Classification of SCI severity
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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
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\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"5248",leadTitle:null,fullTitle:"Structural Bridge Engineering",title:"Structural Bridge Engineering",subtitle:null,reviewType:"peer-reviewed",abstract:"There are many books on preliminary studies and research in bridge design as well as basic knowledge on bridge engineering, but most books supply the needs of practicing engineers who may have problems in estimating, designing or constructing suspension bridges. Therefore, this book is intended to serve as a source of information for problems related to bridge engineering including sustainable bridge development, traditional approaches and recent advances in highway bridge traffic loading, aesthetic analysis issues in designing a new bridge, applications of various methods for the dissipation of seismic energy for bridges, new technologies of bridge design as well as structural identification of bridges using non-destructive experimental measurement tests.",isbn:"978-953-51-2689-8",printIsbn:"978-953-51-2688-1",pdfIsbn:"978-953-51-6684-9",doi:"10.5772/61683",price:119,priceEur:129,priceUsd:155,slug:"structural-bridge-engineering",numberOfPages:198,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"8a6b781d7ca98b6008887c99915a62ec",bookSignature:"Shahiron Shahidan, Shahrul Niza Mokhatar, Mohd Haziman Wan Ibrahim, Norwati Jamaluddin, Zainorizuan Mohd Jaini and Noorwirdawati Ali",publishedDate:"October 12th 2016",coverURL:"https://cdn.intechopen.com/books/images_new/5248.jpg",numberOfDownloads:14917,numberOfWosCitations:3,numberOfCrossrefCitations:8,numberOfCrossrefCitationsByBook:2,numberOfDimensionsCitations:9,numberOfDimensionsCitationsByBook:2,hasAltmetrics:0,numberOfTotalCitations:20,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 3rd 2015",dateEndSecondStepPublish:"November 24th 2015",dateEndThirdStepPublish:"February 20th 2016",dateEndFourthStepPublish:"March 21st 2016",dateEndFifthStepPublish:"June 27th 2016",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"145588",title:"Dr.",name:"Shahiron",middleName:null,surname:"Shahidan",slug:"shahiron-shahidan",fullName:"Shahiron Shahidan",profilePictureURL:"https://mts.intechopen.com/storage/users/145588/images/system/145588.jpg",biography:"Ts. Dr. Shahiron Shahidan CEng MIET, was born in Perlis, Malaysia, in 1983. He received his early education at Sekolah Kebangsaan Kampong Salang, Perlis. He continued his secondary education at Al Madrasah Al Alawiyah Ad Diniah, Arau Perlis, and Sekolah Menengah Teknik Butterworth, Penang. He furthered his studies and graduated in 2007 with a B. Eng. (Civil) (Hons) from the University Industry Selangor. After graduation, Dr. Shahidan was employed as a Bridge Engineer at a consulting engineering firm (HSS Integrated, Bandar Sri Permaisuri, Kuala Lumpur) for almost a year before making an academic career switch at Universiti Tun Hussein Onn Malaysia (UTHM). In 2008, Dr. Shahidan furthered his studies at a master’s degree level and graduated with a Master in Structural Engineering from Universiti Putra Malaysia (UPM). In 2014 he completed his PhD. in Structural Engineering at the University of Science, Malaysia (USM). Currently, he is a Senior Lecturer in the Department of Structural and Material Engineering at the Faculty of Civil and Environmental Engineering, Universiti Tun Hussein Onn Malaysia (UTHM), Malaysia. Dr. Shahidan has experience teaching undergraduate and graduate courses such as Bridge Design, Railway Engineering, Prestressed Concrete Design, Reinforced Concrete Design and Structural Analysis. Throughout his studies and career, he was involved in a number of professional international and national societies . He is a Chartered Engineer (CEng) from Engineering UK, Member of The Institution Engineering Technology (MIET), Profesional Tecnologist (P.Tech),Member of the Board of Engineers Malaysia (BEM); Member of the American Concrete Institute (ACI), Kuala Lumpur, Malaysia; Member of the Concrete Society of Malaysia (CSM); and Grad. Engr. of the Institution of Engineers Malaysia. Dr. Shahidan has also been actively publishing his work in high-impact journals, Thomson Reuters and Scopus indexed, he wrote several book chapters while also being active as a conference attender and oftenly a keynote speaker.",institutionString:"Tun Hussein Onn University of Malaysia",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Tun Hussein Onn University of Malaysia",institutionURL:null,country:{name:"Malaysia"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"202629",title:"Dr.",name:"Mohid Haziman",middleName:null,surname:"Wan Ibrahim",slug:"mohid-haziman-wan-ibrahim",fullName:"Mohid Haziman Wan Ibrahim",profilePictureURL:"https://mts.intechopen.com/storage/users/202629/images/system/202629.png",biography:"Dr. Mohd Haziman Wan Ibrahim is an Associate Professor at the Department of Structure and Material Engineering at the Universiti Tun Hussein Onn Malaysiat. He graduated in Civil Engineering from the Universiti Tun Hussein Onn Malaysia (UTHM), Malaysia, in 2004 and in 2011 he has been awarded Ph.D. in philosophy from the same university. \nHe is involved in different projects in the field of concrete technology and masonry engineering. He has authored more than 60 publications.",institutionString:"Tun Hussein Onn University of Malaysia",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Tun Hussein Onn University of Malaysia",institutionURL:null,country:{name:"Malaysia"}}},coeditorTwo:{id:"202630",title:"Dr.",name:"Norwatie",middleName:null,surname:"Jamaluddin",slug:"norwatie-jamaluddin",fullName:"Norwatie Jamaluddin",profilePictureURL:"https://mts.intechopen.com/storage/users/202630/images/5021_n.jpg",biography:"Dr. Norwati Jamaluddin is lecturer at the Department of Structure and Material Engineering at the Universiti Tun Hussein Onn Malaysiat since 2003.\nShe graduated in Structural Engineering from the Universiti Teknologi Malaysia in 2003 and in 2011 she has been awarded Ph.D. in philosophy from the University of Leeds. \nHer major research interests are in steel structural, composite steel-concrete structural, finite element modeling. \nDr. Jamaluddin is a member of the International Association Protective Structures (IAPS)\n, of the Malaysian Steel Structural Association (MSSA)\n and she is a member of the Board of Engineers Malaysia (BEM). 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Dr. Ali is a member of the Board of Engineers Malaysia.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorFour:{id:"202632",title:"Dr.",name:"Sharulniza",middleName:null,surname:"Mokhatar",slug:"sharulniza-mokhatar",fullName:"Sharulniza Mokhatar",profilePictureURL:"https://mts.intechopen.com/storage/users/202632/images/5022_n.png",biography:"Dr. Shahrul Niza Bin Mokhatar is a senior lecturer at the Department of Structure and Material Engineering at the Universiti Tun Hussein Onn Malaysiat .\nHe has been awarded Ph.D. in Civil Engineering from Kyushu University in 2013. Dr. Mokhatar\\'s major research interests are structural engineering, computational modeling of reinforced concrete (nonlinear finite element analysis, smoothed particle hydrodynamics method) and impact engineering.\nHe is a member of the Board of Engineers Malaysia (BEM)\n, of The Institution of Engineers, Malaysia (IEM)\n, of the International Association of Protective Structures (IAPS)\n and a nembe of the Japan Concrete Institute (JCI).\nHe has authored more than ten articles in international journals and nine conference/proceeding publications.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorFive:{id:"202633",title:"Dr.",name:"Zainorizuan",middleName:null,surname:"Mohd Jaini",slug:"zainorizuan-mohd-jaini",fullName:"Zainorizuan Mohd Jaini",profilePictureURL:"https://mts.intechopen.com/storage/users/202633/images/5023_n.png",biography:"Dr. Zainorizuan Mohd Jaini is a senior lecturer and researcher at the Department of Structure and Material Engineering at the Universiti Tun Hussein Onn Malaysiat.\nHe has been awarded Ph.D. in Civil and Computational Engineering) from Swansea University, UK. \nDr. Mohd Jaini research interests are structural damage and dynamic responses under high loading rates, finite/discrete element method\n, computational multi-scale modeling, vibration and progressive collapse\n, innovative structures. \nHe is a member of the Institution of Structural Engineers (ISE), the Institution of Engineers Malaysia (IEM), Association for Computational Mechanics in Engineering (ACME), International Association of Protective Structures (IAPS), International Association for Computational Mechanics (IACM), European Association for Structural Dynamics (EASD), Concrete Society of Malaysia (CSM). \nHe has authored more than twenty publications between journal articles and conference proceedings.