

Chapter 1. Invited Lectures Whither the Etiopathogenesis (and Scoliogeny) of Adolescent Idiopathic Scoliosis? R. Geoffrey Burwell and Peter H. Dangerfield Pre-Existent Rotation of the Normal Spine at Different Ages and Its Consequences for the Scoliotic Mechanism René M. Castelein

3

20

Chapter 2. Genetics and Aetiology

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Podium Presentations Role of High Central Leptin Activity in a Scoliosis Model Created in Bipedal Amputated Mice Tao Wu, Xu Sun, Zezhang Zhu, Xin Zheng, Bangping Qian, Feng Zhu, Jack C.Y. Cheng and Yong Qiu Maternal Age at Birth: Does It Dictate the Epigenotypic Expression of the Trunkal Asymmetry of a Child? Theodoros B. Grivas, Constantinos Mihas, Christina Mazioti, Nikolaos Zisis, Samantha Sakellaropoulou, Antonios Akriotis and R. Geoffrey Burwell Secondary Scoliosis After Thoracotomy in Patients with Aortic Coarctation and Patent Ductus Arteriosus Marek Roclawski, Rafal Pankowski, Andrzej Smoczynski, Marcin Ceynowa, Wojciech Kloc, Wojciech Wasilewski, Piotr Jende, Wieslaw Liczbik, Piotr Beldzinski, Witold Libionka, Olaf Pierzak, Stanislaw Adamski and Miroslaw Niedbala Association Study of IL-17RC, CHL1, DSCAM and CNTNAP2 Genes Polymorphisms with Adolescent Idiopathic Scoliosis Susceptibility in a Chinese Han Population Song Zhou, Zezhang Zhu, Xusheng Qiu, Weifei Wu, Weijun Wang, Zhen Liu, Feng Lv and Yong Qiu Mutation Analysis of MESP2, HES7 and DUSP6 Gene Exons in Patients with Congenital Scoliosis Xu-Sheng Qiu, Song Zhou, Hua Jiang, Ming-Liang Ji, Qi Ding, Feng Lv, Zhen Liu, Nelson Tang, Jack C.Y. Cheng and Yong Qiu

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Poster Presentations Estrogen Receptor 2 Expression in Back Muscles of Girls with Idiopathic Scoliosis – Relation to Radiological Parameters Błażej Rusin, Tomasz Kotwicki, Aleksandra Głodek, Miroslaw Andrusiewicz, Paulina Urbaniak and Małgorzata Kotwicka Ever-Present Factors in Healthy Children that Can Deform Their Spines. Opposition to Dickson’s Paradigm on Lordosis P.J.M. van Loon A Similar Approach in Bracing of Adolescent Scoliosis and Kyphosis with the Use of Growth Itself in Thoracolumbar Lordotic Intervention (TLI) P.J.M. van Loon, M. Roukens, F.B. Thunnissen and J. Munneke

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Chapter 3. Biomechanics, Movement, Posture

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Podium Presentations The Structure of Postural Disorders and Spinal Deformities in Age and Gender According to Computer Optical Topography 77 V.N. Sarnadskiy Integrated Assessment of Back Muscles Bioelectrical Activity and H-Reflex Research in AIS 83 I. Syngayevskaya, S. Bumakova, D. Pinchuk and M. Dudin Peculiarities of Brain Functioning in Children with Adolescence Idiopathic Scoliosis (AIS) According to EEG Studies 87 D. Pinchuk, M. Dudin, S. Bekshayev and O. Pinchuk Patterns of Weight Bearing Impact Sagittal Spinal Balance 91 Hans-Rudolf Weiss A Multibody-Based Approach to the Computation of Spine Intervertebral Motions in Scoliotic Patients 95 Gabriel Abedrabbo, Paul Fisette, Pierre-Antoine Absil, Philippe Mahaudens, Christine Detrembleur, Maxime Raison, Xavier Banse, Carl-Eric Aubin and Maryline Mousny Finite Element Model of Spinal Hemiepiphysiodesis: Effect of Contact Conditions, Initial Conditions, and Growth 99 B. Kumar, D.I. Bylski-Austrow and Y. Liu The Effect of Leg Length Discrepancy on Pelvis and Spine Kinematics During Gait 104 R. Needham, N. Chockalingam, D. Dunning, A. Healy, E.B. Ahmed and A. Ward LBP and Lower Limb Discrepancy: 3D Evaluation of Postural Rebalancing via Underfoot Wedge Correction 108 Moreno D’Amico, Piero Roncoletta, Francesca Di Felice, Daniele Porto, Rosa Grazia Bellomo and Raoul Saggini

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Lombo-Sacral Joint Efforts During Gait: Comparison Between Healthy and Scoliotic Subjects Maxime Raison, Laurent Ballaz, Christine Detrembleur, Philippe Mahaudens, Julien Lebleu, Paul Fisette and Maryline Mousny The Effect of Frontpacks, Shoulder Bags and Handheld Bags on 3D Back Shape and Posture in Young University Students: An ISIS2 Study J. Bettany-Saltikov and L. Cole

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Poster Presentations Biomechanical Analysis of Spino-Pelvic Parameters in Adolescent Idiopathic Scoliosis After Spinal Instrumentation and Fusion: A Case Study Saba Pasha, Carl-Eric Aubin, Hubert Labelle, Stefan Parent and Jean-Marc Mac-Thiong Variations in Bioelectric Activity During Symmetric Loading and Asymmetric Stretching of Paraspinal Extensors in Young Adult Women with Mild Single Curve Scoliosis Wiesław Chwała, Maciej Płaszewski and Paweł Kowalski Present Day Explanation of the Clinical Signs in the Biomechanical Aetiology of the So-Called Idiopathic Scoliosis (1995–2011). The Relationship Between the “Model of Hips Movement” and the Character of Scoliosis; Three Groups and Four Types. The Causative Role of “Gait” and “Standing ‘at Ease’ on the Right Leg” Tomasz Karski Typical and Atypical AIS. Pathogenesis M. Dudin and D. Pinchuk Leg Length Discrepancy in Scoliotic Patients Moreno D’Amico, Piero Roncoletta, Francesca Di Felice, Daniele Porto, Rosa Grazia Bellomo and Raoul Saggini Validation of a Multi-Segment Spinal Model for Kinematic Analysis and a Comparison of Different Data Processing Techniques R. Needham, N. Chockalingam, R. Naemi, T. Shannon and A. Healy Inter-Examiner, Intra-Session and Inter-Session Reliability of Gait Measurement Justyna Leszczewska, Dariusz Czaprowski, Paulina Pawłowska, Karolina Białobrzewska, Anna Gębicka and Tomasz Kotwicki Classification of Postural Disorders and Spinal Deformities in the Three Dimensions According to Computer Optical Topography V.N. Sarnadskiy The Evolution of State of Vertebral Column in Three Planes Victor Pecherskiy, Ludmila Lihacheva, Aleksei Chicherin, Michail Dudin and Dmitrii Pinchuk Neurohumoral Regulation in Children with Idiopathic Scoliosis T. Khaymina, T. Avaliani, M. Dudin and D. Pinchuk Photodynamic Impact on the Epiphyseal Plates S. Kurchenko, A. Shashko, M. Dudin, V. Mikhailov, G. Netylko and V. Ashmarov

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Chapter 4. Growth and Metabolism Podium Presentations The Value of Different Risser Grading Systems in Determining Growth Maturity of Girls with Adolescent Idiopathic Scoliosis Weijun Wang, Xin Zhen, Xu Sun, Zezhang Zhu, Feng Zhu, T.P. Lam, Jack C.Y. Cheng and Yong Qiu Upper Arm Length Model Suggests Transient Bilateral Asymmetry Is Associated with Right Thoracic Adolescent Idiopathic Scoliosis (RT-AIS) with Implications for Pathogenesis and Estimation of Linear Skeletal Overgrowth R. Geoffrey Burwell, Ranjit K. Aujla, Michael P. Grevitt, Tabitha L. Randell, Peter H. Dangerfield, Ashley A. Cole, Alanah S. Kirby, Frances J. Polak, Roland K. Pratt, John K. Webb and Alan Moulton Analysis of Body Growth Parameters in Girls with Adolescent Idiopathic Scoliosis: Single Thoracic Idiopathic Scoliosis Versus Single Lumbar Idiopathic Scoliosis Zhen Liu, Zezhang Zhu, Jing Guo, Saihu Mao, Weijun Wang, Bangping Qian, Feng Zhu, Winnie Chu, Jack C.Y. Cheng and Yong Qiu Height Velocity Curves in Female Patients with Idiopathic Scoliosis Masaaki Chazono, Sigeru Soshi, Yoshikuni Kida, Kurando Hashimoto, Takeshi Inoue, Yousuke Nakamura, Akira Shinohara, Keishi Marumo, Katsuki Kono and Nobumasa Suzuki

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Poster Presentations The In-Vivo Effect of Torque on Growth in Caudal Vertebrae Robert Rizza, XueCheng Liu and John Thometz Early Development of the Costovertebral Joints Po-Jung Chen and Witold Wozniak Severe Spinal Deformity and Multiple Vertebral Collapses in Juvenile Cushing Syndrome: A Case Report Enrico Pola, Barbara Rossi, Marilda Mormando, Luigi Aurelio Nasto, Debora Colangelo, Silvia Della Casa, Laura De Marinis and Lorenzo Aulisa

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Chapter 5. Imaging and Measurement Podium Presentations An Improved Kinematic Model of the Spine for Three-Dimensional Motion Analysis in the Vicon System Mirosława M. Długosz, Daria Panek, Paweł Maciejasz, Wiesław Chwała and Witold Alda Discordance in Spinal and Thoracic Correction Using Powerful Full Screw Constructs in Idiopathic Scoliotic Konstantinos Soultanis, Theodoros B. Grivas, Konstantinos A. Starantzis, Nikolaos A. Stavropoulos, Christos Markopoulos and Panayotis Papagelopoulos

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The Rib Vertebra Angle Difference and Its Measurement in 3D for the Evaluation of Early Onset Scoliosis G. Foley, C.E. Aubin, H. Labelle, J. Sanders, J. d’Astous, C. Johnston and S. Parent Analysis of the Anterior Trunk Symmetry Index (ATSI). Preliminary Report Lukasz Stolinski, Tomasz Kotwicki, Dariusz Czaprowski, Joanna Chowanska and Nobumasa Suzuki Goniometer Evaluation of Thoracic Kyphosis and Lumbar Lordosis in Subjects During Growth Age: A Validity Study Aristide R. Gravina, Claudio Ferraro, Antonio Frizziero, Marco Ferraro and Stefano Masiero

