The American Association for the Surgery of Trauma (AAST) liver injury scale (2018 revision).
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"intechopen-signs-new-contract-with-cepiec-china-for-distribution-of-open-access-books-20210319",title:"IntechOpen Signs New Contract with CEPIEC, China for Distribution of Open Access Books"},{slug:"150-million-downloads-and-counting-20210316",title:"150 Million Downloads and Counting"},{slug:"intechopen-secures-indefinite-content-preservation-with-clockss-20210309",title:"IntechOpen Secures Indefinite Content Preservation with CLOCKSS"},{slug:"intechopen-expands-to-all-global-amazon-channels-with-full-catalog-of-books-20210308",title:"IntechOpen Expands to All Global Amazon Channels with Full Catalog of Books"},{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"}]},book:{item:{type:"book",id:"7534",leadTitle:null,fullTitle:"Role of Microbes in Human Health and Diseases",title:"Role of Microbes in Human Health and Diseases",subtitle:null,reviewType:"peer-reviewed",abstract:"Microbes are ubiquitous and have ecological interactions with almost all life forms. Likewise, humans invariably engage in host-microbial interactions that could induce short-term or long-term effects. Some of these long-term crossover interactions have allowed successful colonization of microbes within or on the human body, collectively known as the human microbiome or human microbiota. The human microbiome is identified as playing a key role in various physiological processes like digestion, immunity, defense, growth, and development. Any dysbiosis in the human microbiome structure could induce the onset of various metabolic or physiological disorders. Cumulatively, the human microbiome is considered as a virtual human organ that is essential for host survival. Additionally, short-term biological interactions of the host and microbes have exposed microbes to the human cellular system. This exposure could have allowed the microbes to invade human cells for their growth and reproduction-induced onset of various infectious diseases. This book incorporates a number of studies highlighting the role of microbes in human health and diseases.",isbn:"978-1-83880-234-9",printIsbn:"978-1-83880-233-2",pdfIsbn:"978-1-83880-718-4",doi:"10.5772/intechopen.76595",price:100,priceEur:109,priceUsd:129,slug:"role-of-microbes-in-human-health-and-diseases",numberOfPages:82,isOpenForSubmission:!1,isInWos:1,hash:"ad71073664357a1e5e73eb81f08be582",bookSignature:"Nar Singh Chauhan",publishedDate:"June 5th 2019",coverURL:"https://cdn.intechopen.com/books/images_new/7534.jpg",numberOfDownloads:2875,numberOfWosCitations:3,numberOfCrossrefCitations:4,numberOfDimensionsCitations:6,hasAltmetrics:0,numberOfTotalCitations:13,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 9th 2018",dateEndSecondStepPublish:"June 1st 2018",dateEndThirdStepPublish:"July 31st 2018",dateEndFourthStepPublish:"October 19th 2018",dateEndFifthStepPublish:"December 18th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,editors:[{id:"216883",title:"Prof.",name:"Nar Singh",middleName:null,surname:"Chauhan",slug:"nar-singh-chauhan",fullName:"Nar Singh Chauhan",profilePictureURL:"https://mts.intechopen.com/storage/users/216883/images/system/216883.jpeg",biography:"Dr. Nar Singh Chauhan is currently a teaching faculty in the Department of Biochemistry, Maharishi Dayanand University, Rohtak, India. His doctor of philosophy degree, with thesis research on \\'Arsenic detoxification mechanisms in unculturable bacteria using function metagenomics\\' at the CSIR-Institute of Genomics and Integrative Biology, was granted by Savitribai Phule Pune University, Pune, India. His current research focus is on the metagenomic characterization of diverse microbiome for their native community structure, physiological functions, survival strategies under abiotic stress, colonization factors, and host-microbial interactions. In this direction, he has established an association of the human microbiome with the onset of celiac disease and chronic obstructive pulmonary disease. Dr. Chauhan is the author of a number of peer-reviewed research publications in reputed international journals (Genome Biology & Evolution, Scientific Reports, Frontiers in Microbiology, etc.) and has also been awarded many