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null},topics:[{id:"712",title:"Structural Engineering",slug:"engineering-civil-engineering-structural-engineering"}],chapters:[{id:"50780",title:"History of Sustainable Bridge Solutions",doi:"10.5772/63461",slug:"history-of-sustainable-bridge-solutions",totalDownloads:2306,totalCrossrefCites:3,totalDimensionsCites:2,hasAltmetrics:0,abstract:"The chapter is a voice in the discussion concerning sustainable bridge development. Nowadays, the term has rather been abused, and therefore the presented approach refers to these elements of design, construction and maintenance of bridges—with regard to their role in transport and social life—which have been present in bridge construction for a long time and can be easily incorporated into the concept of sustainable bridge construction. Sustainable development, sustainable construction and so on are multidimensional. In the considered bridge construction area, looking at construction processes as interfering with the environment and which could and should be restricted is a new element. Nevertheless, other proven constructional solutions and technologies are characterised by their reliability. Assuming that the constructed bridges are to serve the next two or three generations of users, we can try to extrapolate current technical conditions on the next 30 or 60 years, i.e., up to three generations. We can do it if we know and are able to critically assess the history of bridge construction. Following this reasoning, the history in question is referred to in this paper, although rather subjectively and with the omission of numerous important personalities and technologies as well as instructive failures due to the publishing limitations.",signatures:"Slawomir Karas",downloadPdfUrl:"/chapter/pdf-download/50780",previewPdfUrl:"/chapter/pdf-preview/50780",authors:[{id:"182839",title:"Dr.",name:"Slawomir",surname:"Karas",slug:"slawomir-karas",fullName:"Slawomir Karas"}],corrections:null},{id:"51540",title:"Highway Bridge Traffic Loading",doi:"10.5772/63967",slug:"highway-bridge-traffic-loading",totalDownloads:2107,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"In this chapter, traditional approaches and recent advances in highway bridge traffic loading are described, which are of great significance for structural safety assessment of bridges. Indeed, it is widely accepted that consideration of site-specific traffic features can enable significant savings in maintenance operations. While short spans are governed by free-flowing traffic plus an allowance for the dynamic effects, long spans are governed by congested conditions. For the former, a promising research trend is the investigation of the dynamic vehicle-bridge interaction, which is shown to lead to dynamic effects much lower than previously thought. For the latter, advances in traffic flow modelling enable the simulation of realistic congestion patterns based on widely available free-flowing traffic data, thus partially overcoming a long-standing shortage of congestion data. Here, emphasis is given to the promising application of traffic microsimulation to long-span bridge loading, combined with a probabilistic approach based on the extreme value theory, to compute site-specific characteristic loading values.",signatures:"Alessandro Lipari",downloadPdfUrl:"/chapter/pdf-download/51540",previewPdfUrl:"/chapter/pdf-preview/51540",authors:[{id:"183534",title:"Dr.",name:"Alessandro",surname:"Lipari",slug:"alessandro-lipari",fullName:"Alessandro Lipari"}],corrections:null},{id:"51848",title:"3D and 4D Models Used in Bridge Design and Education",doi:"10.5772/64675",slug:"3d-and-4d-models-used-in-bridge-design-and-education",totalDownloads:2110,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"A bridge is the type of structure whose appearance normally deserves more attention because it not only has an evident impact on the environment but also represents considerable investment, both of which justify careful evaluation. The aesthetic analysis is an important issue that must be considered when designing a new bridge, especially when it is to be built in an urban or road environment. In this context, the automatic generation of three‐dimensional (3D) geometric models of the bridge under analysis, and the walk around and aerial simulation allowed over it, which can be generated, helps bridge designers to evaluate its aesthetic concept and environmental impact. The bridge construction process can also be simulated, helping designers and builders to review the progress of the construction work in situ. For that, 4D (3D + time) models of the most frequent bridge construction methods were generated, using virtual reality (VR) technology. The simulation of the construction activity made possible by the developed interactive 4D model helps bridge designers to analyse the whole construction process. The present study aims to analyse the mechanisms of how to generate 3D models of a bridge automatically and how to simulate its construction using VR capacities.",signatures:"Alcínia Z. Sampaio",downloadPdfUrl:"/chapter/pdf-download/51848",previewPdfUrl:"/chapter/pdf-preview/51848",authors:[{id:"13640",title:"Prof.",name:"Alcínia Zita",surname:"Sampaio",slug:"alcinia-zita-sampaio",fullName:"Alcínia Zita Sampaio"}],corrections:null},{id:"52386",title:"The Structural Performance of Stone-Masonry Bridges",doi:"10.5772/64752",slug:"the-structural-performance-of-stone-masonry-bridges",totalDownloads:3504,totalCrossrefCites:5,totalDimensionsCites:7,hasAltmetrics:0,abstract:"The structural performance of old stone-masonry bridges is examined by studying such structures located at the North-West of Greece, declared cultural heritage structures. A discussion of their structural system is included, which is linked with specific construction details. The dynamic characteristics of four stone bridges, obtained by temporary in situ instrumentation, are presented together with the mechanical properties of their masonry constituents. The basic assumptions of relatively simple three-dimensional (3-D) numerical simulations of the dynamic response of such old stone bridges are discussed based on all selected information. The results of these numerical simulations are presented and compared with the measured response obtained from the in situ experimental campaigns. The seismic response of one such bridge is studied subsequently in some detail as predicted from the linear numerical simulations under combined dead load and seismic action. The performance of the same bridge is also examined applying 3-D non-linear numerical simulations with the results used to discuss the structural performance of stone-masonry bridges that either collapsed or may be vulnerable to future structural failure. Issues that influence the structural integrity of such bridges are discussed combined with the results of the numerical and in situ investigation. Finally, a brief discussion of maintenance issues is also presented.",signatures:"George C. Manos, Nick Simos and Evaggelos Kozikopoulos",downloadPdfUrl:"/chapter/pdf-download/52386",previewPdfUrl:"/chapter/pdf-preview/52386",authors:[{id:"43298",title:"Dr.",name:"Nikolaos",surname:"Simos",slug:"nikolaos-simos",fullName:"Nikolaos Simos"},{id:"152143",title:"Prof.",name:"George",surname:"Manos",slug:"george-manos",fullName:"George Manos"},{id:"185538",title:"M.Sc.",name:"Evangelos",surname:"Kozikopoulos",slug:"evangelos-kozikopoulos",fullName:"Evangelos Kozikopoulos"}],corrections:null},{id:"51368",title:"Different Solutions for Dissipation of Seismic Energy on Multi-Span Bridges",doi:"10.5772/63821",slug:"different-solutions-for-dissipation-of-seismic-energy-on-multi-span-bridges",totalDownloads:1585,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This chapter deals with the application of various methods for the dissipation of seismic energy in order to adjust the response to seismic forces of an existing bridge with multiple spans.",signatures:"Alessandro Contin and Andrea Mardegan",downloadPdfUrl:"/chapter/pdf-download/51368",previewPdfUrl:"/chapter/pdf-preview/51368",authors:[{id:"182884",title:"Dr.",name:"Andrea",surname:"Mardegan",slug:"andrea-mardegan",fullName:"Andrea Mardegan"},{id:"182886",title:"Dr.",name:"Alessandro",surname:"Contin",slug:"alessandro-contin",fullName:"Alessandro Contin"}],corrections:null},{id:"50890",title:"Fluid Viscous Dampers and Shock Transmitters in Realization of Multi-Span Steel-Concrete Viaducts",doi:"10.5772/64038",slug:"fluid-viscous-dampers-and-shock-transmitters-in-realization-of-multi-span-steel-concrete-viaducts",totalDownloads:1655,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This chapter discusses the methodology for the dissipation of seismic energy, designed for the construction of a steel-concrete viaduct in a variable-orography land. The viaduct has a total length of 1102 m and typical spans of 75 m, with piers, of a maximum height of 65 m, significantly varies from each other. The viaduct is subjected to a redesign step in order to adapt it to the requirements of Italian standard ‘D.M. 14/01/2008’. The new design has reformulated the sequence of spans and, consequently, redefined the structures constituting the foundations, piles, steel girders, inferior bracings and especially the typology of bearings and seismic devices.",signatures:"Alessandro Contin and Andrea Mardegan",downloadPdfUrl:"/chapter/pdf-download/50890",previewPdfUrl:"/chapter/pdf-preview/50890",authors:[{id:"182884",title:"Dr.",name:"Andrea",surname:"Mardegan",slug:"andrea-mardegan",fullName:"Andrea Mardegan"}],corrections:null},{id:"51519",title:"Nondestructive Testing Structural Bridge Identification",doi:"10.5772/64288",slug:"nondestructive-testing-structural-bridge-identification",totalDownloads:1652,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The bridges are one of the most important engineering structures. Determination of the bridge responses during their service life has gained great importance using nondestructive test methods with the changing of aims, usages, environmental conditions, material deteriorations by time, and damages during