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Poster Presentations Correlation of Idiopathic Scoliosis Assessments Between Newly Developed Milwaukee Topographic Scanner and Quantec C.H. Lim, C. Tassone, X.C. Liu, J.G. Thometz and R. Lyon Trunk Asymmetry in one Thousand School Children Aged 7–10 Years Lukasz Stolinski and Tomasz Kotwicki How to Measure Kyphosis in Everyday Clinical Practice: A Reliability Study on Different Methods Fabio Zaina, Sabrina Donzelli, Monia Lusini and Stefano Negrini Why X-Rays Are Not Reliable to Assess Sagittal Profile: A Cross Sectional Study Fabio Zaina, Paolo Pizzetti, Sabrina Donzelli, Francesco Negrini and Stefano Negrini The Method of Geometrical Comparison of 3-Dimensional Objects Created from DICOM Images Dominik Gaweł, Kamil Danielewicz and Michał Nowak Assessment of Trunk Asymmetry in Transversal Plane by Geometric Outline of Trunk Deformation (GOTD) I.M. Kowalski, T. Giżewski, K. Zaborowska-Sapeta, H. Protasiewicz-Fałdowska and P. Siwik Investigation of a Low Cost Method to Quantify Cosmetic Defect Thomas Shannon and Nachiappan Chockalingam Is Curve Direction Correlated with the Side of Dominant Displacement of Cerebellar Tonsil and Syrinx Deviation in Thoracic Scoliosis Secondary to Chiari Malformation Type I and Syringomyelia? Tao Wu, Zezhang Zhu, Xu Sun, Huang Yan, Xin Zheng, Bangping Qian, Feng Zhu, Winnie Chu, Jack C.Y. Cheng and Yong Qiu Telediagnostic 3D School Screening of Back Curvatures and Posture Using Structured Light Method – Pilot Study Wojciech Glinkowski, Jakub Michoński, Bożena Glinkowska, Agnieszka Żukowska, Robert Sitnik and Andrzej Górecki

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Chapter 6. Treatment

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Podium Presentations Biomechanical Analysis of Proximal Junctional Kyphosis: Preliminary Results M. Cammarata, X. Wang, J.-M. Mac-Thiong and C.E. Aubin Biomechanical Analysis of Pedicle Screw Density in Spinal Instrumentation for Scoliosis Treatment: First Results Xiaoyu Wang, Carl-Eric Aubin, A. Noelle Larson, Hubert Labelle and Stefan Parent Biomechanical Analysis of Forces Sustained by Iliac Screws in Spinal Instrumentation for Deformity Treatment: Preliminary Results Frederique D. Perrault, Carl-Eric Aubin, Xiaoyu Wang and Richard M. Schwend Operative Treatment of Isthmic Spondylolisthesis with Posterior Stabilization and ALIF. Cages Versus Autogenous Bone Grafts Rafal Pankowski, Andrzej Smoczynski, Marek Roclawski, Marcin Ceynowa, Wojciech Kloc, Wojciech Wasilewski, Piotr Jende, Wieslaw Liczbik, Piotr Beldzinski, Witold Libionka, Olaf Pierzak, Stanislaw Adamski and Miroslaw Niedbala Surgical Treatment of Neuromuscular Scoliosis: Current Techniques T. Greggi, F. Lolli, M. Di Silvestre, K. Martikos, F. Vommaro, E. Maredi, S. Giacomini, A. Baioni and A. Cioni Intraoperative Neurophysiologic Monitoring (INM) in Scoliosis Surgery Rafal Pankowski, Krzysztof Dziegiel, Marek Roclawski, Andrzej Smoczynski, Marcin Ceynowa, Wojciech Kloc, Wojciech Wasilewski, Piotr Jende, Wieslaw Liczbik, Piotr Beldzinski, Witold Libionka, Olaf Pierzak, Stanislaw Adamski and Miroslaw Niedbala Toward the Next Generation of Simulator for Intraoperative Navigation of Scoliotic Spine Surgeries Olivier Cartiaux, Carl-Éric Aubin, Hubert Labelle and Farida Cheriet Surgical Treatment for Scoliosis Associated with Rare Disease T. Greggi, F. Lolli, E. Maredi, M. Di Silvestre, K. Martikos, F. Vommaro, S. Giacomini, A. Baioni and A. Cioni Surgical Treatment of Early Onset Scoliosis in Neurofibromatosis Tiziana Greggi and Konstantinos Martikos Complications Incidence in the Treatment of Early Onset Scoliosis with Growing Spinal Implants T. Greggi, F. Lolli, M. Di Silvestre, K. Martikos, F. Vommaro, E. Maredi, S. Giacomini, A. Baioni and A. Cioni Smart Brace Versus Standard Rigid Brace for the Treatment of Scoliosis: A Pilot Study Edmond Lou, Douglas Hill, Jim Raso, Andreas Donauer, Marc Moreau, James Mahood and Douglas Hedden Correlation Between in-Brace Radiographic Correction and Short Time Brace Results Fabio Zaina, Sabrina Donzelli, Monia Lusini and Stefano Negrini

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Brace Wear Characteristics During the First 6 Months for the Treatment of Scoliosis Edmond Lou, Douglas Hill, Jim Raso, Andreas Donauer, Marc Moreau, James Mahood and Douglas Hedden Inclusion Criteria for Physical Therapy Intervention Studies on Scoliosis – A Review of the Literature H.R. Weiss Characteristics of Patients with More than 20° of Improvement or Worsening During Conservative Treatment of Adolescent Idiopathic Scoliosis Stefano Negrini, Sabrina Donzelli, Monia Lusini and Fabio Zaina

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Poster Presentations SpineCor, Exercise and SPoRT Rigid Brace: What Is the Best for Adolescent Idiopathic Scoliosis? Short Term Results from 2 Retrospective Studies Fabio Zaina, Sabrina Donzelli, Alessandra Negrini, Michele Romano and Stefano Negrini Corrective Exercises in Multimodality Therapy of Idiopathic Scoliosis in Children – Analysis of Six Weeks Efficiency – Pilot Study N. Pugacheva The Effectiveness of Percutaneous Vertebroplasty in the Treatment of Different Aetiology Vertebral Body Fractures Wojciech Kloc, Witold Libionka, Olaf Pierzak, Wieslaw Liczbik, Piotr Beldzinski, Beata Szopa, Marek Roclawski, Rafal Pankowski, Andrzej Smoczynski and Marcin Ceynowa The Effect of Pressure Pad Location of Spinal Orthosis on the Treatment of Adolescent Idiopathic Scoliosis (AIS) M.S. Wong, M. Li, B. Ng, T.P. Lam, M. Ying, A. Wong and J. Cheng Results of SpineCor Dynamic Bracing for Idiopathic Scoliosis Aleksand Szwed and Maciej Kołban Brace Treatment in Infantile/Juvenile Patients with Progressive Scoliosis Is Worthwhile Hans-Rudolf Weiss Short-Term Effect (ATR, Kasperczyk’s Scale, Chest’s Mobility) of Using of Physiotherapy Method in the Treatment of AIS – Pilot Study I. Blicharska, A. Brzek and J. Durmala Bracing Can Reduce High Degree Curves and Improve Aesthetics Immediately After the End of Growth. Final Results of a Retrospective Case Series Stefano Negrini, Sabrina Donzelli, Monia Lusini and Fabio Zaina Idiopathic Scoliosis, Growth Zones, Magnetic Therapy A. Arsenev, M. Dudin, V. Lednev, N. Belova, V. Mikhailov and G. Sokolov Short-Term Effects of Combination of Several Physiotherapy Methods on the Respiratory Function – A Case Report of Adolescent Idiopathic Scoliosis Bartosz Wnuk, Joanna Frackiewicz, Jacek Durmala, Krzysztof Czernicki and Karol Wadolowski Rate of Surgey in a Sample of Patients Fulfilling the SRS Inclusion Criteria Treated with a Chêneau Brace of Actual Standard Hans-Rudolf Weiss and Mario Werkmann

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A Comparison of the Effects of Deep Tissue Massage and Therapeutic Massage on Chronic Low Back Pain Mateusz Romanowski, Joanna Romanowska and Marcin Grześkowiak

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Chapter 7. Quality of Life Podium Presentations Quality of Life and Stress Level in Adolescents with Idiopathic Scoliosis Subjected to Conservative Treatment Edyta Kinel, Tomasz Kotwicki, Anna Podolska, Marianna Białek and Wanda Stryła The Influence of the Degree of Spine Curvature on the Quality of Life Assessment Among Patients Treated Surgically with the Cotrel-Dubousset Method Bożena Gorzkowicz and Maciej Kołban Psychological Aspects of Scoliosis Surgery in Children Ryszard Tomaszewski and Magdalena Janowska Is the SRS-22 Able to Detect Quality of Life (QoL) Changes During Conservative Treatments? Stefano Negrini, Sabrina Donzelli, Monica Dulio and Fabio Zaina Bracing Does Not Change the Sport Habits of Patients Stefano Negrini, Sabrina Donzelli, Francesco Negrini, Michele Romano and Fabio Zaina

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Chapter 8. Abstracts

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Genetics and Aetiology Scoliosis in the 22q11 Deletion Syndrome D. Colo, C. van Weelden, M. Kruyt and R. Castelein Ethiopathogenesis of the Adolescent Idiopathic Scoliosis Basing on Neuroimaging and Neurophysiological Examinations with the Special Emphasizing of Motor Evoked Potentials (MEP) J. Huber and P. Rogala Abnormally Lower Expression of Melatonin Receptor in Osteoblasts of Adolescent Idiopathic Scoliosis Girls A.P.Y. Yim, G.Q. Sun, H.Y. Yeung, K.M. Lee, K.W. Ng, T.P. Lam, Y. Qiu and J.C.Y. Cheng Association of CHD7 Polymorphism with Susceptibility to and Severity of Idiopathic Scoliosis in Central European Population: Preliminary Study P. Janusz, T. Kotwicki, M. Kotwicka and M. Andrusiewicz Identification of Key Disease-Modifying Factors in Adolescent Idiopathic Scoliosis M. Elbakry, M. Taheri, S. Bouhanik, M. Akoume and A. Moreau The Identification of Unique Gene Expression Profiles Associated with Cellular and Biochemical Endophenotypes of Idiopathic Scoliosis K.F. Gorman, C. Julien, Q. Yuan, A. Franco, D.S. Wang, S. Bouhanik, G. Larouche, G. Lacroix and A. Moreau

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Genetic Association Studies in Idiopathic Scoliosis – Who Was Really Tested? P. Harasymczuk, P. Janusz and T. Kotwicki Adolescent Idiopathic Scoliosis (AIS): Metabolic Factors, Biomechanical Stress and Estrogen Impact F. Moldovan, I. Villemure, K. Fendri, G. Grimard, C. Zaouter, S. Parent, A. Moreau, H. Labelle and S.A. Patten Exome Sequencing Identifies Novel Candidate Mutations in Idiopathic F. Moldovan, S.A. Patten, K. Fendri, S. Girard, C. Zaouter and P. Edery A Line of Zebrafish with Increased Incidence of Spinal Deformities H.G. Tomasiewicz, X.C. Liu, C. Tassone, P. North and J. Thometz