research patents.",institutionString:"Maharishi Dayanand University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Maharshi Dayanand University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"895",title:"Medical Microbiology",slug:"medical-microbiology"}],chapters:[{id:"66113",title:"Introductory Chapter: Human and Microbes in Health and Diseases",doi:"10.5772/intechopen.85217",slug:"introductory-chapter-human-and-microbes-in-health-and-diseases",totalDownloads:445,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Nar Singh Chauhan",downloadPdfUrl:"/chapter/pdf-download/66113",previewPdfUrl:"/chapter/pdf-preview/66113",authors:[{id:"216883",title:"Prof.",name:"Nar Singh",surname:"Chauhan",slug:"nar-singh-chauhan",fullName:"Nar Singh Chauhan"}],corrections:null},{id:"64638",title:"The Therapeutic Potential of the “Yin-Yang” Garden in Our Gut",doi:"10.5772/intechopen.80881",slug:"the-therapeutic-potential-of-the-yin-yang-garden-in-our-gut",totalDownloads:555,totalCrossrefCites:1,totalDimensionsCites:1,signatures:"Shabarinath Srikumar and Séamus Fanning",downloadPdfUrl:"/chapter/pdf-download/64638",previewPdfUrl:"/chapter/pdf-preview/64638",authors:[null],corrections:null},{id:"63743",title:"The Role of Leather Microbes in Human Health",doi:"10.5772/intechopen.81125",slug:"the-role-of-leather-microbes-in-human-health",totalDownloads:799,totalCrossrefCites:2,totalDimensionsCites:3,signatures:"Richard O. Oruko, John O. Odiyo and Joshua N. Edokpayi",downloadPdfUrl:"/chapter/pdf-download/63743",previewPdfUrl:"/chapter/pdf-preview/63743",authors:[null],corrections:null},{id:"64720",title:"Extra Pulmonary Tuberculosis: An Overview",doi:"10.5772/intechopen.81322",slug:"extra-pulmonary-tuberculosis-an-overview",totalDownloads:1077,totalCrossrefCites:1,totalDimensionsCites:2,signatures:"Onix J. Cantres-Fonseca, William Rodriguez-Cintrón, Francisco Del Olmo-Arroyo and Stella Baez-Corujo",downloadPdfUrl:"/chapter/pdf-download/64720",previewPdfUrl:"/chapter/pdf-preview/64720",authors:[null],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},relatedBooks:[{type:"book",id:"548",title:"Antibiotic Resistant Bacteria",subtitle:"A Continuous Challenge in the New Millennium",isOpenForSubmission:!1,hash:"f8a58b7ebbb9cd01db5c16fbf9f80b44",slug:"antibiotic-resistant-bacteria-a-continuous-challenge-in-the-new-millennium",bookSignature:"Marina Pana",coverURL:"https://cdn.intechopen.com/books/images_new/548.jpg",editedByType:"Edited by",editors:[{id:"77349",title:"Dr.",name:"Marina",surname:"Pana",slug:"marina-pana",fullName:"Marina Pana"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5193",title:"Probiotics and Prebiotics in Human Nutrition and Health",subtitle:null,isOpenForSubmission:!1,hash:"facfb45c80773cd5151d8f53b902be39",slug:"probiotics-and-prebiotics-in-human-nutrition-and-health",bookSignature:"Venketeshwer Rao and Leticia G. Rao",coverURL:"https://cdn.intechopen.com/books/images_new/5193.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5197",title:"Microbial Biofilms",subtitle:"Importance and Applications",isOpenForSubmission:!1,hash:"51bccaa7388a26d55298525fd28dd8f1",slug:"microbial-biofilms-importance-and-applications",bookSignature:"Dharumadurai Dhanasekaran and Nooruddin Thajuddin",coverURL:"https://cdn.intechopen.com/books/images_new/5197.jpg",editedByType:"Edited by",editors:[{id:"48914",title:"Dr.",name:"Dharumadurai",surname:"Dhanasekaran",slug:"dharumadurai-dhanasekaran",fullName:"Dharumadurai Dhanasekaran"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5853",title:"Mycobacterium",subtitle:"Research and Development",isOpenForSubmission:!1,hash:"073e7ca9fbfdd31da5499271f17ecdf2",slug:"mycobacterium-research-and-development",bookSignature:"Wellman Ribón",coverURL:"https://cdn.intechopen.com/books/images_new/5853.jpg",editedByType:"Edited by",editors:[{id:"88491",title:"Dr.",name:"Wellman",surname:"Ribón",slug:"wellman-ribon",fullName:"Wellman Ribón"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8019",title:"Alginates",subtitle:"Recent Uses of This Natural Polymer",isOpenForSubmission:!1,hash:"61ea5c1aef462684a3b2215631b7dbf2",slug:"alginates-recent-uses-of-this-natural-polymer",bookSignature:"Leonel Pereira",coverURL:"https://cdn.intechopen.com/books/images_new/8019.jpg",editedByType:"Edited