some dramatical events. This chapter presents the nondestructive experimental measurement test results of the bridges for structural identification. Ten different bridges, which have different type and carrier systems, such as historical masonry arch bridges, long span concrete highway bridges, base isolated bridges, footbridges, steel bridges, and old riveted bridges, are selected for numerical examples. The measurements are conducted under environmental excitations of pedestrian movement, traffic, wind-induced vibration, and the response signals are collected using uniaxial- and triaxial-sensitive seismic accelerometers. Operational modal analysis or ambient vibration tests are performed to extract the dynamic characteristics such as natural frequencies, mode shapes, and damping rations using enhanced frequency domain decomposition method in the frequency domain and stochastic subspace identification method in the time domain. It is demonstrated that the ambient vibration measurements are enough to identify the most significant modes of all bridge types.",signatures:"Ahmet Can Altunışık",downloadPdfUrl:"/chapter/pdf-download/51519",previewPdfUrl:"/chapter/pdf-preview/51519",authors:[{id:"181092",title:"Dr.",name:"Ahmet Can",surname:"Altunişik",slug:"ahmet-can-altunisik",fullName:"Ahmet Can Altunişik"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"5503",title:"Wood in Civil Engineering",subtitle:null,isOpenForSubmission:!1,hash:"fb659c92f0d45acc8f960d9a656b54e2",slug:"wood-in-civil-engineering",bookSignature:"Giovanna Concu",coverURL:"https://cdn.intechopen.com/books/images_new/5503.jpg",editedByType:"Edited by",editors:[{id:"108709",title:"Dr.",name:"Giovanna",surname:"Concu",slug:"giovanna-concu",fullName:"Giovanna Concu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2193",title:"Advances on Analysis and Control of Vibrations",subtitle:"Theory and Applications",isOpenForSubmission:!1,hash:"926bac5ebecf5b70140e42105b5e2527",slug:"advances-on-analysis-and-control-of-vibrations-theory-and-applications",bookSignature:"Mauricio Zapateiro de la Hoz and Francesc Pozo",coverURL:"https://cdn.intechopen.com/books/images_new/2193.jpg",editedByType:"Edited by",editors:[{id:"148213",title:"Dr.",name:"Mauricio",surname:"Zapateiro",slug:"mauricio-zapateiro",fullName:"Mauricio Zapateiro"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8822",title:"Advances in Structural Health Monitoring",subtitle:null,isOpenForSubmission:!1,hash:"429d24d493e64821ae08df0a71d33e37",slug:"advances-in-structural-health-monitoring",bookSignature:"Maguid H.M. 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Hassan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6957",title:"New Trends in Structural Engineering",subtitle:null,isOpenForSubmission:!1,hash:"8c26eaf65a25f29d43abd17ff651746f",slug:"new-trends-in-structural-engineering",bookSignature:"Hakan Yalciner and Ehsan Noroozinejad Farsangi",coverURL:"https://cdn.intechopen.com/books/images_new/6957.jpg",editedByType:"Edited by",editors:[{id:"72283",title:"Associate Prof.",name:"Dr. Hakan",surname:"Yalçıner",slug:"dr.-hakan-yalciner",fullName:"Dr. Hakan Yalçıner"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10028",title:"Structural Integrity and Failure",subtitle:null,isOpenForSubmission:!1,hash:"3bf0a0d2767ca9f748ec686d2725ba0e",slug:"structural-integrity-and-failure",bookSignature:"Resat Oyguc and Faham Tahmasebinia",coverURL:"https://cdn.intechopen.com/books/images_new/10028.jpg",editedByType:"Edited by",editors:[{id:"239239",title:"Associate Prof.",name:"Resat",surname:"Oyguc",slug:"resat-oyguc",fullName:"Resat Oyguc"}],equalEditorOne:{id:"211659",title:"Dr.",name:"Faham",middleName:null,surname:"Tahmasebinia",slug:"faham-tahmasebinia",fullName:"Faham Tahmasebinia",profilePictureURL:"https://mts.intechopen.com/storage/users/211659/images/system/211659.jpg",biography:"Faham Tahmasebinia holds ME and ME-Research degrees in Civil/Structural Engineering from the University of Wollongong – Australia. 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More than 1.3 million patients are currently living with a spinal cord injury (SCI) in North America (Reeve Foundation). There is no cure for SCI although recent advances in acute care interventions (
ASIA-A | No voluntary motor control and no sensation below injury level |
ASIA-B | No voluntary motor control, some sensations below injury level |
ASIA-C | Some motor control (< grade 3) and some sensations below injury level |
ASIA-D | Some motor control ("/> grade 3) and some sensations below injury level |
ASIA-E | Normal voluntary motor control and sensation below injury level |
Classification of SCI severity
Advanced rehabilitation ‘activity-based’ strategies such as body weight-supported treadmill training or BWSTT (leg movements generated passively by manual assistance from therapists) and functional electrical stimulation (FES)-biking are increasingly used especially with motor-incomplete (ASIA-C and ASIA-D) patients. Indeed, given that spared descending pathways exist and, thus, some voluntary motor control remains in these subclasses of patients, it becomes possible to further increase voluntary ambulation using BWSTT training (Dobkin et al., 2006; Hicks & Ginis, 2008). However, motor system, metabolic outcomes or health benefits associated with these approaches remain unclear (Hicks & Ginis, 2008; Duffell et al., 2009). In turn, chronic SCI patients classified as motor-complete (ASIA-A & ASIA-B) generally experience greater health problems often referred to as ‘secondary complications’ that are associated with significant changes of the motor, locomotor, skeletal, cardiovascular, circulatory and hematologic problems (Huang & DeVivo, 1990; Bauman, 1999; Riegger et al., 2009; Rouleau et al., 2010,2011; Spungen, 2003). No safe, effective and regulatory agency-approved treatments against these chronic problems exist yet.
In the last few years, great therapeutic hopes for motor-complete SCI patients (ASIA-A and ASIA-B) have emerged from physical activity-based studies performed in adult complete paraplegic cats showing that basic locomotor movements (i.e., hindlimb stepping) can be restored partially with regular treadmill training, weight support, passively generated movement and administration (
Initial hospitalization | $140,000 |
1st year paraplegics | $152,000 |
1st year tetraplegics | $417,000 |
Averaged life time paraplegics | $428,000 |
Averaged life time tetraplegics | $1,350,000 |
Costs of SCI in U.S. dollars (source: http://www.sci-info-pages.com/facts.html)
Although, these therapeutic approaches may not be designed to repair or cure SCI, they would nonetheless contribute at preventing (in acutely injured patients), reducing or reversing (in chronic SCI patients) secondary complications associated with motor system changes and significantly reduced physical activity (see also
The motor system may be divided into several organs and structures. There is the central nervous system (CNS) that comprises the brain and the spinal cord. Its one hundred billion neurons are involved in motor and sensory functions (Kandel et al., 2000). The brain consists of the pyramidal and extrapyramidal system specifically associated with voluntary motor control. These brain structures constitute the main command centres that control voluntary muscular contraction. Most of their neuronal commands are sent to neurons and motoneurons located in the spinal cord where sensory motor integration and final motor commands sent to muscle are organized for proper induction of coordinated movements.
In contrast, locomotion and other rhythmic and partially involuntary motor behaviours are largely controlled by signals and neuronal commands generated in the brainstem and spinal cord. In fact, complex neuronal circuits located in these non-cortical areas of the CNS are known to be capable of generating motor functions even in absence of descending inputs from cortical areas and other brain regions (Guertin & Steuer, 2009; Guertin, 2010). In fact, locomotion, micturition, ejaculation, scratching, erection, and respiration are amongst the motor behaviours that are mainly controlled by spinal cord and brainstem circuits (see Fig.1).
Neuronal networks in the spinal cord that control, brain-independently, complex motor behaviours. Respiration (not shown here) is also largely controlled by non-cortical structures including the brainstem (e.g., Pre
Thus, the CNS controls either directly or indirectly the muscular systems. Although some types of muscles such as the cardiac and smooth muscles are considered controlled by the autonomic nervous system and hormones, the striated skeletal muscle system is directly controlled by the CNS. This is the main reason why after SCI, an immediate and irreversible loss of sensory and voluntary motor control is found. This said, increasing evidence suggests that functions controlled mainly by the spinal cord can nonetheless be elicited despite SCI using specific pharmacological or electrical approaches (see
In humans, the striated skeletal muscle system comprises approximately 650 muscles. It is formed by different fiber types and properties including slow-twitch fibers (type I) and relatively fast to very fast-twitch fibers (IIa, IIb and IIx)(Table 3). The main action of skeletal muscles in motor control is to allow movement execution. Almost all skeletal muscles either originate or insert on the skeleton. When a muscle moves a portion of the skeleton, that movement results into flexion, extension, adduction, abduction, etc. (Martini & Nath, 2011).