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Biomechanics, Movement, Posture High Osteopontin Plasma Level Associated with Abnormal Cortical Bone Mineral Density in Girls with Adolescent Idiopathic Scoliosis G.Q. Sun, T.P. Lam, N.G. Bobby, P.Y. Yim, K.M. Lee, A. Moreau, Y. Qiu and J.C.Y. Cheng Abnormal Bone Matrix Mineralization in Patients with Adolescent Idiopathic Scoliosis G.Q. Sun, T.P. Lam, N.G. Bobby, P.Y. Yim, K.M. Lee, Y. Qiu and J.C.Y. Cheng Porcine Spine Finite Element Model as an Alternative Tool for the Validation of a Novel Fusionless Device B. Hachem, C.E. Aubin, M. Driscoll and S. Parent Static and Dynamic Postural Control in Girls with Idiopathic Scoliosis Marzena Wiernicka, Dawid Łochyński, Tomasz Kotwicki, Łukasz Michałowski, Ewa Kamińska, Jacek Lewandowski and Elżbieta Hurnik Vertebral Long Fusion is a Tubular Bone. A 3-D Analysis of Bone Fusion Remodelling in Scoliosis Surgery Without, with and After Removal the Instrumentation A. Valassina, A.G. Aulisa and L. Aulisa The Pelvic Lordosis: An Essential Adaptation in Human Evolution, and a Determinant of Spinopelvic Alignment M.M.A. Janssen, T. Vrtovec, F. Pernuš, F.C. Öner, E.E. Vereecke, A.J. Channon, M.A. Viergever, K.L. Vincken and R.M. Castelein Sagittal Spinal Profile and Spinopelvic Balance in Parents of Scoliotic Children, as Compared to Normal Controls M.M.A. Janssen, K.L. Vincken, S.M. van Raak, T. Vrtovec, B. Kemp, M.A. Viergever, L.W. Bartels and R.M. Castelein Influence on Mastication of Adolescent Idiopatic Scoliosis: Prevalence of Reverse Chewing Cycles with and Without Brace M.G. Piancino, T. Vallelonga, G. Frongia, M. Brayda, D. Braddebin, C. Debernardi and P. Bracco Analysis of Changes in Selected Body Characteristics in Many Years of Observation of Children and Adolescents with Faulty Body Posture M. Kluszczynski and J. Czernicki

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Growth and Metabolism Influence of Dynamic Loading Parameters on Bone Growth Modulation A.-L. Menard, B. Valteau, I. Londono, F. Moldovan, G. Grimard and I. Villemure Association of Volumetric Bone Mineral Density with Leptin and Soluble Leptin Receptor in Girls with Adolescent Idiopathic Scoliosis E.M.S. Tam, F.W.P. Yu, Z. Liu, T.P. Lam, B.K.W. Ng, K.M. Lee, Q. Yong and J.C.Y. Cheng Bone Quality in Adolescent Idiopathic Scoliosis Girls – A Case-Control Study W.S. Yu, K.Y. Chan, F.W.P. Yu, H.Y. Yeung, K.M. Lee, K.W. Ng, Y. Qiu, T.P. Lam and J.C.Y. Cheng Elevated Soluble Leptin Receptor Level and Association with Body Composition in Girls with Adolescent Idiopathic Scoliosis E.M.S. Tam, H.Y. Yeung, Z. Liu, T.P. Lam, T. Ting, J.Y.F. Lok, B.K.W. Ng, K.M. Lee, Q. Yong and J.C.Y. Cheng Is AIS Under 20–30° a Chaotic Dynamical System? J.C. de Mauroy and J.M. Ginoux Abnormal Skeletal Growth Patterns in Adolescent Idiopathic Scoliosis – A Longitudinal Study Till Skeletal Maturity A.P.Y. Yim, H.Y. Yeung, W.J. Wang, V.W.Y. Hung, L. Qin, K.M. Lee, T.P. Lam, Y. Qiu and J.C.Y. Cheng Lower Handgrip Strength in Girls with Adolescent Idiopathic Scoliosis (AIS) – A Case-Control Study W.S. Yu, K.Y. Chan, F.W.P. Yu, H.Y. Yeung, K.M. Lee, K.W. Ng, Y. Qiu, T.P. Lam and J.C.Y. Cheng Nutritional Status of Children and Adolescents with Idiopathic Scoliosis – Preliminary Results E. Matusik, J. Durmala, P. Matusik and E. Malecka-Tendera

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Imaging and Measurement Neuronavigation-Guided Spine Surgery P. Bełdziński, W. Kloc, O. Pierzak, W. Libionka, W. Liczbik and B. Szopa Computational Morphometry of Semicircular Canals in Adolescent Idiopathic Scoliosis (AIS) Based on High-Resolution MR Images W.C.W. Chu, L. Shi, D. Wang and J.C.Y. Cheng Statistical Difference in Cerebral Cortical Thickness in Patients with Adolescent Idiopathic Scoliosis and Normal Controls Using Computational Techniques – The Updated Data W.C.W. Chu, L. Shi, D. Wang and J.C.Y. Cheng Systematic Analysis of the Neurocentral Junction (NCJ) in the Normal Infantile, Juvenile and Adolescent Spine T. Schlösser, M. Janssen, H. Attrach, M. Viergever, K. Vincken and R. Castelein Are Bending Films Useful for Lenke Classification of Idiopathic Scoliosis? M. Tyrakowski, T. Kotwicki, A. Koch, M. Drwięga, K. Lisiecka, D. Ławniczak, S. Pietrzak and J. Czubak

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Sensitivity-to-Change of Full Torso Surface Topography Measurements in Adolescents with Idiopathic Scoliosis and a Main Thoracic Curve E.C. Parent, P.Q. Zhang, D. Hill, M. Moreau, D. Hedden and E. Lou A New 3D Topographic Device for Monitoring Scoliosis Progression in Children X.C. Liu, J.C. Tassone, J.G. Thometz, R.M. Lyon, S. Tarima, C.H. Lim and L.C. Paulsen

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Treatment Late Results of Surgical Treated Scoliosis with the Use of Selective and Extend Instrumentation S. Snela, G. Sokół and P. Jasiński Radiological Correction of Severe Thoracic Idiopathic Scoliosis: Comparison of Three Surgical Approaches Applied to Similar Curves A. Koch, P. Janusz, P. Harasymczuk, D. Ławniczak and T. Kotwicki A Survey Data Base Use by SRS Members V.J. Raso, J. Sanders, D. Kumar, R. Knight, D. Burton, R. Bowen and K. Spratt The Influence of the Development of Scoliosis Posterior Surgery on 3-Planar Deformity Correction R. Pankowski, M. Rocławski, A. Smoczyński, M. Ceynowa, W. Kloc, W. Wasilewski, P. Jende, W. Liczbik, P. Bełdziński, W. Libionka, O. Pierzak, S. Adamski and M. Niedbała An Alternative to a Randomized Control Design for Assessing the Efficacy and Effectiveness of Bracing in AIS D. Fong, K. Cheung, Y. Wong, W. Cheung, I. Fu, E. Kuong, K. Mak, M. To and K. Luk Standard Technique vs. CAD/CAM and Biomechanical Simulations for the Design of Braces in Adolescent Idiopathic Scoliosis: First Results F. Desbiens-Blais, J. Clin, S. Parent, H. Labelle and C.E. Aubin Congenital Scoliosis, Riyadh Experience M. Alfawareh, W. Attia, K. Almusrea and M. Halwani Osteopathic Method for Treatment of Discal Hernias Olga Kalinovskaya Treatment’s Results of the Idiopathic Scoliosis, Depending on the Used Instrumentation S. Snela, P. Jasiński and G. Sokół Osteoid Osteoma of the Lumbar Spine: Resection Without Fusion. Case Report of Two Children A. Koch, T. Kotwicki and A. Szulc Comparison of Influence of Three Physiotherapeutic Techniques: Postisometric Relaxation, Kinetic Control and Stabilization Exercises on the Flexibility of Pelvic Girdle Muscles: Prospective, Randomized, Single Blinded Study D. Czaprowski, J. Leszczewska, A. Kolwicz, P. Pawłowska, A. Afeltowicz-Mich, D. Sitarski, A. Gębicka and T. Kotwicki

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Validation of the Transpedicular Screws Implantation in Patients with Idiopathic Scoliosis Using Computed Tomography S. Kasongo, W. Jurasz and Ł. Bartochowski The Effectiveness of Surgical Treatment of Spondylolisthesis with Transpedicular Instrumentation Ł. Bartochowski, W. Jurasz and A. Nowakowski

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Quality of Life 505

Subject Index Author Index

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Polish Validation of Brace Questionnaire (BrQ) E. Kinel, T. Kotwicki, A. Podolska, M. Białek and W. Stryła

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Morey Sargent Moreland, M.D. 1939–2011 Morey Moreland was born in March 1939 and died on the 2nd October 2011 in Pittsburgh. Without him, there would probably be no IRSSD. In 1980, he hosted the first International Symposium on Surface Topography and Spinal Deformity. While the focus of this meeting was narrow, he nurtured a steady evolution of further biennial meetings – to include surface topography, and then to incorporate all three dimensional aspects of spinal and trunk deformity. Then the need to take the broadest possible view of the causes and treatment of spinal deformity became evident. The 3D meetings in 1992 in Montreal and 1994 in Pescara led to the formation of the International Research Society of Spinal Deformity, and Morey served as our President at the first meeting in 1996 in Stockholm. He purchased a gavel for future Presidents to use at our meetings. Morey never limited the scope of his work and his enthusiasm. As a paediatric orthopaedic surgeon he concentrated his clinical and surgical expertise on spinal deformity and hip dysplasia. After completing his Surgical Residency at the University of Vermont, he researched mechanically modulated growth at the Nuffield Orthopaedic Centre in Oxford, focusing on the effects of torsion on the growth plate, and the implications for development and treatment of these deformities. However, his work was primarily about the people – the children and their parents, the researchers in the lab, and his colleagues in the clinic and the operating room. His special gift and contribution was to bring people together to collaborate effectively, and to develop the careers of young researchers and surgical residents. He did this selflessly. Morey and his wife Marilyn have travelled several times to San Pedro Sula, Honduras to provide pediatric orthopedic care and to help train local physicians as part of the medical mission by CURE International (Honduras).

Morey and Marilyn sailing their boat on Lake Champlain, 1979. Research into Spinal Deformities 8, IOS Press, Incorporated, 2012. ProQuest Ebook Central,

Personally, I knew Morey as a colleague, friend and mentor. We worked together from 1980 to 1989, and he and Marilyn would invite me to their house, and to share their passion for skiing at Mad River Glen, and sailing their boat on Lake Champlain. We always made a point to spend time together at IRSSD meetings. Morey’s legacy lives on, but we shall miss him.