by",editors:[{id:"279788",title:"Dr.",name:"Leonel",surname:"Pereira",slug:"leonel-pereira",fullName:"Leonel Pereira"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5162",title:"The Gut Microbiome",subtitle:"Implications for Human Disease",isOpenForSubmission:!1,hash:"f21c4722be61a42e7e6ed30cb898b9ad",slug:"the-gut-microbiome-implications-for-human-disease",bookSignature:"Gyula Mozsik",coverURL:"https://cdn.intechopen.com/books/images_new/5162.jpg",editedByType:"Edited by",editors:[{id:"58390",title:"Dr.",name:"Gyula",surname:"Mozsik",slug:"gyula-mozsik",fullName:"Gyula Mozsik"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8292",title:"Oral Health by Using Probiotic Products",subtitle:null,isOpenForSubmission:!1,hash:"327e750e83634800ace02fe62607c21e",slug:"oral-health-by-using-probiotic-products",bookSignature:"Razzagh Mahmoudi",coverURL:"https://cdn.intechopen.com/books/images_new/8292.jpg",editedByType:"Edited by",editors:[{id:"245925",title:"Dr.",name:"Razzagh",surname:"Mahmoudi",slug:"razzagh-mahmoudi",fullName:"Razzagh Mahmoudi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],ofsBooks:[]},correction:{item:{id:"74918",slug:"corrigendum-to-a-hybrid-control-approach-based-on-the-combination-of-pid-control-with-lqr-optimal-co",title:"Corrigendum to: A Hybrid Control Approach Based on the Combination of PID Control with LQR Optimal Control",doi:null,correctionPDFUrl:"https://cdn.intechopen.com/pdfs/74918.pdf",downloadPdfUrl:"/chapter/pdf-download/74918",previewPdfUrl:"/chapter/pdf-preview/74918",totalDownloads:null,totalCrossrefCites:null,bibtexUrl:"/chapter/bibtex/74918",risUrl:"/chapter/ris/74918",chapter:{id:"74293",slug:"a-hybrid-control-approach-based-on-the-combination-of-pid-control-with-lqr-optimal-control",signatures:"Ibrahim K. Mohammed",dateSubmitted:"July 8th 2020",dateReviewed:"November 4th 2020",datePrePublished:"December 3rd 2020",datePublished:null,book:{id:"9887",title:"Advance Innovation and Expansion of PID Controllers",subtitle:null,fullTitle:"Advance Innovation and Expansion of PID Controllers",slug:null,publishedDate:null,bookSignature:"Prof. Wei Wang",coverURL:"https://cdn.intechopen.com/books/images_new/9887.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"101176",title:"Prof.",name:"Wei",middleName:null,surname:"Wang",slug:"wei-wang",fullName:"Wei Wang"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null}},chapter:{id:"74293",slug:"a-hybrid-control-approach-based-on-the-combination-of-pid-control-with-lqr-optimal-control",signatures:"Ibrahim K. Mohammed",dateSubmitted:"July 8th 2020",dateReviewed:"November 4th 2020",datePrePublished:"December 3rd 2020",datePublished:null,book:{id:"9887",title:"Advance Innovation and Expansion of PID Controllers",subtitle:null,fullTitle:"Advance Innovation and Expansion of PID Controllers",slug:null,publishedDate:null,bookSignature:"Prof. Wei Wang",coverURL:"https://cdn.intechopen.com/books/images_new/9887.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"101176",title:"Prof.",name:"Wei",middleName:null,surname:"Wang",slug:"wei-wang",fullName:"Wei Wang"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null},book:{id:"9887",title:"Advance Innovation and Expansion of PID Controllers",subtitle:null,fullTitle:"Advance Innovation and Expansion of PID Controllers",slug:null,publishedDate:null,bookSignature:"Prof. Wei Wang",coverURL:"https://cdn.intechopen.com/books/images_new/9887.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"101176",title:"Prof.",name:"Wei",middleName:null,surname:"Wang",slug:"wei-wang",fullName:"Wei Wang"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"10799",leadTitle:null,title:"Phenolic Compounds",subtitle:null,reviewType:"peer-reviewed",abstract:"\r\n\tThis book intends to provide the up-to-date information on the naturally occurring phenolic compounds. The book will cover practical and applied evidence based data extracted from thousands in vitro, in vivo, preclinical, and clinical scientific research to provide the interested scientists as well as the community with a highly reliable source for many challenging health issues including COVID-19, degenerative diseases, and chronic complex health problems. Interestingly, this book may open a new horizon for developing new therapeutic agents from natural phenolic compounds with multi-target purposes.