The human skeleton consists of both fused and individual bones supported by ligaments, tendons, muscles and cartilage. Among several functions, it primarily serves as a scaffold for movements controlled by the CNS and muscles as mentioned earlier. The biggest bone in the body is the femur which is also the main skeletal structure affected after chronic SCI, disuse or immobilization. Finally, energy and other metabolic processes involved in motor control and movements largely depend upon the integrity of the circulatory and hematologic systems – i.e., distribution of erythrocytes and oxygen to muscles.
Type I | Slow twitch, high fatigue resistant, high oxidative, low glycolytic |
Type IIa | Moderately fast twitch, fairly high fatigue resistant, high oxidative, high glycolytic |
Type IIx | Fast twitch, intermediate fatigue resistant, intermediate oxidative, high glycolytic |
Type IIb | Very fast twitch, low fatigue resistant, low oxidative, high glycolytic |
Muscle fiber types and main properties
All in all, the main components of the motor system described above are changed and altered specifically in patients with complete and motor-complete SCI as well as in patients suffering of chronic disuse and immobilization (burn patients, AIDS patients, some patients with cardiac or pulmonary problems)(Huang & DeVivo, 1990; Bauman, 1999; Riegger et al., 2009; Rouleau et al., 2010,2011; Spungen, 2003; Lainscak et al., 2007).
In brief, all experimental procedures were conducted in accordance with the Canadian Council on Animal Care guidelines. Mice were generally housed 4-5 animals per cage in a controlled-temperature environment (22 ± 3°C), maintained under a 12h light:dark cycle with free access to water and food. Before surgery, pre-operative care was provided 30 minutes prior to anesthesia. It included subcutaneous injections of 1.0 ml of lactate-Ringer’s solution, 0.1 mg/kg of buprenorphine, and 5 mg/kg of Baytril, an antibiotic. Initially, complete anesthesia was conducted using 2.5% isoflurane in a cage of induction. Anesthetized animals were then shaved dorsally (2-cm) from the mid-dorsal area to the neck. Then, each animal was maintained under complete anesthesia using a specially adapted facial mask delivering directly 2.5% isoflurane to the animal. The shaved area was cleaned with 70 % (
Once the surgical procedures completed, anesthesia was interrupted and mice were placed in a large cage equipped with a heating pad placed underneath. It is critically important to use only minimal heating intensity (35°C) to avoid rapid dehydration, heat shock and death during the recovery period. Generally, the animals recovered completely within 15 min although we normally left them on the heating pad overnight with free access to food and water. The recovery procedure was found to be critical to ensure a high percentage of survival post-surgery (typically around 95% if everything is performed as described). The next day, the animals were replaced in their initial cage with their initial cage mates in order to reduce potential aggressions and fights.
Spinal cord histology. Luxol blue and Cresyl violet staining of a longitudinal section of the spinal cord from a non-laminectomized spinal cord-transected mouse one week post-surgery.
Postoperative care, provided a few hours after surgery as well as every day for the next 4 days, included injections of lactate-Ringer’s solution (2 x 1 ml/day, s.c.), buprenorphine (2 x 0.1 mg/kg/day, s.c.), and Baytril (5 mg/kg/day). Bladders were also manually emptied twice a day until a spontaneous return of some micturition reflexes. For voiding, the bladder was gently squeezed between the thumb (side of the bladder) and two fingers (e.g., the index and one other finger placed the other side of the bladder). This maneuver requires time and experience. In male mice, it was specifically challenging since, in addition, penises have to be maintained against a paper towel throughout the maneuver to improve successful voiding (i.e., it appeared to contribute, perhaps via capillary action, to urine expulsion outside the urinary tract). The belly and sexual organ were cleaned daily using paper towels and chlorhexidine gluconate solution (0.05 %
This approach led to complete paraplegia (Figs. 2 & 3) – an immediate and irreversible loss of sensory and voluntary motor control below injury level (low-thoracic level). Although, it is possible to maintain these animals relatively healthy for severaonmonths post-spinal transection, a number of neuronal, muscular, skeletal, vascular, and hematologic changes were rapidly displayed. A detailed characterization of these changes is presented in the following subsections.
Video images of a paraplegic mouse placed on a treadmill. A complete loss of hindlimb movement is encountered immediately following the spinal cord transection.
Nearly all SCI individuals experience a drastic loss of bone mineral content (up to 30% at the femoral level) leading to a marked increase of fracture incidence within one year after injury (Ragnarsson & Sell, 1981; Garland et al., 1992; Wilmet et al., 1995; Lazo et al., 2001; Sabo et al., 2001). Although, the basic mechanisms underlying osteoporosis in post-menopausal women have been extensively studied, those involved in chronic immobilization and disuse have received considerably less attention. In animal models of disuse, traditionally in rats, hindlimb immobilization has been found to induce a drastic and sudden loss of femoral bone tissue suggesting that different mechanisms may be involved in disuse vs. estrogen-deficiency/aging-related osteoporosis (Bagi & Miller, 1994). For instance, a 10-30% decrease of cancellous bone has been reported within only a few weeks in the ipsilateral femur of rats that had their hindlimbs immobilized with a cast or an elastic bandage (Ito et al., 1994; Ma et al., 1995; Mosekilde et al., 2000). Comparable changes have been found in other models of disuse such as in tail-suspended rats (Wronski et al., 1989). Some of these disuse-related changes are believed to be mediated by both an increase of osteoclastic bone resorption and a decrease of osteoblastic bone formation (Rantakokko et al., 1999). On the other hand, growing evidence suggests that several factors other than mechanical unloading
Here, we characterized some of the main structural and functional adaptive changes occurring specifically within a few weeks in adult spinal cord transected mice. In brief, within a few weeks post-transection, paraplegic mice were weighed, sacrificed and the femoral bones dissected and cleaned of soft tissue. The femurs were wrapped in saline-soaked gauze and frozen at -20 degrees C in sealed vials until testing. For histomorphometry, the left femoral bones were fixed with paraformaldehyde, decalcified, paraffin embedded and stained with acid fuchine using the Masson’s trichrome procedures. Histomorphometric analyses were performed with a NOVA Prime, Biioquant’s image analysis system (R&M Biometric, Nashville, TN) for primary bone morphometric parameters. Three bone slices at the metaphyseal level were analyzed. For densitometry, measurements were made with the rigth femoral bones of sham and paraplegic mice. Bone mineral content (BMC, g) from the femora of each animal was assessed using dual-energy X-ray absoptiometry (DEXA, model Piximus II, Lunar Corporation, Madison WI, for details, see Kolta S, De Vernejoul M.C. et al. 2003). Bone mineral density (BMD, g/cm2) was calculated as BMC divided by projected bone area. Each femur was scanned separately for whole bone analysis. For biomechanical assessment, on the day of testing, the femur was slowly (4 hours) tawed at room temperature. They were placed horizontally on the three-point bending device (MTS, Eden Prairie, MN). The mechanical resistance to failure was tested using a servo-controlled electromechanical system (Intron, Instron, Canton, MA). The crosshead speed for all tests was 10 mm/sec until the femur fractured. Displacement and load values were acquired at 100 Hz, recorded and stored on PC. Off-line data analyses were performed to calculate maximal strength (N), stiffness (slope of the linear part of the curve to failure, N/cm), and elasticity deformation (N). Bones were kept wet throughout testing and used for histomorphometrical testing (proximal end).
All histomorphometric measurements and analyses were made from the metaphyseal area of the left femora. The cancellous bone volume was found to decrease by 25.2% in paraplegic mice (within 1 month post-transection) compared with control (non-paraplegic). The average trabecular bone thickness was found to decrease by 10.65%. The thickness was initially of 25.55 micron in the control groups and of only 22.83 micron in the paraplegic group. The number of trabecular bone areas decreased rapidly also after injury. In the control group, the average trabecular number was 3.38 nbr/mm2 whereas in the paraplegic group, it decreased to only 2.89 nbr/mm2 representing a 14.50% decrease. On the other hand, the trabecular separation, defined as the space between trabecular bone areas, increased after injury. In fact, on average, the trabecular separation increased by 24.03% within 1 month post-SCI (Picard et al., 2008).
The bone mineral density (BMD) of the left femora measured by dual-energy X-ray absorptiometry (DEXA) significantly changed after injury. The BMD was just below 0.09 g/cm2 in control and of 0.0731 in paraplegic mice. Bone mineral content (BMC) also proportionally decreased after injury (see
The maximum force in N required for the crosshead to fracture the right femora at the mid-diaphyseal level was decreased by 13% on average within a few weeks post-transection (Fig.4D). The stiffness in N/mm was also reduced after injury with average values of 57.23 and 51.08 in control and paraplegic groups, respectively, representing a 10.8% decrease (Fig.4B). The elastic force decreased also by approximately 15% in early spinal transected mice compared with control (Fig.4C).