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Ian Stokes

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Chapter 1

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Invited Lectures

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Research into Spinal Deformities 8 T. Kotwicki and T.B. Grivas (Eds.) IOS Press, 2012 © 2012 The authors and IOS Press. All rights reserved. doi:10.3233/978-1-61499-067-3-3

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Whither the etiopathogenesis (and scoliogeny) of adolescent idiopathic scoliosis? R Geoffrey BURWELL,a* and Peter H DANGERFIELD,b,c,d Centre for Spinal Studies and Surgery, Nottingham University Hospitals Trust, Queen’s Medical Centre Campus, Derby Road, Nottingham, NG7 2UH, UK. b University of Liverpool, Ashton Street, L69 3GE, UK, cStaffordshire University, Leek Road, Stoke-on-Trent, ST4 2DF. UK, dRoyal Liverpool Children’s Hospital, Eaton Road, Liverpool, L12 2AP, UK. a

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Abstract Although considerable progress had been made in the past two decades in understanding the etiopathogenesis of adolescent idiopathic scoliosis (AIS), it still lacks an agreed theory of etiopathogenesis. One problem may be that AIS results not from one cause, but several that interact with various genetic predisposing factors. There is a view there are two other pathogenic processes for idiopathic scoliosis namely, initiating (or inducing), and those that cause curve progression. Twin studies and observations of family aggregation have revealed significant genetic contributions to idiopathic scoliosis, that place AIS among other common disease or complex traits with a high heritability interpreted by the genetic variant hypothesis of disease. We summarize etiopathogenetic knowledge of AIS as theories of pathogenesis including recent multiple concepts, and blood tests for AIS based on predictive biomarkers and genetic variants that signify disease risk. There is increasing evidence for the possibility of an underlying neurological disorder for AIS, research which holds promise. Like brain research, most AIS workers focus on their own corner and there is a need for greater integration of research effort. Epigenetics, a relatively recent field, evaluates factors concerned with gene expression in relation to environment, disease, normal development and aging, with a complex regulation across the genome during the first decade of life. Research on the role of environmental factors, epigenetics and chronic noncommunicable diseases (NCDs) including adiposity, after a slow start, has exploded in the last decade. Not so for AIS research and the environment where, except for monozygotic twin studies, there are only sporadic reports to suggest that environmental factors are at work in etiology. Here, we examine epigenetic concepts as they may relate to human development, normal life history phases and AIS pathogenesis. Although AIS is not regarded as an NCD, like them, it is associated with whole organism metabolic phenomena, including lower body mass index, lower circulating leptin levels and other systemic disorders. Some epigenetic research applied to Silver-Russell syndrome and adiposity is examined, from which suggestions are made for consideration of AIS epigenetic research, cross-sectional and longitudinal. The word scoliogeny is suggested to include etiology, pathogenesis and pathomechanism. Keywords: Scoliosis, etiology, pathogenesis, scoliogeny, epigenetics 1

Corresponding Author: [email protected]

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1.

R.G. Burwell and P.H. Dangerfield / Whither the Etiopathogenesis (and Scoliogeny) of AIS?

Terminology

The word etiology strictly means the factor(s) causing the AIS, pathogenesis mode of origin of the morbid process, and pathomechanism sequence of events in the evolution of its structural and functional changes that result from the pathological process [1]. The word etiopathogenesis is used to embrace etiology and pathogenesis. We suggest the word scoliogeny as the collective noun to include etiology, pathogenesis and pathomechanism.

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2.

Introduction

Research into the causation of adolescent idiopathic scoliosis (AIS) draws heavily from mechanical and biological disciples, but still lacks an agreed theory of etiopathogenesis [2-7]. Genetic factors are believed to play an important role in the etiology of AIS with considerable heterogeneity [4,5]. The research problem is complicated by the suspicion that AIS may result not from one cause, but several that interact [2,8]. Genetic, and now genomic, research on AIS have not yet provided the therapeutically-required etiologic understanding. In other diseases and particularly diseases of developmental origin [9] and late-onset chronic non-communicable diseases (NCDs) [10], research on the role of environmental factors and epigenetics after a slow start has exploded in the last decade [10-15]. Not so for AIS research and the environment where, except for monozygotic twin studies, there are only sporadic reports suggesting that environmental factors are at work in etiology [16]. Epigenetics, a relatively recent field evaluates factors concerned with gene expression in relation to environment, disease, normal development and aging, with a complex regulation across the genome during the first decade of life. Elsewhere we commented on etiopathogenetic concepts as they may relate to normal spine development and AIS pathogenesis [16]. Here we consider: (1) some theories of pathogenesis including recent multiple concepts; (2) blood tests for AIS based on predictive biomarkers and genetic variants that signify disease risk; (3) epigenetic concepts as they may relate to human development and life history phases; (4) AIS linked to the aging process as a non-communicable disease (NCD); (5) findings from epigenetic methods applied to the Silver-Russell syndrome and adiposity; and (6) suggestions for applying epigenetic methods to AIS etiopathogenesis in crosssectional and longitudinal studies.

3.

Etiopathogenesis 2011

In a review of Top Theories of AIS Wang et al [4] concluded: • considerable progress had been made in the past two decades in understanding the etiopathogenesis of AIS; • current knowledge is still fragmented; • we are still far from understanding fully the different etiopathogenetic pathways and mechanisms for example –

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• • • •

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4.

5

the general skeletal and relative anterior spinal overgrowth (RASO) of AIS girls have not been related securely to endocrinology, and the abnormal extra spinal skeletal length asymmetries of AIS girls are of unknown pathogenetic significance; current treatment at best is treating the morphologic and functional sequelae of AIS and not the cause of the disease; whatever hypothesis or theory, several fundamental questions and facts of AIS need to be properly addressed and explained with 11 items listed.

Pathogenesis – theories, hypotheses and concepts 2012

Several theories, hypotheses and concepts for AIS pathogenesis more recently implicating AIS as a systemic and/or multifactorial disorder, are providing hypotheses to test. [2-4, 6]. These include: • Relative anterior spinal overgrowth (RASO) [17]. • Asynchronous spinal neuro-osseous growth [18, 19]. • Thoracospinal concept [20]. • Dorsal shear forces and axial rotation instability [21]. • Flexural-torsional buckling from flexibility anisotropy [22]. • Biomechanical spinal growth modulation [23]. • Biomechanical theory [24]. • Intervertebral disc disorder [25-31]. • Deforming three joint complex hypothesis [32]. • Motor control disorder [33-35]. • Sensorimotor integration disorder & dystonia [35,36]. • Sensory integration disorder [37]. • Vestibular disorder [38]. • Body spatial orientation disorder [39]. • Neurodevelopmental disorder [40]. • Systemic and metabolic disorders involving – o Platelet calmodulin [41,42]. o Melatonin [43-46]. o Melatonin-signalling defect (MSD) [47,48]. o Osteopontin (OPN) and soluble CD44 (sCD44). Azeddine et al [49] reported mean plasma OPN levels to be increased in: • patients with idiopathic scoliosis, correlating significantly with curve severity, and • “an asymptomatic at-risk group” (offspring born from at least one scoliotic parent); this finding, if confirmed, suggests predictive biomarkers and possibly a prodromal stage with the prospect of intervention early in deformity evolution. In contrast, mean plasma levels of sCD44 were significantly lower in patients with Cobb angles of 45 degrees or more. Drawing on evidence from mouse models, it was concluded that OPN is essential to induce scoliosis formation and curve progression through interactions with CD44 receptors, “thus offering a first molecular concept to explain the pathomechanism leading to the asymmetrical growth of the spine in idiopathic scoliosis.” [49].

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• • •

5.

Moreau and colleagues report that blood tests could be useful markers for the diagnosis of idiopathic scoliosis and the prognosis of curve progression: a functional scoliosis test [47-50], further refined recently using a more accurate technology called cellular dielectric spectroscopy [51]; and a biochemical scoliosis test using raised plasma OPN and lower sCD44 values. Moreau [52] states that OPN and sCD44 are not diseasespecific but when observations of both are combined they become highly specific for idiopathic scoliosis. By binding free OPN, sCD44 can prevent OPN from triggering scoliosis or curve progression. Moreau considers that environmental factors could potentially affect the circulating levels of OPN in humans. With colleagues he is conducting tests to identify potentially useful therapeutic agents [52]. o Estrogens [53,54]. o Leptin [6,54-56] (see 9.1.3) o Osteopenia [57-59]. Developmental instability & symmetry control dysfunction [60,61]. Intrinsic growth plate asymmetry hypothesis [62,63]. Multiple pathogenetic processes. o Double neuro-osseous theory [6,64]. o Three metabolic processes [65]. o Four pathomechanisms [66].

Some comments on theories, hypotheses and concepts 2012

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5.1. Attempts at integration of theories None of the above theories entirely explain the pathogenesis of AIS [2-4,66]. In recent surveys of these theories for AIS [2-4,6,65,66] integration is attempted involving interacting pathomechanisms. In addition to predisposing factors [2,5], there is a view that there are two other pathogenic processes for idiopathic scoliosis namely, initiating (or inducing), and those that cause curve progression [2,67]. There is evidence that curve progression, which increases during the curve acceleration phase [68], increases through disc wedging during the rapid growth spurt with progressive vertebral wedging occurring later [29,30]; and that in scoliosis the simultaneous occurrence of vertebral displacement in 3-D, rather than a specific single disturbance of any one of the three planes, triggers development of the deformity [69]. 5.2. RASO phenomenon and asynchronous spinal neuro-osseous growth concept Relative anterior spinal overgrowth (RASO) is established as a sagittal plane phenomenon associated with scoliosis. Its etiologic mechanisms are unknown but curve progression is thought to involve the Hueter-Volkmann effect [23]. Some workers adduce evidence that RASO results from a spinal neuro-osseous growth disorder – variously termed vertebra-neural (Roth, van Loon), uncoupled (Porter), and asynchronous [18] – of unknown etiology. Without riders these sagittal plane theories, like other biomechanical theories, do not accommodate – • normal trunk bilateral asymmetry [64,70,71], • normal thoracic spinal axial vertebral rotation [72],

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7

• bilateral skeletal asymmetries of AIS [6,73], • some bilateral neural [34,35] and vestibular [38] asymmetries, and • the systemic and metabolic disorders associated with AIS. The riders are secondary effects (epiphenomena) [2] and/or multiple factors possibly of different weight in individuals with similar deformities. 5.3. Sensory and sensorimotor integration disorder and dystonia There is increasing evidence for the possibility of an underlying neurological disorder for AIS; this research needs to ne extended. The findings relate to sensory integration [37], sensorimotor integration and dystonia [34-36], spinal cord [18,19], brain stem [8], motor control [33], motor cortex [34], supplementary motor area [35], brain white matter [74] as part of the Human Connectome [75], cerebral cortex as a whole [76] and vestibular system [38]. The two papers by Domenech et al focus attention on bilateral asymmetric activity respectively of motor cortex [34] and supplementary motor area [SMA, 35] as pathomechanisms for idiopathic scoliosis (IS). Reviewing the SMA paper [35] Benoist [77] writes: “These findings support the hypothesis that a sensorimotor integration underlies the pathogenesis of IS. In addition, as suggested by the authors, these abnormal MRI findings may represent a biomarker of IS disease and open the way to novel therapeutic targets. This paper, winner of the EuroSpine Full Paper Award for 2010, has limitations, which have been summarized in a Reviewer’s Comment by Freeman [78].”

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5.4. Lessons from brain research – brain in a box The wide gap between the above theories reveals current ignorance about the causation of AIS indicating more integrated knowledge is needed. Like brain research [79,80], most AIS workers are focused on their own corner. In brain research, which generates about 60,000 papers per year, one team in Europe is planning to integrate these discoveries and achieve a comprehensive understanding of the brain; this would be done by building unifying computer models (‘brain in a box’) for which one billion euros is being sought in 2012 from the European Union’s new decade-long Flagship initiatives [79]. 5.5. Grand unifying theory for AIS scoliogeny – brain and scoliosis in a box? In AIS, the possible creation of a network approach to the pathogenesis by constructing AIS diseasomes [81] was suggested [16]. The attainment of a grand unifying theory for adolescent idiopathic scoliogeny seems unlikely at present. Finite element analysis of spinal models of AIS pathogenesis (‘scoliosis in a box’) has provided for the testing of specific questions, recently in connection with how accelerated growth profiles may increase scoliosis progression and pose a progressive risk factor [82]. Building a unifying computer model for AIS pathogenesis might be considered using supercomputers with ever increasing memory. (‘brain and scoliosis in a box’)

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5.6. The biological Higgs – aging, AIS and scoliogeny Biologists have recently pondered what fundamental discoveries might match the excitement of the Higgs boson, the so-called ‘God Particle’ [83]. Some scientists consider that the ability to slow aging would address Higgs-like fundamental questions about human life. AIS, we suggest, may be viewed as a disorder of aging processes during development. So questions about what pathways control aging – highly unlikely to result from a unitary cause [83,84] – and some age-related diseases, may be relevant to the scoliogeny of AIS (see 9.1.1). 5.7. Genetics, epigenetics and AIS scoliogeny After mentioning genetics we focus on epigenetics and how it might relate to AIS scoliogeny.