\r\n\r\n\tThis book will present clear and applied unambiguous data to be implemented in academia, the drug industry, nutraceuticals and the food industry. New highly reliable methodologies will be presented with full data to help reproduce the outcomes in all applied fields with a high degree of accuracy and reproducibility.
\r\n\r\n\tThis book aims to be a great asset to many interested scientists including young and senior researchers, nutraceutical, pharmaceutical, and drug industry as well as clinicians.
",isbn:"978-1-83969-347-2",printIsbn:"978-1-83969-346-5",pdfIsbn:"978-1-83969-348-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"339199f254d2987ef3167eef74fb8a38",bookSignature:"Prof. Farid A. Badria",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10799.jpg",keywords:"Dietary Intake, Bioavailability, Bioactivity, Pharmacokinetics, Food, Medicinal Plants, Nutraceuticals, Multitarget Drugs, Chronic Diseases, Health, Phytoestrogen, Therapeutic Applications",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 1st 2021",dateEndSecondStepPublish:"March 29th 2021",dateEndThirdStepPublish:"May 28th 2021",dateEndFourthStepPublish:"August 16th 2021",dateEndFifthStepPublish:"October 15th 2021",remainingDaysToSecondStep:"25 days",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"A pioneering researcher in drug discovery, developing new therapies for liver disease, skin disorders, and cancer. Appointed head of liver research lab and holder of 20 patents over 10 marketed pharmaceutical products.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.png",biography:"Professor Farid Badria, Ph.D., MSc, is the recipient of several awards including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; World Intellectual Property Organization (WIPO) Gold Medal for Best Inventor; State Recognition Outstanding Award in Medicine (Egyptian Academy of Science); Outstanding Arab Scholar, Kuwait; and Khawrazmi International Award, Iran. He is also a scholar of the Arab Development Fund, Kuwait; International Cell Research Organization (ICRO)-United Nations Educational, Scientific and Cultural Organization (UNESCO) International, Chile; and UNESCO Biotechnology France.\nDr. Badria has 20 patents, 250 publications, more than a dozen books, several marketed pharmaceutical products, and many plenary lectures and workshops to his credit. He continues to lead research projects on developing new therapies for liver disease, skin disorders, and cancer.",institutionString:"Mansoura University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"6",institution:{name:"Mansoura University",institutionURL:null,country:{name:"Egypt"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"6",title:"Biochemistry, Genetics and Molecular Biology",slug:"biochemistry-genetics-and-molecular-biology"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"247041",firstName:"Dolores",lastName:"Kuzelj",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/247041/images/7108_n.jpg",email:"dolores@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"5767",title:"Natural Products and Cancer Drug Discovery",subtitle:null,isOpenForSubmission:!1,hash:"6d12d5b2fe98bfc2a6411f1b26d8f028",slug:"natural-products-and-cancer-drug-discovery",bookSignature:"Farid A. Badria",coverURL:"https://cdn.intechopen.com/books/images_new/5767.jpg",editedByType:"Edited by",editors:[{id:"41865",title:"Prof.",name:"Farid A.",surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7258",title:"Resveratrol",subtitle:"Adding Life to Years, Not Adding Years to Life",isOpenForSubmission:!1,hash:"b02655d4c4df83b50688fa1a22661d49",slug:"resveratrol-adding-life-to-years-not-adding-years-to-life",bookSignature:"Farid A. Badria",coverURL:"https://cdn.intechopen.com/books/images_new/7258.jpg",editedByType:"Edited by",editors:[{id:"41865",title:"Prof.",name:"Farid A.",surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1516",title:"Pharmacotherapy",subtitle:null,isOpenForSubmission:!1,hash:"5913f56353d16d5484d5a0955843db96",slug:"pharmacotherapy",bookSignature:"Farid Badria",coverURL:"https://cdn.intechopen.com/books/images_new/1516.jpg",editedByType:"Edited by",editors:[{id:"41865",title:"Prof.",name:"Farid A.",surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4500",title:"Evidence-based Strategies in Herbal Medicine, Psychiatric Disorders and Emergency