It is well-documented in various rat models that the contractile properties of slow twitch muscles change into more fast-like muscles after chronic spinalization (Roy et al., 1991; Talmadge, 2000). Hindlimb extensor muscles such as soleus (SOL) typically exhibit extended atrophy (e.g., up to 50%) and type I to type II muscle fiber conversion following spinalization in rats (Krikorian et al., 1982; Lieber et al., 1986 a,b; Midrio et al., 1988; Talmadge et al., 1995). Contraction and relaxation times as well as maximal tetanic force (Po) and maximal twitch force (Pt) have also been found to be importantly decreased in rat SOL several months after spinalization (Davey et al., 1981; Talmadge et al., 2002).
Evidence from other models of inactivity and immobilization suggests that some of these changes, in fact, are induced very early after inactivity and reduced muscular activity and loading. For example, a 10% loss of body weight (Pierotti et al., 1990) accompanied by a 40-50% decrease of SOL mass, TPT and 1/2 RT (Frenette et al., 2002) and a rapid reduction in slow myofibril proteins (Thomason et al., 1987) have been reported after 1-2 weeks of hindlimb suspension in rats. Comparable results have been found within less than 2 weeks in rats after spinal cord isolation (i.e., de-afferented and spinalized, Grossman et al., 1998) or in microgravity (Fitts et al., 2001). In addition, a 40% reduction of SOL cross sectional area has been found only 10 days post-spinal cord transection in rats (Dupont-Versteegden et al., 1999). The possibility that other early changes may occur after spinal cord transection is largely unexplored.
Bone mechanical properties. Two-point bending test (A) revealed decreased femoral stiffness (B), elasticity (C) and maximal force (D) in untrained spinal transected mice (spinal, black) versus control (intact animals, white)(unpublished data).
Here, we characterized some of the earliest adaptations in gross anatomy and muscle properties at only 7 days following spinal cord transection in adult mice (Landry et al., 2004). In brief, whole body weight was measured daily during the first week post-spinalization. After dissection of SOL for functional tests in vitro (see section below), animals were sacrificed with pentobarbital overdose. Forelimbs and hindlimbs were surgically removed just below the shoulder and the hip joints respectively. Paws as well as all parts of the pectoral and back muscles attached to the forelimbs were removed. Tests included weight measurement of the left forelimb and hindlimb as well as of the right SOL. To further assess muscle atrophy, limbs were weighed in air and in water to measure volume changes. Volume was calculated as follows with a volumic mass of 0.998 for water at room temperature (22oC):
For measurement of contractile properties, we anesthetized animals with pentobarbital sodium (50 mg/kg). The right SOL was carefully dissected and incubated in fully oxygenated Krebs-Ringer bicarbonate buffer solution maintained at 25oC and supplemented with glucose (2 mg/ml).
We reported that paraplegic mice at 7 days post-surgery encountered a drastic loss in body weight (Landry et al., 2004). On average, a 24% decrease in weight was found at 7 days post-spinalization. A similar loss was found in another group of paraplegic mice that received instead daily injection of lactate-Ringer’s solution (2 ml/day, s.c.) during the first week post-spinalization suggesting that dehydration did not contribute to weight loss.
The specific weight of individual body parts was also examined in paraplegic mice. In intact mice, the average weight of forelimbs and hindlimbs was 436 and 1239 mg respectively. At 7 days post-spinalization, hindlimb weight decreased by 28% compared to intact mice. Interestingly, a 21% reduction in the forelimbs of paraplegic mice was also observed during the same period of time. Relative to body weight, the loss observed in hindlimbs was greater than the one in forelimbs. Similar reductions in volume were found respectively in hindlimbs and forelimbs.
Regarding properties, for soleus mass displayed significantly lower values (-32%) in untrained paraplegic mice at 7 days post-spinalization compared with intact animals. A 33% decrease of Po was measured at 7 days post-spinalization. The absolute tension generated at different frequencies of stimulation showed mainly that SOL force was reduced in paraplegic mice compared to control at stimulation frequencies above 35 Hz. On the other hand, maximal tension was reached at lower stimulation frequencies for paraplegics compared to control.
Our data showed also in soleus a change toward faster-type properties in the first few days post-immobilization (transection).The surprising initial and rapid conversion to slower contractile properties at 7 days post-spinalization is further supported by changes found in contraction and relaxation times (TPT and 1/2 RT respectively). TPT became slower (i.e., increased time of contraction) by 21% at 7 days compared to control. Similar changes were observed with 1/2 RT which became slower (i.e., increased time of relaxation) by 48% at 7 days post-spinalisation.
As mentioned above, it is well-known that there is an important shift in fiber phenotype distribution a few weeks post-SCI even more so in soleus. Generally, slow fibers tend to change for a faster phenotype after 2 weeks post-spinal cord transection. After spinal cord transection, 50-55% of the slow type fibers showed important fiber type conversion, shifting to a hybrid isoform (faster phenotype) whereas fiber type conversion was not observed in another hindlimb muscle, EDL, often classified as a purely fast-twitch muscle (Table 4).
Fiber type % | Non-TX | TX untrained |
EDL type II | 98.7 ± 0.3 | 98.7 ± 0.6 |
EDL hybrid | 1.3 ± 0.3 | 1.3 ± 0.6 |
SOL type I | 54.6 ± 2.6 | 2.9 ± 1.5 |
SOL type II | 45.4 ± 2.6 | 46.5 ± 2.5 |
SOL hybrid | 0 ± 0 | 50.7 ± 3.3 |
Fiber type conversion in normal (non-TX) and untrained paraplegic (TX untrained)(unpublished data).
Among the cardiovascular and pulmonary problems associated with SCI, deep venous thrombosis (DVT) is one of the most serious complications in patients that survive to the accident. Indeed, DVT constitutes the third most common cause of death in SCI patients (Waring & Karunas, 1991; DeVivo, 1999) and, despite prophylaxic methods (e.g. anticoagulant administration), a significant proportion of SCI patients will develop a pulmonary embolism caused by DVT (Deep et al., 2001).
Complete paraplegic and tetraplegic individuals are particularly vulnerable given that spasticity, typically found in incomplete SCI patients, may decrease the risks of DVT formation (Green et al., 2003). Generally, DVT formation is attributed to a combination of factors including also venous stasis, venous injury, and hypercoagulability. In turn, these factors facilitate platelet, LDL-cholesterol, and leukocyte adhesion, procoagulant system activation, and hence, thrombin generation. Although, few animal models of DVT and/or pulmonary embolism exist (Frisbie, 2005), none have been developed to study these complications after SCI which may explain why the specific mechanisms of DVT formation in paralytics remain poorly understood.
Here, we characterized, in spinal cord transected (Tx) mice, some of the physiological changes occurring after SCI that could possibly contribute to DVT formation (Rouleau & Guertin, 2007; Rouleau et al., 2007). Specifically, we characterized also alterations of deep vein diameter in the hindlimbs of Tx mice because venous distensibility and capacity changes may participate to DVT formation (Miranda & Hassouna, 2000). We took advantage of this experimental model to measure with great precision (µm), using
In brief, we put the tail on a heated cushion to dilate the tail vein 10 min before injection. Then 200 µl of 5 mg/ml fluorescein isothiocyanate-dextran (FD-40) (Sigma, St-Louis, MO) dilute in injectable endotoxin-free dPBS (Sigma), was injected intravenously into the tail vein. Animals were killed by CO2 asphyxiation around 10 min after injection. The skin was cut to access to the femoral and saphenous veins. Microscope observation and measurement were performed with an Olympus BX61WI confocal system and analysed with Fluoview 300 (Carsen group, Markhan, Canada).
For hematologic data, peripheral blood was collected at various times post-transection by cardiac puncture. Each blood sample was analyzed for platelet quantification with a CELL-DYN 3700® automatic blood cell analyzer (CD3700)(Abbott Laboratories, North Chicago, IL).