6. Genetics and the genetic variant hypothesis for complex disease 2012 6.1. Etiology of AIS is poorly understood Twin studies and observations of family aggregation have revealed significant genetic contributions to idiopathic scoliosis that position AIS among other common disease or complex traits with high heritability [85]. However, despite many investigations, the underlying etiology of idiopathic scoliosis is poorly understood [5,86].

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6.2. Position for AIS Based on gene-linkage studies, candidate gene approach and genome-wide association studies, Wang et al [4] summarized the then position as follows: “Recent evidence not only suggests that genetic factors play an important role in the etiology of AIS but also revealed the considerable heterogeneity. Although the continuation of the search for the exact genetic factors is inevitable, it is also very important to look at the functional and biological aspects to allow better understanding of the etiopathogenesis if AIS.” 6.3. AIS Prognostic Test (Scoliscore) Genetic profiling using 53 single nucleotide polymorphisms (SNPs), gene-to-gene interactions, and the patient’s initial Cobb angle measurement, produced a score ranging from 1-200 predicting scoliosis curve progression [87-90] and provided a scientific basis for the AIS Prognostic Test (Scoliscore, Axial Biotech, Inc.). 6.4. Genetic variant hypothesis and non-genetic factors for complex disease Butcher and Beck [91] write: “A spate of high-powered genome-wide association studies (GWAS) have recently identified numerous single-nucleotide polymorphisms (SNPs) robustly linked with complex disease. Despite interrogating the majority of common human variation, these

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SNPs only account for a small proportion of the phenotypic variance, which suggests genetic factors are acting in concert with non-genetic factors. Although environmental measures are logical covariants for genotype-phenotype investigations, another nongenetic intermediary exists, epigenetics.”

7. Epigenetics – perspective for AIS 7.1. Definition and epigenetic modifications Epigenetics is generally defined as information heritable during cell division but not contained within the DNA sequence itself, termed epigenetic modifications [16,92,93]. There are the three major ways organisms alter their DNAs inherited messages [93,94]: • enzymes methylate DNA to modulate transcription; • histone modifications and nucleosome positioning to induce or repress target sequences; and • non-coding small RNAs (including microRNAs and short interfering RNAs) which attach themselves to messenger RNA to modify the expression of specific genes. 7.2. DNA methylation According to Talens et al [95]: “DNA methylation may be the most suitable epigenetic mark for large-scale epidemiological studies, since methyl groups are covalently bound to CpG dinucleotides and are not lost during routine DNA extraction, unlike histone modifications. This opens the possibility of exploiting existing DNA biobanks for research purposes, to discover epigenetic risk factors for complex disease.”

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7.3. Epigenetics at the epicentre of modern medicine Epigenetics evaluates factors concerned with gene expression in relation to environment, disease, normal development and aging, with a complex regulation across the genome during the first decade of life [14-16]. Feinberg [11] writes: “Epigenetics, the study of non-DNA sequence-related heredity, is at the epicenter of modern medicine because it can help to explain the relationship between an individual's genetic background, the environment, aging, and disease…” 7.4. Environmental factors and AIS In the last 20 years, sporadic reports have suggested environmental factors are involved in the etiopathogenesis and phenotypic expression in some subjects with AIS. We review the evidence elsewhere [16]. 7.5. Hypothesis of developmental instability for scoliosis Speculation that genetic and environmental factors are involved the etiopathogenesis of idiopathic scoliosis [96,97] was further developed by Goldberg and colleagues [60,61]

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who suggested that scoliosis is caused by environmental stress causing developmental instability: 7.6. Heated indoor swimming pools, infants and AIS as a delayed epigenetic effect McMaster et al [98,99] reported a statistically significant correlation between the introduction of infants to heated indoor swimming pools and the development of AIS. A neurogenic hypothesis was formulated to explain how neurotoxins produced by chlorine may act on the infant’s immature central nervous system with an implication of the brain's barrier and cerebral spinal fluid being involved. The delayed epigenetic effects with the bony trunk deformity of AIS do not become evident until adolescence [100]. There may be many such environmental factors acting in the first year of life to initiate AIS and differing around the world (see Figure 1). Whatever the effects the neurotoxic products may have on the immature brain, the process of puberty with its increased growth velocity is suggested to play a role in the delayed phenotypic expression of AIS [68,101]. Elsewhere we outlined and commented on etiopathogenetic concepts as they may relate to normal spine development and AIS pathogenesis [16].

8. Human development – normal life history phases and epigenetics 8.1. Developmental plasticity and epigenetic programming

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Reviewing child health, developmental plasticity and epigenetic programming, Hochberg et al [9] describe how transition between life-history phases defines pre-adult phases of predictive adaptive responses (plasticity) (Figure 1). • Infancy-to-childhood (I/C) transition is associated with GH-IGFI axis activation that affects adult height; • Childhood-to-juvenility (C/J) transition affects body composition, adiposity rebound and circulating leptin levels. 8.2. Life history phases, epigenetics and AIS We applied this concept speculatively to AIS pathogenesis in susceptible girls [102].

9.

Environment, non-communicable diseases

9.1. Idiopathic chronic non-communicable diseases (NCDs) 9.1.1. Types of NCDs, risk factors and prevention Common chronic NCDs include obesity, diabetes, cardiovascular disease, respiratory disease, cancer and schizophrenia attributed to genetic and environmental factors [10] with a pathogenetic link being defined between obesity and cancer [103]. Risk factors for NCDs include age, unhealthy diet, smoking, alcohol abuse, chemicals, and lack of physical activity [83,100,104,105], the last possibly by impairing each of autophagy,

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Figure 1. Pre-adult periods of adaptive plasticity in the transition between life history phases (from Burwell et al [102] after modification from Hochberg et al [9].

mitochondrial upgrade and energy production [106]. In studying the prevention of NCDs, there is a move away from adults to mother, father, pregnancy and child [107], with recent research revealing a link between gene promoter methylation in umbilical cord tissue and later adiposity (Figure 2) [108].

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9.1.2. AIS as an NCD? Although AIS is not regarded as an NCD, like them and particularly like obesity, it is often associated with whole organism but opposite metabolic phenomena, namely lower body mass index (BMI) [109,110], lower circulating leptin levels [54-56], and other systemic disorders [41-52]. 9.1.3. AIS, obesity, hypothalamic sensitivity and resistance to leptin In the leptin-hypothalamic-sympathetic nervous system (LHS) concept for AIS pathogenesis of girls, scoliosis initiation is attributed to increased hypothalamic sensitivity to leptin [for central leptin activity see 111-113] with sympathoactivation becoming asymmetric as an adverse hormetic effect [6,114,115]; this places AIS with lower BMI at the opposite end of the spectrum from the central leptin resistance concept for obesity [6]. The putative asymmetric sympathoactivation is viewed as initiating the costo-vertebral asymmetry of right thoracic AIS in girls [6,20] that produces the major phenotypic abnormality namely the scoliosis of a whole organism (systemic) disorder.

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Figure 2. Diagram summarizing the study of Godfrey KM et al [108] who state that genome-wide association studies showed fixed genetic variation makes little contribution to the risk of obesity, heart disease, or diabetes. Godfrey et al conclude that their findings “…raise the possibility that the developmental environment component may be equally or more important. We suggest that after consideration of the selection of appropriate candidate genes, umbilical cords may be stored and the children later evaluated for trunk deformity of both AIS and normal trunk asymmetry [64, 70, 71]

10. Methodological application of epigenetics to epidemiological studies

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Some methods in DNA methylation profiling are reported by Zuo et al [116]. The application of epigenetic methods to epidemiological studies is discussed here in relation to some other diseases, and then how these methods might be applied to AIS.

11. Applying epigenetic methods to some other diseases Mazzio and Solkiman [15] write: “One of the greatest challenges in the study of epigenetics as it relates to disease is the enormous diversity of proteins, histone modifications and DNA methylation patterns associated with each unique maladaptive phenotype. This is further complicated by a limitless combination of environmental cues that could alter the epigenome of specific cell types, tissues, organs and systems.” We examine here what has been found epigenetically for • Silver-Russell syndrome, • Idiopathic chronic non-communicable diseases (NCDs) some of which afflict children, 11.1. Silver-Russell syndrome (SRS) Silver-Russell syndrome is a clinically and genetically heterogeneous congenital disorder characterized by severe growth retardation [117] with bilateral skeletal

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asymmetry and genital anomalies. Bruce et al [118] found a dose-response relationship between the degree of H19 hypomethylation and phenotype severity in SRS. The association between severe H19 hypomethylation and specific anomalies of the spine, elbows, hands and feet, and genital defects, was shown for the first time. 11.2. Idiopathic non-communicable diseases (NCDs) 11.2.1. Fixed genomic variation According to Godfrey et al [108]: “Fixed genomic variation explains only a small proportion of the risk of adiposity in animal models; maternal diet alters offspring body composition, accompanied by epigenetic changes in metabolic control genes. Little was known about whether such processes operate in humans.” 11.2.2. Gene promoter methylation in umbilical cord tissue at birth and later adiposity (Figure 2). Using Sequenom MassARRAY, Godfrey et al [108] measured the methylation status of 68 CpGs 5’ from five candidate genes in umbilical cord tissue DNA of healthy neonates. Methylation varied greatly at particular CpGs. They related methylation status to maternal pregnancy diet and to child’s adiposity at age 9 years (by dual energy X-ray absorptiometry) with replication established in a second independent cohort. They concluded that: (1) a substantial component of metabolic disease risk has a prenatal developmental basis, and (2) perinatal epigenetic analysis may have utility in identifying individual vulnerability to later obesity and metabolic disease.

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12. Suggestions for applying epigenetic methods to AIS etiopathogenesis 12.1. Methylation of candidate genes – cross-sectional study As for Silver-Russell syndrome [117,118], we suggest that the possible selection of appropriate candidate genes and evaluating their methylation status in relation to physical and other characteristics of AIS subjects be considered. Familial and sporadic AIS might be evaluated. 12.2. Methylation of DNA in umbilical cord tissue at birth and later AIS – longitudinal study As for adiposity (Figure 2) [108], the stored umbilical cords of children who later show trunk distortion [64,70,71] and AIS deformity may be evaluated for their DNA methylation status, similar to 11.2.2, and with familial and sporadic AIS again evaluated.

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12.3. Methylation in buccal smear DNA and later AIS – longitudinal study An evaluation similar to 12.2 might be considered using buccal smear DNA starting, say at 5 years, with familial and sporadic AIS being evaluated. 13. The future – memorandum of understanding for AIS scoliogenic research? We suggest consideration be given to forming a group to work out details of a possible international collaborative effort for epigenetic scoliogenic research on AIS, perhaps initially preparing a Memorandum of Understanding. Acknowledgements The research in Nottingham quoted in this paper has been undertaken in collaboration with: Susan I Anderson, School of Graduate Entry Medicine and Health, University of Nottingham Medical School, Derby, UK. Ranjit K Aujlaa,Ashley A Colea , Michael P Grevitta. Theodoros B Grivas, Department of Trauma and Orthopedics, "Tzanio" General Hospital, Tzani and Afendouli 1 st, Piraeus 18536, Greece. Alanah S Kirbya. Alan Moulton, Department of Orthopaedic Surgery, King’s Mill Hospital, Sutton Road, Mansfield NG17 4JL, UK. Frances J Polaka   

 Tabitha L Randell, Department of Child Health, Nottingham University Hospitals Trust, Queen’s Medical Centre Campus, Nottingham,UK. John K Webba. We thank Mr Lyndon Cochrane for the art work.

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[53] Leboeuf D, Letellier K, Alos N, Edery P, Moldovan F: Do estrogens impact adolescent idiopathic scoliosis? Trends Endocrinol Metab 2009 20(4):147-52. [54] Lombardi G, Akoume MY, Colombini A, Moreau A, Banfi G: Biochemistry of adolescent idiopathic scoliosis. Adv Clin Chem 2011 54:165-82. [55] Qiu Y, Sun X, Qiu X, Li W, Zhu Z, Zhu F, Wang B, Yu Y, Qian B: Decreased circulating leptin level and its association with body and bone mass in girls with adolescent idiopathic scoliosis. Spine 2007 32(24):2703-2710. [56] Liu Z, Tam EM, Sun GQ, Lam TP, Zhu ZZ, Sun X, Lee KM, Ng TB, Qiu Y, Cheng JC, Yeu ng HY: Abnormal Leptin Bioavailability in Adolescent Idiopathic Scoliosis - an Important New Finding. Spine (Phila Pa 1976). 2012 37(7):599-604. [57] Hung VWY, Qin L, Cheung CSK, Lam TP, Ng BKW, Tse YK, Go X, Lee KM, Cheng JCY: Osteopenia: a new prognostic factor of curve progression in adolescent idiopathic scoliosis. J Bone Joint Surg Am 2005 87-A: 2709-16. [58] Szalay EA, Bosch P, Schwend RM, Buggie B, Tandberg D, Sherman F.: Adolescents with idiopathic scoliosis are not osteoporotic. Spine 2008 33(7):802-6. [59] Park WW, Suh KT, Kim JI, Kim SJ, Lee JS: Decreased osteogenic differentiation of mesenchymal stem cells and reduced bone mineral density in patients with adolescent idiopathic scoliosis. Eur Spine J 2009 18(12):1920-6. [60] Goldberg CJ, Dowling FE, Fogarty EE, Moore DP: Adolescent idiopathic scoliosis as developmental instability. Genetica 1995 96(3):247-55. [61] Goldberg CJ, Fogarty EE, Moore DP, Dowling FE: Scoliosis and developmental theory: adolescent idiopathic scoliosis. Spine 1997 22(19):2228-37. [62] Burwell RG, Grevitt MP, Randell TL, Dangerfield PH, Ranjit RK, Cole AA, Pratt RK, Webb JK, Moulton A, Anderson SI: Abnormal bilateral skeletal asymmetries and their putative genetic and epigenetic origins in enantiomorphic growth plates of girls with adolescent idiopathic scoliosis (AIS)(abstract). Clin Anat 2012 25(2); 267. [63] Burwell RG, Aujla RK, Randell TL, Dangerfield PH, Moulton A, Anderson SI: Regional skeletal sizes of healthy girls relative to size attained at 10 years as the comparator: percentage size trajectories reveal effects of differential growth consistent with intrinsic growth-plate programs involving time-tally patterning, genetically- and epigenetically-determined (abstract). Clin Anat 2012 25(2); 268. [64] Grivas TB, Burwell RG, Mihas C, Vasiliadis ES, Triandaffylopoulos G, Kaspiris A: Relatively lower body mass index is associated with an excess of severe truncal asymmetry in healthy adolescents. Do body fat, leptin, hypothalamus and sympathetic nervous system influence truncal growth asymmetry? Scoliosis 2009 4(1):13.doi:10, 1186/1748-7161-4-13. [65] Acaroglu E, Bobe R, Enouf J, Marcucio R, Moldovan F, Moreau A: The metabolic basis of adolescent idiopathic scoliosis: 2011 report of the "metabolic" workgroup of the Fondation Yves Cotrel. Eur Spine J 2012 Mar 9. [Epub ahead of print] [66] de Sèze M, Cugy E: Pathogenesis of idiopathic scoliosis: A review. Ann Phys Rehabil Med 2012 Jan 27. [Epub ahead of print] (French). [67] Burwell RG: Aetiology of idiopathic scoliosis: current concepts. Pediatr Rehabil 2003 6(3-4):137-70. [68] Sanders JO, Browne RH, McConnell SJ, Margraf SA, Cooney TE, Finegold DN: Maturity assessment and curve progression in girls with idiopathic scoliosis. J Bone Joint Surg Am 2007 89(1):64-73. [69] Xiong B, Sevastik B, Sevastik J, Hedlund R: Early three dimensional radiographic changes in scoliosis. Edited by Dansereau J, International Symposium on 3-D Scoliotic Deformities joined with the VIIth International Symposium on Spinal Deformity and Surface Topography. dition de l’cole Polytechnique de Montral:Gustav Fischer Verlag, 1992 498-504. [70] Burwell RG, James NJ, Johnson F, Webb JK, Wilson YG: Standardised trunk asymmetry scores; a study of back contour in healthy school children. J Bone Joint Surg Br 1983 65(4):452-63. [71] Nissinen M, Heliövaara M, Seitsamo J, Poussa M: Trunk asymmetry, posture, growth, and risk of scoliosis. A three-year follow-up of Finnish prepubertal school children. Spine 1993, 18(1):8-13. [72] Janssen MM, Kouwenhoven JW, Schlösser TP, Viergever MA, Bartels LW, Castelein RM, Vincken KL: Analysis of preexistent vertebral rotation in the normal infantile, juvenile, and adolescent spine. Spine (Phila Pa 1976). 2011 Apr 1 36(7):E486-91. [73] Burwell RG, Aujla RK, Grevitt MP, Randell TL, Dangerfield PH, Cole AA, Kirby AS, Polak FJ, Pratt RK, Webb JK, Moulton A: Upper arm length model suggest transient bilateral asymmetry is associated with right thoracic adolescent idiopathic scoliosis (RT-AIS) with implications for pathogenesis and estimation of linear growth. 2012 This Meeting. 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[76] Wang D, Shi L, Chu WC, Burwell RG, Cheng JC, Ahuja AT: Abnormal cerebral cortical thinning pattern in adolescent girls with idiopathic scoliosis. Neuroimage 2012 16;59(2):935-42. [77] Benoist M: The Michel Benoist and Robert Mulholland yearly European Spine Journal review: a survey of the "medical" articles in the European Spine Journal, 2011. Eur Spine J 2012 21(2):185-94. [78] Freeman BJ: Reviewer's comment concerning ''Abnormal activation of the motor cortical network in idiopathic scoliosis demonstrated by functional MRI'' (doi:10.1007/s00586-011-1776-8) by J. Domenech et al. Eur Spine J 2011 20(7):1079-80. [79] Waldrop MM: Computer modelling: Brain in a box. Nature 2012 482(7386):456-8. doi: 10.1038/482456a. [80] Koch C, Reid RC: Neuroscience: Observatories of the mind. Nature 2012 483(7390):397-8. doi: 10.1038/483397a. [81] Barabasi AL, Gulbahce N, Loscalzo J: Network medicine: a network-based approach to human disease.Nat Rev Genet. 2011 12(1):56-68. [82] Shi L, Wang D, Driscoll M, Villemure I, Chu WC, Cheng JC, Aubin CE: Biomechanical analysis and modeling of different vertebral growth patterns in adolescent idiopathic scoliosis and healthy subjects. Scoliosis 2011 6:11. [83] Ledford H: Life-changing experiments: The biological Higgs. Nature 2012 483(7391):528-30. doi: 10.1038/483528a. [84] Kirkwood TB, Melov S: On the programmed/non-programmed nature of ageing within the life history. Curr Biol. 2011 Sep 27;21(18):R701-7 [85] Tang NL, Yeung HY, Hung VW, Liao CD, Lam TP, Yeung HM, Lee KM, Ng BK, Cheng JC: Genetic epidemiology and heritability of AIS: A study of 415 Chinese female patients. J Orthop Res 2012 Feb 23. doi: 10.1002/jor.22090. [86] Sharma S, Gao X, Londono D, Devroy SE, Mauldin KN, Frankel JT, Brandon JM, Zhang D, Li QZ, Dobbs MB, Gurnett CA, Grant SF, Hakonarson H, Dormans JP, Herring JA, Gordon D, Wise CA: Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes. Hum Mol Genet. 2011 20(7):1456-62. [87] Ward K, Ogilvie JW, Singleton MV, Chettier R, Engler G, Nelson LM:. Validation of DNA-based prognostic testing to predict spinal curve progression in adolescent idiopathic scoliosis. Spine (Phila Pa 1976). 2010, 35(25):E1455-64. [88] Ogilvie JW: Update on prognostic genetic testing in adolescent idiopathic scoliosis (AIS). J Pediatr Orthop 2011 31(1 Suppl):S46-8. [89] Cahill KS, Wang MY: DNA-based prediction of scoliosis curve progression. World Neurosurg 2011,76(5):371. [90] Carlson B: Scoliscore AIS prognostic test personalizes treatment for children with spinal curve. Biotechnol Healthc 2011 8(2):30-31. [91] Butcher LM, Beck S: Future impact of integrated high-throughput methylome analyses on human health and disease. J Genet Genomics 2008 35(7):391-401. [92] Bjornsson HT, Fallin MD, Feinberg AP: An integrated epigenetic and genetic approach to common human disease. Trends Genet. 2004 Aug;20(8):350-8. [93] Nelissen EC, van Montfoort AP, Dumoulin JC Evers JL Epigenetics and the placenta. Hum Reprod Update 2011 17(3):397-417. [94] Silahtaroglu A Stenvang J: MicroRNAs, epigenetics and disease. Essays Biochem. 2010 20;48(1):165-85 [95] Talens RP, Boomsma DI, Tobi EW, Kremer D, Jukema JW, Willemsen G, Putter H, Slagboom PE, Heijmans BT: Variation, patterns, and temporal stability of DNA methylation: considerations for epigenetic epidemiology. FASEB J. 2010 Sep:24(9):3135-44. [96] Burwell RG, Dangerfield PH, Vernon CL: Anthropometry and scoliosis. In Scoliosis, Proceedings of a Fifth Symposium, Edited by Zorab PA, London: Academic Press, 1977:123-163. [97] Burwell, RG, Dangerfield PH, James NJ, Johnson F, Webb JK, Wilson YG: Anthropometric studies of normal and scoliotic children: axial and appendicular skeletal asymmetry, sexual dimorphisms and age-related changes. In Pathogenesis of idiopathic scoliosis. Proceedings of an international conference. Edited by Jacobs RR, Chicago: Scoliosis Research Society, 1984:27-44. [98] McMaster M, Lee AJ, Burwell RG: Physical activities of patients with adolescent idiopathic scoliosis (AIS) compared with a control group: implications for etiology and possible prevention. International Research Society of Spinal Deformities Symposium, Edited by Bonita J Sawatzky, Vancouver 2004 6871. [99] McMaster M, Lee AJ, Burwell RG: Indoor heated swimming pools: vulnerability of some infants to develop spinal asymmetries years later. Stud Health Technol Inform 2006 123:151-155. [100] McMaster ME: Heated indoor swimming pools, infants, and the pathogenesis of adolescent idiopathic scoliosis: a neurogenic hypothesis. Environ Health 2011 10:86.