We found by measuring deep vein diameter using
The hematologic data revealed mild anemia that occurs as early as at 7 days post-transection. Specifically, average counts of erythrocytes (10.11 x 1012 /L in control mice) decreased to values ranging from 9.91 to 9.54 x 1012 /L in paraplegic mice. Hemoglobin concentrations were decreased from 164.9 ± 2.8 g/L in controls to 153.3 g/L in paraplegic mice. Decreased hematocrit levels were also found in paraplegic mice (range from 0.46 ± 0.01 to 0.44 ± 0.01 L/L) compared with controls (0.48 ± 0.01 L/L, Fig. 1C)
The Central Pattern Generator (CPG) for locomotion is a network of neurons located in the lumbar area of the spinal cord that is capable of producing the basic commands for stepping even when isolated from supraspinal and sensory inputs (Grillner & Zangger, 1979, see also Guertin, 2010). Early evidence of a CPG emerged a century ago from the pioneer work of Sherrington (1910) and Brown (1914). In the 70s, low-thoracic spinalized rabbits and cats were used to show that an endogenous release of 5-HT induced by 5-HTP can generate fictive locomotor-like rhythms in the spinal cord (recorded with electroneurograms) of acute spinal cord-transected animals (Viala & Buser, 1971) or increase extensor muscle activity in regularly treadmill-trained and sensory-stimulated spinal animals (Barbeau & Rossignol, 1990, 1991). A clear demonstration of its existence was provided in 1979 by Grillner who could induce, with L-DOPA, locomotor-like neural activity in the motor nerves of completely de-afferented, curarized, and spinal cord-transected cats (Grillner & Zangger, 1979). In rats, the CPG was found, with activity-dependent labeling (e.g., c-fos), to be located mainly in rostral segments of the lumbar spinal cord (Cina & Hochman, 2000). Comparable results were found in mice where CPG activity was found to originate from lumbar segments with critical elements in L1-L2 (Nishimaru et al., 2000).
In the 80s and 90s,
In humans, evidence of a CPG was provided after showing that \'automatic\' (involuntary) stepping-like movements could be triggered spontaneously under certain conditions or by epidural stimulation at the L2 level in SCI patients confined to a bed (Dimitrijevic et al., 1998). Although a completely isolated CPG can produce locomotor rhythms, sensory inputs (
Changes post-spinal cord transection were also found in sublesionally-located neurons (below injury level). Since most of these changes were found in neurons located in upper lumbar segments of the spinal cord, they were postulated to correspond with changes in CPG neuron candidates. Immediate early genes (IEGs) constitute a large family of genes well-known as early regulators of cell growth, differentiation signals, learning and memory. We reported in low-thoracic spinal cord-transected mice, that IEGs such as
Other key elements including transmembranal receptors may be considered good candidates for plasticity and reorganization of motor and locomotor networks located sublesionally following a spinal cord-transection (and probably to some extent also after partial injuries). For instance, we found using
All in all, it is unclear how these changes of neuronal properties and gene expression below lesion level may affect functional recovery and, specifically, the development of approach designed to reactivate behaviours-generating neuronal networks (e.g., CPGs for locomotion, micturition, ejaculation, etc.). Nonetheless, it has been postulated by others that such changes may contribute to increase sublesional network excitability and, thus, may facilitate training-induced learning and rehabilitation.
Given that no cure exists yet to repair the spinal cord, an interesting avenue to prevent or reduce some of the motor system changes described in previous sections of this chapter may be to pharmacologically induce episodes of locomotion. To achieve this, an alternative strategy could be to develop a CPG-activating drug treatment that could temporarily re-activate this sublesional network in tetraplegic and most paraplegic subjects.
Experiments mainly conducted in my laboratory since 2004 have led to a better understanding of pharmacological CPG activation
This identification of a potent CPG-activating tritherapy (Guertin et al., 2010) recently received support from a special NIH program (Rapid Access to Interventional Development program) to conduct some of the preclinical studies (toxicity and safety pharmacology in rats). It has been determined that a tri-therapy composed of L-DOPA, carbidopa and buspirone is safe and ideally suited for further development at the clinical level (i.e., each drug is already FDA approved for diseases other than SCI and no abnormal pharmacology or toxicology data was found) as a first-in-class CPG activating drug treatment candidate. However, although efficacy in early chronic SCI mice has recently been demonstrated (Guertin et al., 2010; Guertin et al. 2011), it remains unclear how repeated administration over several weeks would affect disuse-related motor system changes.
As mentioned earlier, chronic SCI patients (especially motor-complete also called ASIA-A or ASIA-B patients) experience often life-threatening health problems also referred to as ‘secondary complications’ including motor system changes reported here also in this paraplegic mouse model. Using combination therapy, we obtained preliminary data suggesting that repeatedly-treated paraplegic mice can partially prevent some pathophysiological motor system changes found after SCI (Guertin et al., 2011).
Video images of a paraplegic mouse placed on a treadmill 15 minutes following administration of a CPG-activation tritherapy. Involuntary movements were generated for approximately 30 to 45 min. Then a complete return to complete paraplegia occurred.
Subcutaneous administration (several times per week) of a first-generation combination treatment was found, upon each injection (within 15 min), to repeatedly induce temporarily (during approx. 30-45 min) episodes of weight bearing stepping in non-assisted paraplegic mice at least during one month.
Regarding body weight values, combination therapy-treated paraplegic animals progressively displayed a moderate increase in weight suggesting that repeated administration of this combination therapy was well-tolerated (i.e., a loss of weight would have suggested toxic effects and additional health problems). No significant difference was found in bone mineral density (BMD) values in femoral bones of tritherapy-treated vs. placebo-treated paraplegic mice. Post-mortem examination of muscle size (whole surface area and fiber cross-sectional area or CSA) measured from cryostat transverse sections prepared from two hindlimb muscles,
All in all, these results revealed that pharmacological activation of the CPG four times per week during 1 month can prevent anemia and prevent partially muscle atrophy. Circulatory systems were not further examined in this study. On the other hand, this study showed that bone loss typically occurring post-transection in this animals can not be prevented in these conditions. Altogether, it is suggested that training conditions or treatments may have to be optimized for further physiological effects on all parts of the motor system.
Along this idea, we recently conducted a study where paraplegic animals received an anabolic agent, namely clenbuterol, in addition to tritherapy-induced locomotor training. We found that tritherapy-treated paraplegic mice with or without clenbuterol treatment displayed significant locomotor function recovery during 2 months upon each administration of the CPG-activating therapy (Fig.7). To further characterize movements induced by the tritherapy-training, angular excursion at the hip, knee and ankle, as well as movement amplitude values were analysed. Typical examples of hindlimb kinematics are shown in figure 7. Hip, knee and ankle angular displacement showed similar patterns in intact, tritherapy-trained alone and tritherapy-trained + clenbuterol paraplegic animals. Untrained paraplegic animals displayed a consistent lack of angular excursion at the hip level although some displacements were found at the knee and ankle levels (hip: 85°, knee: 30-47°, ankle: 28-125°). Hindlimb movement amplitude values measured by calculating toe displacement in X and Y axis (step “length” and “height”) revealed that intact mice had greater step length values than both tritherapy-trained paraplegic groups. On the other hand, both groups of tritherapy-trained paraplegic animals showed similar step length values which were significantly greater than those in untrained paraplegic mice. The coefficient of variation (CV) was higher in untrained mice. Intact, tritherapy-trained and tritherapy-trained + clenbuterol paraplegic mice showed similar step height values. However, differences were found in the variability of the step height, as shown by CV, where intact animals displayed less variability than the other groups of tritherapy-trained animals. No Y axis movement amplitude was observed in paraplegic untrained mice since no weight-bearing movement are normally expressed spontaneously. Overall, a significant increase in performances over time was observed in tritherapy-trained groups of paraplegic mice movement kinematic values were comparable with those from intact animals.
Kinematic analyses in intact (non-Tx), paraplegic (Tx) untrained, paraplegic tritherapy-trained and tritherapy-trained and treated with clenbuterol. Step parameters from both tritherapy-trained paraplegic mice were similar with those from intact animals suggesting that the tritherapy appropriately restored episodes of locomotor movements.
Femoral BMD and BMC values were measured in order to address whether tritherapy-training alone or combined with clenbuterol can prevent or at least reduce bone loss normally found in untrained paraplegic mice. However, in all groups of paraplegic animals, important losses were found. Untrained paraplegic mice (BMD: 0.0767 ± 0.0010 g/cm2, BMC: 0.0381 ± 0.0008 g) and tritherapy-trained paraplegic animals (BMD: 0.0766 ± 0.0011 g/cm2, BMC: 0.0378 ± 0.0009 g) showed comparable values whereas in paraplegic trained + clenbuterol groups, femoral BMD (0.0731 ± 0.0012) and BMC (0.0349 ± 0.0009) further decreased.
Morphometric analyses of soleus and EDL were performed in order to further characterize specific muscular property changes in all groups. Muscle CSA, fiber type-specific CSA and relative distribution values were analysed. For soleus CSA, untrained and tritherapy-trained paraplegic mice had significantly lower muscle CSA values than intact animals and tritherapy-trained + clenbuterol paraplegic groups. However soleus CSA in untrained paraplegic mice was not significantly lower than tritherapy-trained paraplegic animals. For EDL, in contrast with muscle mass changes, CSA values showed statistical differences between groups. Tritherapy-trained + clenbuterol paraplegic mice showed higher EDL CSA values than all the other groups. Untrained and tritherapy-trained paraplegic mice had lower CSA values than intact animals.