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[101] Herring JA: Scoliosis: Chapter 11, In: Tachdjian’s Pediatric Orthopaedics,Volume 1, Philadelphia, Third Edition, WB Saunders 2002 215. [102] Burwell RG, Grevitt MP, Randell TL, Dangerfield PH, Cole AA, Pratt RK, Webb JK, Moulton A, ,Anderson SI: Grivas TB: Several phenotypic features of girls with adolescent idiopathic scoliosis (AIS) are explained by postulating hypothalamic alterations in two successive normal life-history phase transitions (abstract). Clin Anat In Press. [103] Taubes G: Unraveling the obesity-cancer connection, Science. 2012 Jan 6:335(6064):28-32. [104] Reardon S: A world of chronic disease. Science 2011 333(6042):558-9. [105] Reardon S. U.N. Summit on noncommunicable diseases. Meeting brings attention but little action on chronic diseases. Science 2011 333(6049):1561. [106] Garber K: Autophagy. Explaining exercise. Science. 2012 335(6066):281. [107] Gluckman P, Hanson M: Fat fate & disease. Oxford University Press, 2012 pp 288. [108] Godfrey KM, Sheppard A, Gluckman PD, Lillycrop KA, Burdge GC, McLean C, Rodford J, SlaterJefferies JL, Garratt E, Crozier SR, Emerald BS, Gale CR, Inskip HM,Cooper C, Hanson MA: Epigenetic gene promoter methylation at birth is associated with child's later adiposity. Diabetes 2011 60(5):1528-34. [109] Davey RC, Cochrane T, Dangerfield PH, Chockalingam N, Dorgan JC: Anthropometry and body composition in females with adolescent idiopathic scoliosis, International Research Society of Spinal Deformities Symposium, Edited by Bonita J Sawatzky, Vancouver 2004 323-6. [110] Barrios C, Cortés S, Pérez-Encinas C, Escrivá MD, Benet I, Burgos J, Hevia E, Pizá G, Domenech P: Anthropometry and body composition profile of girls with nonsurgically treated adolescent idiopathic scoliosis. Spine (Phila Pa 1976). 2011 36(18):1470-7. [111] Iwaniec UT, Boghossian S, Lapke PD, Turner RT, Kalra SP: Central leptin gene therapy corrects skeletal abnormalities in leptin-deficient ob/ob mice Peptides 2007 28(5):1012-9. [112] Iwaniec UT, Wong CP, Lindenmaier LB, Philbrick KA, Olson DA, Turner RT; Reduced peripheral leptin signaling drastically reduces bone formation. In: Proceedings of ASBMR Annual Meeting, September 16-20, 2011 San Diego, California, USA. [113] Wu T, Sun X, Zhu Z, Zheng X, Qian B Zhu F, Cheng JCY, Qiu Y: Role of high central leptin activity in a scoliosis model created in bipedal amputated mice. 2012 This Meeting. [114] Burwell, RG, Aujla, RK, Grevitt MP, Dangerfield PH, Cole AA, Kirby AS, Polak FJ, Pratt RK, Moulton A, Webb JK, Anderson SI: Leptin, asymmetric bone growth, pathogenesis of adolescent idiopathic scoliosis (AIS), and hormesis: Lower spine scoliosis (abstract). Clin Anat 2009 22 (3):411. [115] Burwell, RG, Aujla, RK, Grevitt MP, Dangerfield PH, Moulton A, Randell TL, Anderson SI: Pathogenesis of adolescent idiopathic scoliosis (AIS) in girls - a double neuro-osseous theory involving disharmony between two nervous systems, somatic and autonomic expressed in the spine and trunk: possible dependency on sympathetic nervous system and hormones with implications for medical therapy. Stud Health Technol Inform 2010 158: 212. [116] Zuo T, Tycko B, Liu TM, Lin JJ, Huang TH: Methods in DNA methylation profiling. Epigenomics 2009 1(2):331-45. [117] Lin SY, Lee CN, Hung CC, Tsai WY, Lin SP, Li NC, Hsieh WS, Tung YC, Niu DM, Hsu WM, Chen LY, Fang MY, Tu MP, Kuo PW, Lin CY, Su YN, Ho HN: Epigenetic profiling of the H19 differentially methylated region and comprehensive whole genome array-based analysis in Silver-Russell syndrome.Am J Med Genet A. 2010 152A(10):2521-8. [118] Bruce S, Hannula-Jouppi K, Peltonen J, Kere J, Lipsanen-Nyman M: Clinically distinct epigenetic subgroups in Silver-Russell syndrome: the degree of H19 hypomethylation associates with pheotype severity and genital and skeletal anomalies. J Clin Endocrinol Metab 2009 94(2):579-87.

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Research into Spinal Deformities 8 T. Kotwicki and T.B. Grivas (Eds.) IOS Press, 2012 © 2012 The authors and IOS Press. All rights reserved. doi:10.3233/978-1-61499-067-3-20

Pre-existent Rotation of the Normal Spine at Different Ages and Its Consequences for the Scoliotic Mechanism a

René M. CASTELEIN a, 1 Department of Orthopaedics, University Medical Center Utrecht, The Netherlands

Abstract. The normal spine is not a symmetrical structure, as has been appreciated for a long time. The reason why the main thoracic vertebrae in idiopathic scoliosis predominantly rotate to the left at the infantile age and to the right at the adolescent age is unclear. We provided an in-depth analysis of the rotational patterns of the normal growing and adult spine in relation to closure of the neurocentral junctions, organ anatomy and the convexity of the curve in idiopathic scoliosis. We believe that the delicate upright human spino-pelvic balance can be disturbed by a multitude of offenses and consequently an idiopathic scoliosis will develop due to the rotational instability. From our results it can be concluded that once this rotation starts to occur, it will naturally follow the pre-existent rotational patterns that we have demonstrated to exist already in the normal spine. Keywords. Pre-existent vertebral rotation, idiopathic scoliosis, closure of the neurocentral junctions, organ anatomy

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Introduction Idiopathic scoliosis is a classic and intriguing orthopedic problem in which the spine collapses into a three-dimensional deformity without any known cause. Idiopathic scoliosis develops during the infantile, or in its most common form, during the adolescent growth spurt. Prior to the growth spurts and after cessation of growth no manifest persistent disorder, other than the spinal deformity, can consistently be identified in these patients [1]. Therefore the etiology is termed multi-factorial. An important component of the three-dimensional deformity is axial vertebral rotation. The reason why the main thoracic vertebrae in idiopathic scoliosis predominantly rotate to the left at the infantile age and to the right at the adolescent age is unclear. A number of factors have been held responsible for the predominance of right sided thoracic curves in idiopathic scoliosis, in particular asymmetry of the thoracic and abdominal organs and the predominance of right handedness in the general population. As has been appreciated for a long time, the normal spine is also not a symmetrical structure [2, 3]. In our line of research we investigated the rotational patterns of the normal paediatric and adult spine in relation to closure of the neurocentral junctions and organ anatomy.

1

Corresponding Author: René M. Castelein, MD, PhD, Department of Orthopaedics, G05.228, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; E-mail: [email protected] Research into Spinal Deformities 8, IOS Press, Incorporated, 2012. ProQuest Ebook Central,

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1. Pre-existent rotation in the normal adult spine

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We hypothesized that there is a pre-existent axial rotational pattern of the normal, nonscoliotic adult spine that corresponds to the direction of rotation seen predominantly in adolescent idiopathic scoliosis . For this research line we developed a new semi-automatic analysis method to calculate the axial vertebral rotation of each vertebral level on transverse CT images in a systematic and reproducible way (Figure 1) [4, 5, 6]. We observed that in the normal nonscoliotic spine there is a pre-existent rotation to the left at high thoracic levels and to the right at mid and low-thoracic levels (Figure 2) [4]. In a study on the in vivo effect of three different body positions on the rotation of the normal spine, we observed that the vertebral rotation of the thoracic spine was less pronounced in quadrupedal position in comparison with the supine and uprightpositions [7]. The fact that the rotation of the normal adult spine is not randomly distributed or symmetrical might explain the most prevalent patterns of rotation in adolescent idiopathic scoliosis. Apparently, once the spine starts to decompensate into a scoliosis, it will follow this built-in rotational pattern, rather than revert to the opposite direction.

Figure 1. CT slice at level T5 in the transverse plane. Vertebral rotation was defined as the angle between the mid-sagittal axis (line between the center of the sternum [S] and the center of the spinal canal [C]) and the longitudinal axis of the vertebra (line through the anterior half of the vertebral body [V] and spinal canal [C]). (Data compiled from Kouwenhoven et al. and Janssen et al. [4, 5, 6])

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Figure 2. Vertebral rotation in the horizontal plane (mean and 95% confidence interval) at level T2-L5 in 50 persons with a normal nonscoliotic spine (black), and 37 persons with situs inversus totalis (grey). All measurements are in degrees. (Data compiled from Kouwenhoven et al.[4, 6])

2. Pre-existent rotation in the normal growing spine

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In the paediatric population we observed different rotational patterns in different age cohorts. In infantiles (0-3 years old), the whole thoracolumbar spine was rotated to the left, in juveniles (4-9 years old) the high thoracic vertebra were rotated to the left and the mid and low thoracic vertebra predominantly to the right. At the adolescent age (10-16 years old) an even more pronounced rotational pattern was seen as compared to the juvenile age (Figure 3). These results match the convexity of the predominant curves in infantile, juvenile and adolescent idiopathic scoliosis and support the hypothesis that the direction of deformity in most types of scoliosis is determined by the rotational pattern present in the normal spine [5, 8].