Femoral BMD and BMC in intact (non-Tx), paraplegic (Tx) untrained, paraplegic tritherapy-trained and tritherapy-trained and treated with clenbuterol. Unfortunately, bone loss was not prevented in both tritherapy-trained paraplegic mice compared with intact animals suggesting that the tritherapy with or without clenbuterol failed to restore bone properties.
Soleus and EDL cross-sectional area values in intact (non-Tx), paraplegic (Tx) untrained, paraplegic tritherapy-trained and tritherapy-trained and treated with clenbuterol. Although encouraging anti-atrophying effects were found in tritherapy-treated paraplegic mice, only paraplegic animals that received both clenbuterol + tritherapy displayed a complete restoration of muscle size (even a relative hypertrophic effect was induced compared with intact animals).
More differences were found when analysing individually fiber type-specific CSA values. Specifically, for soleus fiber types, all three fiber types from tritherapy-trained + clenbuterol paraplegic animals displayed larger CSA values than all other groups (type I: 1656.7 ± 80.8 µm2, type II: 987.2 ± 16.7 µm2, hybrid: 1145.5 ± 18.0 µm2). Conversely, untrained paraplegic mice displayed the lowest soleus fiber type CSA of all groups (type I: 783.1 ± 15.1 µm2, type II: 753.2 ± 9.1 µm2, hybrid: 750.0 ± 8.1 µm2). In EDL, type II fiber CSA differences between groups were similar to soleus type II (intact: 1063.5 ± 15.9 µm2, paraplegic untrained: 908.1 ± 11.4 µm2, paraplegic trained: 963.4 ± 10.9 µm2, paraplegic trained + clenbuterol: 11.65.2 ± 17.9 µm2).
These findings provided proof-of-concept data strongly supporting the idea that physical activity can prevent or restore motor system adaptations normally expressed after SCI. However, that study was exploratory and thus, it remains unclear the extent to which physical activity elicited with this pharmacological approach can extensively prevent or reverse secondary complications. Although anemia and partial muscle atrophy were prevented in CPG-activating tritherapy-trained paraplegic mice, addition of anabolic aids such as clenbuterol appeared to synergistically affect positively the motor system in paraplegic mice (complete reversal of atrophy, complete lack of anemia, etc.). Effects on other elements of the motor systems such as blood vessels (e.g., deep vein size) or skeleton remain to be explored or improved. From a scientific perspective, it remains also to be determined clearly what role physical inactivity may play on motor system adaptations post-SCI and corresponding health problems in humans. This said, motor system changes post-SCI obtained in this murine model was found to resemble those typically encountered in patients with SCI or disuse. It may therefore be useful to further study basic cellular mechanisms underlying these changes of the musculoskeletal systems in these conditions. It may also serve to accelerate the development of new therapeutic strategies aimed at reducing or preventing completely all musculoskeletal and biomechanical changes in SCI patients or in patients suffering of disuse or immobilization.
Endometriosis is a frequent disease in reproductive-age women [1], consisting of the presence of endometrial tissue outside the uterine cavity. Endometriosis is frequently associated with infertility, being present in 25–50% of infertile patients [2]. On the other hand, 30–50% of endometriosis patients report difficulties to become pregnant [2]. In a large cohort study, women with endometriosis younger than 35 years old had a two-fold higher risk of infertility in comparison with women without endometriosis [3]. The mechanisms underlying the association between endometriosis and infertility are incompletely clarified, with both anatomical and microenvironmental disturbances being suggested [4]. While in infertile patients with advanced-stage endometriosis anatomical changes might be involved (peritubal and periovarian adhesions), the presence of infertility in milder forms of endometriosis suggests other mechanisms. Thus, decreased ovarian reserve, altered folliculogenesis, oocyte quality and endometrial receptivity were reported as possible contributors to infertility [4].
The extent and severity of endometriosis lesions are variable, ranging from few implants on the pelvic peritoneum to surrounding organs infiltration or extension outside the pelvis. Several grading systems for endometriosis have been created, but their predictive value for fertility is unclear. One of these classification systems, the Endometriosis Fertility Index (EFI) which is based on the scores from the American Society for Reproductive Medicine (ASRM) system [5] combined with anamnestic and information from surgery, gives a score from 0 to 10 points [6]. It was shown that a score between 0 and 3 is associated with a 10% probability of obtaining pregnancy after 3 years with non-IVF treatments, while a score of 9–10 points is associated with a 75% chance of pregnancy [6, 7]. The predictive value of the EFI score for pregnancy was also confirmed for IVF treatments [8].
The impact of variate treatments for endometriosis on chances to obtain pregnancy and the efficacy of infertility treatments is still a matter of discussion. Thus, whether surgery contributes to the improvement of fertility in endometriosis or is preferable to perform infertility treatments needs further clarification.
In minimal or mild endometriosis without anatomical disruption, it was shown that laparoscopic removal of endometriosis implants improves fertility with an increase of risk ratio of 1.44 [9] and an odds ratio of 1.94 [10]. In a large Canadian multicenter study, the monthly fecundity rate and the 36-week cumulative probability of pregnancy increased from 2.4 to 17.7% for a diagnostic laparoscopy to 4.7 and 30.7% for laparoscopic surgery [11]. However, these rates of pregnancy should be discussed with the patients in the light of similar success rates of 30% after only one cycle of IVF taking into account the age, ovarian reserve or the cost of the treatment [12].
In patients with moderate and severe endometriosis surgery aims to remove large endometriomas and to restore the pelvic anatomy. Data regarding the effect of surgery on fertility in this category of patients are lacking. Excision of endometrioma is controversial in infertile patients taking into account the risk to decrease the ovarian reserve and lack of evidence of benefits on IVF outcome [13].
IVF could be a treatment option for infertility in patients with endometriosis. Therefore, the performance of patients with endometriosis at IVF and their predictors should be clarified to elaborate strategies for ovarian stimulation and to improve IVF outcomes. Oocyte yield at IVF is an important predictor of live birth in the general population of patients performing IVF, but it might be affected by the microenvironmental changes associated with endometriosis. Moreover, the AMH production could be disturbed in endometriosis, possibly interfering with its relationship with the ovarian reserve.
Therefore, the present paper aims to review the literature regarding the association of endometriosis with oocytes number and serum AMH level in infertile patients performing IVF, and the predictive value of AMH for the response to controlled ovarian stimulation.
The relationship between endometriosis and serum AMH level is largely debated and data available in infertile women undergoing IVF are scarce. Only a limited number of studies with small study groups evaluated the impact of endometriosis on circulating AMH levels in patients with a wider range of endometriosis lesions [14, 15], most of the studies included only patients with endometrioma. The surgery for endometrioma probably affects the serum AMH level as suggested by two systematic reviews [16, 17] and represents a possible confounder of the relationship between endometrioma and AMH. It was shown that the decrease of serum AMH level after surgery was significant and persistent at 12 months in patients with endometrioma over 7 cm, with bilateral cysts and with endometriosis stage IV [18]. In turn, patients with smaller and unilateral ovarian endometrioma and stage III endometriosis had higher chances to have an only transient decline in circulating AMH [18]. However, a recent meta-analysis showed that the mere presence of endometrioma, without previous surgery, is associated with lower AMH levels in patients without clearly defined fertility status [19]. In this study the serum AMH level was decreased in patients with endometrioma both versus patients with non-endometriotic cysts and with healthy ovaries, suggesting a specific effect of endometriosis independent of mass effect. The dimension of the endometriotic cyst could be an important contributor to the decrease of AMH level, although the available data are limited. In the meta-analysis of Muzii et al. most of the studies included patients with mean endometrioma dimension over 6 cm, being therefore impossible to conclude smaller cysts [19]. A small study found that even endometrioma bigger than 2 cm had lower serum AMH levels in comparison with controls [20]. On the other hand, Yoon et al. failed to find any relationship of ovarian endometrioma size with serum AMH level [21]. A small study with less than 60 patients per study group showed that patients with bilateral endometrioma had lower serum AMH levels in comparison with both unilateral endometrioma and no cysts [22]. Moreover, a negative linear relationship was found between endometrioma size and serum AMH level [22]. A prospective study with 40 women per study group reported that patients with endometrioma have a progressive decline in serum AMH level at an accelerated rate in comparison with patients without endometrioma [23].