Figure 3. Mean vertebral rotation angles on each spinal level are shown for the infantile (0-3 years old), juvenile (4-9 years old), and adolescent (10-16 years old) cohorts. Rotation to the left was defined as negative and to the right as positive. Error bars indicate the standard error. (Preliminary data compiled from Janssen et al. and Schlösser et al. [5, 8])

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3. Pre-existent rotation and closure of the neurocentral junctions

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Asymmetrical growth and closure of the neurocentral junctions (NCJ) occur in the development of pathological rotation of the spine, as is known in naturally occurring scoliosis as well as in experimental scoliosis. The neurocentral junctions (NCJs) of the vertebrae connect the pedicles and laminae to the vertebral body bilaterally, and allow for growth in radial direction of the spinal canal. The cause of the pre-existent rotation of the normal spine is not clear. Asymmetrical growth of the NCJs may play an essential role in the development of pre-existent axial rotation of the spine, without necessarily being related to the etiology of scoliosis. Preliminary results of a recently performed study show that in the normal spine the NCJs close asymmetrically and that this closure is consistent with the pre-existent rotation of the normal growing spine. In the left-sided rotated spine of infantiles, the right NCJs were predominantly larger; whereas in the mid- and low thoracic spine of juveniles, the left NCJ was predominantly larger and the spine was rotated to the right (Figure 4). At the adolescent age the NCJs were already closed. In addition to the closure patterns of the NCJs and rotation it was demonstrated that in the normal spine the NCJs close first at lumbar levels and last in the mid- and low-thoracic spine. The apex of the curvature in idiopathic scoliosis is mostly localized in this spinal region [8]. These preliminary results suggest that the asymmetry and regional pattern of closure of the NCJs match the convexity of the curve in idiopathic scoliosis and the region of onset of the deformity.

Figure 4. The graph shows the mean differences in NCJ surface area for each spinal level in the infantile and juvenile cohorts. Difference in NCJ area was defined as the mean surface area of the right NCJ minus the surface area of the left NCJ. Error bars indicate the standard error. (Preliminary data compiled from Schlösser et al. [8])

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R.M. Castelein / Pre-Existent Rotation of the Normal Spine at Different Ages

4. Pre-existent rotation and organ anatomy In a group of patients with situs inversus, we demonstrated a rotational pattern exactly opposite to what was found in the normal adult population (Figure 2) [6]. In this group handedness was distributed as in the general population, the vast majority was righthanded. Therefore, we concluded that handedness does not influence the pre-existent rotational patterns of the normal spine, but organ anatomy does.

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5. Discussion and Conclusion Our research has shown that: (1) in infantiles the mid and low-thoracic spine is predominantly rotated to the left, while in juveniles, adolescents and adults the midand low thoracic spine is predominantly rotated to the right; (2) the pre-existent rotational vertebral pattern increases if the human spine is brought from quadrupedal to an upright position; (3) these pre-existent rotational patterns match the asymmetrical closure of the NCJs; (4) the pre-existent rotation is related to organ anatomy, and not to handedness; (5) these built-in rotational patterns match the convexity of the curve in the most prevalent types of thoracic idiopathic scoliosis; and (6) the NCJs close last at the levels at which idiopathic scoliosis predominantly occurs. Naturally, the existence of pre-existent axial rotation of the thoracic spine does not automatically result in the onset of scoliosis. However, we observed that the rotational patterns of the normal spine are identical in direction –although less in magnitude- to the rotation that occurs in idiopathic scoliosis in different regions of the spine and at different ages. The human spine is the only spine in nature on which posteriorly directed shear forces consistently act in certain (ill defined) areas. These forces have been shown to decrease rotational stiffness substantially [7, 9, 10]. The occurrence of scoliosis depends on whether the delicate human spino-pelvic balance is disturbed, which can happen due to a multitude of factors [1]. Apparently, once the spine starts to decompensate into scoliosis, it follows these pre-existent rotational patterns. In conclusion, the organ asymmetry and NCJ closure match the rotational patterns of the normal growing and adult spine. It seems likely that once rotation occurs in a developing scoliosis, it will follow the built-in underlying rotational pattern that we have demonstrated to exist in the normal spine.

References [1] Kouwenhoven JW, Castelein RM. The pathogenesis of adolescent idiopathic scoliosis: review of the literature. Spine (Phila Pa 1976) 2008; Dec 15;33(26):2898-908. [2] Nicoladoni C. anatomie und mechanismus der skoliose. in: Kocher, könig, von mikulicz, eds. Bibliotheca medica. stuttgart: Verlag von erwin nagele; 1904. . [3] Tubby AH. Symmetry and asymmetry, and their effect in the production of lateral curvature of the spine. Proc R Soc Med. 1909;2(Sect Study Dis Child):247-57. [4] Kouwenhoven JW, Vincken KL, Bartels LW, Castelein RM. Analysis of pre-existent vertebral rotation in the normal spine. Spine (Phila Pa 1976) 2006; Jun 1;31(13):1467-72. [5] Janssen MM, Kouwenhoven JW, Schlosser TP, Viergever MA, Bartels LW, Castelein RM, et al. Analysis of pre-existent vertebral rotation in the normal infantile, juvenile, and adolescent spine. Spine (Phila Pa 1976) 2011; Apr 1;36(7):E486-91.

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[6] Kouwenhoven JW, Bartels LW, Vincken KL, Viergever MA, Verbout AJ, Delhaas T, et al. The relation between organ anatomy and pre-existent vertebral rotation in the normal spine: magnetic resonance imaging study in humans with situs inversus totalis. Spine (Phila Pa 1976) 2007; May 1;32(10):1123-8. [7] Janssen MM, Vincken KL, Kemp B, Obradov M, de Kleuver M, Viergever MA, et al. Pre-existent vertebral rotation in the human spine is influenced by body position. Eur Spine J 2010; Oct;19(10):1728-34. [8] Schlösser TP, Vincken KL, Attrach H, Kuijf H, Viergever MA, Janssen MA, Castelein RM. Closure of the neurocentral junction as related to pre-existent rotation in the normal growing spine. EPOS 31st Annual Meeting. Journal of Children's Orthopaedics 2012;6(0):1-26. [9] Castelein RM, van Dieen JH, Smit TH. The role of dorsal shear forces in the pathogenesis of adolescent idiopathic scoliosis--a hypothesis. Med Hypotheses 2005;65(3):501-8. [10] Kouwenhoven JW, Smit TH, van der Veen AJ, Kingma I, van Dieen JH, Castelein RM. Effects of dorsal versus ventral shear loads on the rotational stability of the thoracic spine: a biomechanical porcine and human cadaveric study. Spine (Phila Pa 1976) 2007; Nov 1;32(23):2545-50.

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Chapter 2

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Genetics and Aetiology

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Podium Presentations

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Role of high central leptin activity in a scoliosis model created in bipedal amputated mice Tao Wu a, Xu Sun a, Zezhang Zhu a, Xin Zheng a, Bangping Qian a, Feng Zhu a,

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Jack C.Y. Cheng EF, Yong, Qiu a,c,1 a Spine Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China b Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong, China c The Joint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University

Abstract. Significantly lower circulating leptin level has been reported in adolescent idiopathic scoliosis (AIS) compared to healthy adolescents. It was hypothesized that leptin dysfunction might be involved in the etiopathogenesis of AIS. In this study, a scoliosis model of bipedal amputated mice with high central leptin activity was established to validate this hypothesis. Three days after bipedal amputation, the mice were randomly divided into two groups: then 8 mice were injected in the hypothalamus with lentivirus vectors which expressed leptin, whereas the remaining 8 were injected with lentivirus vectors expressing GFP (control vector). X-rays were obtained at 20th week to determine the development of spinal deformity. After that all mice were sacrificed, and blood samples were collected. Then peripheral leptin levels were measured by an ELISA kit. Comparisons for the incidence of scoliosis and the severity of the curves were performed between groups. The body weight was found to be slightly lower in the leptin-vector-treated C3H/HeJ mice when compared with control mice. Significantly higher peripheral serum leptin level was found in leptin-vectortreated mice than control mice. Scoliosis was observed in all leptin-vector-treated mice with an average Cobb angle of 28.2°, and in 4/8 of control with an average Cobb angle of 23.5°. The incidence of scoliosis was significantly higher in leptinvector-treated mice than in control group, although no significant difference was found in terms of curve severity. The results of this study indicated that the high central leptin activity might not only increase the risk of developing a scoliosis in bipedal mice but also contribute to the progression of scoliosis. The high central leptin activity might play an important role in the etiopathogenesis of scoliosis. Keywords. Leptin, dysfunction, bipedal amputated mice, scoliosis,

Introduction Adolescent idiopathic scoliosis (AIS) is a most common 3-dimensional spinal deformity occurring predominantly in peri-pubertal girls [1]. Although the related researches have not yet determine the etiology of AIS, a consensus has been widely reached that growth is an important factor contributing to the development of AIS [2].

Research into Spinal Deformities 8, IOS Press, Incorporated, 2012. ProQuest Ebook Central,

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T. Wu et al. / Role of High Central Leptin Activity in a Scoliosis Model

Abnormal growth pattern has been found in AIS patients, including lower body weight, lower body mass index (BMI) and higher corrected height than the healthy controls throughout the pubertal period[3-4].In addition to these abnormal growth patterns, generalized lower bone mass and osteopenia in AIS patients have also been widely reported in previous studies[5]. Therefore, it is generally believed that AIS is a systemic disease manifested by scoliosis deformity as well as abnormal growth pattern during the pubertal period [6]. Leptin is an important factor involved in the administration of energy expenditure, bone metabolism, body weight, reproduction and the hypothalamic-pituitary system. And leptin dysfunction can explain nearly all of these phenotypic abnormalities in AIS. A hypothesis was supposed by Burwell [7] that high central leptin activity might play an important role in the development of scoliosis deformity as well as the formation of abnormal growth pattern in AIS patients. However, central leptin activity was difficult to be evaluated in human being due to the ethical issues. Hence, a scoliosis model of bipedal amputated mice with high central leptin activity was established to investigate the influence of high central leptin activity on scoliosis.

Copyright © 2012. IOS Press, Incorporated. All rights reserved.

1. Material and methods This study was performed under the approval and supervision of the institutional committee of animal use for research. A total of 16 C3He/ej mice were housed in group cages in an air-conditioned room. Amputation of forelimbs and the tail was performed under anesthesia at the age of 3-week for each mouse. Then, bipedal mice were typically housed in special tall cages, in which these mice need to maintain a standing posture when getting the food and water. Three days after bipedal amputation, these mice were randomly divided into two groups: the half of the mice were injected in the hypothalamus with lentivirus vectors expressing leptin (1.5*108Tu/ml, 15μl), whereas the remaining half were injected with lentivirus vectors expressing GFP (1.5*108Tu/ml, 15μl). Mice were observed to be able to stand with the hindlimbs. After establishing the model of bipedal amputated mice with high central leptin activity, body weight were monitored for them every month. Then X-rays were obtained at 20th weeks under anesthesia to determine the development of spinal deformity. When taking the radiographs, the mice were placed in a prone position with the head fixed by a thread on a support inclined 30° from the horizontal plane of the table to prevent functional lateral scoliosis. Then curves in different locations in the spinal column were identified according to the SRS guidelines and measured using the Cobb method. After that all mice were sacrificed, blood samples were collected for each mice and then were centrifuged for 20 min at 3000 rpm at 4°C; serum samples were then stored at -80°C until required for assay. Then peripheral leptin levels were measured by an ELISA kit. Independent-sample t test and 2 test analysis were used to compare the incidence of scoliosis and the peripheral leptin levels between two groups. Statistical Package for Special Software (SPSS 13, Chicago, IL) was used for all statistical analysis. Statistical significance was set at P0.05 while the biomechanical loading of the sacrum was significantly different between the pre- and postoperative subjects and pre operative subjects and controls p