Data regarding the impact of a wider range of endometriosis lesions on serum AMH levels are limited. A cross-sectional study that evaluated women surgically explored for a benign gynecological condition irrespective of their fertility status reported a similar serum AMH level in endometriosis patients and controls [24]. Patients in this study presented with various types of endometriosis: endometrioma, deep infiltrating endometriosis and superficial lesions [24]. However, in this study, infertile patients with decreased ovarian reserve might be underrepresented since these patients are more probably referred for reproductive treatments rather than for surgery.
Several studies evaluated the relationship between endometriosis and serum AMH levels in patients with infertility. Thus, Yoo et al. found that infertile patients with endometriosis performing IVF had lower AMH in comparison with male factor infertility patients [14]. In this study, the type of the endometriosis lesions was not specified and the number of patients in the two groups was reduced (43 versus 48). Moreover, patients with and without previous surgery for endometriosis were included, without a significant difference in terms of circulating AMH in these two categories of patients. Ashrafi et al. reported that serum AMH level is decreased in patients with deep infiltrating endometriosis with or without endometrioma and infertility [25]. Another small study showed that infertile patients with endometriosis stage I and II have lower circulating AMH levels in comparison with patients with tubal infertility undergoing IVF [15]. Inal et al. found no difference in serum AMH level in infertile patients with and without endometrioma performing IVF [26]. Shebl et al. studied the serum AMH level in patients undergoing IVF and found a decreased AMH only in patients with endometriosis stage III-IV in comparison with male factor infertility, but not in patients with stage I-II endometriosis [27].
The relationship between endometriosis and oocytes yields in infertile patients performing IVF was previously studied, but the results are divergent. Senapati et al. found that patients with endometriosis obtain fewer oocytes in comparison with patients with other causes of infertility undergoing IVF in a big database of 347,185 assisted reproductive technic cycles [28]. In this study, the presence of endometriosis was associated with a lower number of oocytes in patients with isolated endometriosis or association with other causes of infertility, including diminished ovarian reserve [28]. The negative association between endometriosis and oocytes yield was also studied by a meta-analysis that included 20,167 patients with endometriosis and 121,931 without endometriosis [29]. Subgroups with 1703 women with stage III/IV endometriosis were compared with 2227 women with stage I/II endometriosis. Although, a small difference in oocytes yield was observed in favor of non-endometriosis patients, the authors concluded that the quality of the evidence is very low, not allowing meaningful conclusions to be drawn [29]. No significant difference in patients with variate stages of endometriosis was reported [29]. Moreover, in both studies patients with and without previous surgery for endometriosis were included, generating a possible bias [28, 29]. Thus, Dong et al. analyzed only patients with previous surgery for endometriosis and found that patients with stage III/IV endometriosis obtained lower oocytes number in comparison with controls [30], suggesting that surgery for severe endometriosis might negatively affect COS response. Several other studies confirmed the negative association between surgery for endometriosis and oocytes yield in women with advanced-stage endometriosis [31]. In patients operated for endometrioma, laparoscopic cystectomy is associated with decreased oocytes number, with an additional effect of bilateral versus unilateral cystectomy [32]. Similarly, bilateral surgery for endometrioma was shown to decrease the oocytes number in comparison with unoperated patients [33].
Regarding the association of variate types of endometriosis with COS response, a recent meta-analysis found that unoperated endometriomas are associated with reduced oocytes number in IVF cycles [34]. Papaleo et al. found that profound infiltrative endometriosis has an additional negative effect on oocytes yield in comparison with patients with isolated ovarian endometrioma, supporting the hypothesis that variate types of endometriosis lesions can differently impact the ovarian response [35]. In turn, a small study that included only patients with stage I and II endometriosis found similar oocytes number with patients performing IVF for tubal infertility [15].
Although, circulating AMH levels are considered, in general, a valuable tool for the prediction of the ovarian response to COS, in endometriosis its predictive value might be affected. This hypothesis is supported by studies that demonstrated that AMH production could be influenced independently of the ovarian reserve. However, its predictive value in endometriosis is largely unknown.
Yoo et al. showed that serum AMH level is a significant predictor of oocytes yield in endometriosis patients performing IVF [14], while Wahd et al. found no predictive value of AMH in patients with advanced endometriosis [36]. The lack of the predictive ability of AMH was confirmed in another study that analyzed only patients with endometrioma [26]. The design of the studies and differences in study populations might explain the divergent results of the studies, being possible that more severe endometriosis and endometrioma, especially bigger ones to significantly disrupt the relationship between AMH and ovarian reserve.
Despite the negative relationship between endometriosis and circulating AMH reported by several studies, two reports found an increasing serum AMH level with endometrioma size [37, 38]. If this finding will be confirmed by future studies, a possible explanation is a different impact of endometrioma on AMH production from the other endometriosis lesions. The authors hypothesized that the increasing AMH level could be due to higher discharge in the systemic circulation by increased ovarian blood flow as a consequence of the inflammation and neoangiogenesis found in endometriosis. In support of this hypothesis are the studies that reported increased levels of vascular endothelial growth factor (VEGF) in serum and peritoneal fluid of patients with endometriosis [39]. These increased levels are correlated with microvessels density in the endometriotic tissue [40]. Thus, increased vascularization might contribute to disproportionately higher serum AMH levels in comparison with ovarian reserve, therefore affecting its value as a predictor of COS response in endometriosis. However, this mechanism could be particular to endometrioma as suggested by a study that showed that the gene expression of VEGF is increased only in patients with endometrioma and not in those with deep infiltrating endometriosis [41].
Besides the mass effect of the endometrioma, other mechanisms might be also involved in the occurrence of reduced oocytes yield since similar oocytes number was found in the contralateral ovary of women with unilateral endometriomas [42]. Moreover, more severe endometriosis seems to have an additional negative impact on oocytes number [35].
Histological studies found that the cortex of ovaries with endometrioma presents decreased follicular density, increased fibrosis, loss of cortex-specific stroma [43] and high density of atretic follicles [44]. Moreover, activated follicular recruitment was observed in ovaries with endometrioma [44], suggesting follicle ‘burnout’ as a possible cause of decreased follicle number. It was suggested that the structural changes are the consequence of the cytokines produced in the endometriotic tissue which might affect the surrounding ovarian tissue by diffusion [44]. It was also showed that the addition of human endometriotic fluid to mouse preantral follicles decreases the follicles survival rates proportional with the endometriotic fluid supernatant concentration [45]. These data support the hypothesis that endometriotic fluid components can influence the ovarian response to COS through long-term destructive effects of ovarian tissue and, therefore, decreased ovarian reserve, but also by directly influencing the follicles survival [45]. It is also possible that the diffusion of the endometriotic fluid components from the peritoneum or the endometrioma to be able to influence the unaffected ovary function and structure [46].
The decreased serum AMH level in patients with endometriosis might be the consequence of reduced ovarian reserve due to structural ovarian changes. However, it was shown that the endometriotic fluid components can directly induce the dysfunction of the granulosa cells [47]. Tumor necrosis factor (TNF) alpha, one of the cytokines overproduced in endometriosis, was found to be negatively associated with serum AMH level [15], suggesting its involvement in decreased circulating AMH. Indeed, an experimental study showed that TNF alpha administration decreases the expression of AMH in bovine ovarian granulosa cells [48]. In mice, TNF alpha was demonstrated to inhibit the AMH production in testis [49]. Thus, TNF alpha might be the mediator of functional decrease of AMH production in endometriosis.
Another mechanism that can contribute to low oocytes yield is a decreased response to gonadotropin stimulation in endometriosis. Thus, interleukin 1 (IL1) was found to be increased in the peritoneal fluid of patients with endometriosis [50, 51, 52]. Il1 is also a regulator of ovarian function, being able to decrease the ovary receptors of FSH and LH [53], thus inducing a reduced sensitivity to gonadotropin stimulation. Moreover, women with endometriosis seem to have a decreased expression of the soluble decoy receptor IL1-RII which can generate an augmentation of IL1 alpha and IL1 beta effects [51, 54].
The data available in the literature support a negative association between the presence of an endometrioma and serum AMH level. Moreover, previous surgery for endometrioma is associated with decreased serum AMH level, the risk of the persistence of low AMH being higher in patients with bilateral endometrioma, bigger than 7 cm and with stage IV endometriosis. However, in patients with a wider range of endometriosis without clearly defined fertility status the serum AMH level does not seem to be decreased. In infertile patients with endometriosis available studies suggest lower serum AMH levels, although further research is necessary to clarify this aspect. Moreover, endometriosis seems to negatively impact the oocyte yield, especially in patients with previous surgery for severe endometriosis and endometrioma. The impact of variate types of endometriosis on the oocytes yield is incompletely clarified, the available evidence supporting that endometrioma has a deleterious effect on the ovarian response, with a possible additional negative effect of deep infiltrating endometriosis.
The authors declare no conflict of interest.
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