Medicine",subtitle:null,isOpenForSubmission:!1,hash:"de20dd738d0349edc3d0a22274f09cc8",slug:"evidence-based-strategies-in-herbal-medicine-psychiatric-disorders-and-emergency-medicine",bookSignature:"Farid A. Badria",coverURL:"https://cdn.intechopen.com/books/images_new/4500.jpg",editedByType:"Edited by",editors:[{id:"41865",title:"Prof.",name:"Farid A.",surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9086",title:"Drug Repurposing",subtitle:"Hypothesis, Molecular Aspects and Therapeutic Applications",isOpenForSubmission:!1,hash:"5b13e06123db7a16dcdae682eb47ac66",slug:"drug-repurposing-hypothesis-molecular-aspects-and-therapeutic-applications",bookSignature:"Farid A. Badria",coverURL:"https://cdn.intechopen.com/books/images_new/9086.jpg",editedByType:"Edited by",editors:[{id:"41865",title:"Prof.",name:"Farid A.",surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8028",title:"Flavonoids",subtitle:"A Coloring Model for Cheering up Life",isOpenForSubmission:!1,hash:"6c33178a5c7d2b276d2c6af4255def64",slug:"flavonoids-a-coloring-model-for-cheering-up-life",bookSignature:"Farid A. Badria and Anthony Ananga",coverURL:"https://cdn.intechopen.com/books/images_new/8028.jpg",editedByType:"Edited by",editors:[{id:"41865",title:"Prof.",name:"Farid A.",surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6694",title:"New Trends in Ion Exchange Studies",subtitle:null,isOpenForSubmission:!1,hash:"3de8c8b090fd8faa7c11ec5b387c486a",slug:"new-trends-in-ion-exchange-studies",bookSignature:"Selcan Karakuş",coverURL:"https://cdn.intechopen.com/books/images_new/6694.jpg",editedByType:"Edited by",editors:[{id:"206110",title:"Dr.",name:"Selcan",surname:"Karakuş",slug:"selcan-karakus",fullName:"Selcan Karakuş"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"24161",title:"Beta-Cell Function and Failure in Type 1 Diabetes",doi:"10.5772/22089",slug:"beta-cell-function-and-failure-in-type-1-diabetes",body:'\n\t\tGlucose is an essential energy source for all cells. Therefore, maintaining glucose levels within a normal range is essential for life in vertebrates. Glucose homeostasis in the organism is tightly regulated by insulin, a hormone that acts on the major glucose metabolic tissues such as muscle, liver and adipose tissue. Insulin’s main effects include promoting glucose uptake, glycogen synthesis in the liver and muscle, triglyceride formation to be stored in adipocytes, and protein synthesis. Insulin secretion is held by the pancreatic beta-cells, and it is modulated by glucose levels. Insufficient insulin secretion and consequent impairment of insulin’s actions lead to Diabetes Mellitus.
\n\t\t\tDiabetes is a group of metabolic diseases characterized by hyperglycemia, caused by a defect on insulin production, insulin action or both. Type 1 diabetes in particular is due to an autoimmune destruction of the insulin producing pancreatic beta-cell, which usually leads to absolute insulin deficiency (ADA 2009). This type of diabetes accounts for 5-10% of the total cases of diabetes worldwide, and although its onset is commonly during childhood and adolescence, it can occur at any age, even during late adulthood.
\n\t\t\tAs the loss of beta-cells is determinant for the development of overt type 1 diabetes, understanding beta-cell’s normal physiology, namely insulin secretion, and how it may be affected during the progression of this disease is essential. Moreover, the development of new therapeutic interventions for type 1 diabetes, such as islet transplantation, beta cell maintenance and replacement, or stem cell therapy, requires a profound knowledge of how the presence of different nutrients and signals may regulate insulin secretion and beta-cell mass.
\n\t\t\tIn this chapter we aim to review the mechanisms involved in normal beta-cell function and beta-cell mass regulation, and how this function may be modulated by glucose, nutrients and signals in the beta-cell milieu. We also review how these mechanisms may be affected by the onset and progression of type 1 diabetes.
\n\t\tThe pancreas is an endocrine and exocrine gland. The exocrine portion corresponds to acinar tissue, responsible for secreting digestive enzymes into the pancreatic juice, while the endocrine portion comprises the pancreatic islets, which consist of several cell types secreting different hormones: -cells (insulin), -cells (glucagon), -cells (somatostatin), PP-cells (pancreatic polypeptide) and -cells (ghrelin). The endocrine pancreas represents 1% to 5% of the total pancreatic mass (Kim, S.K. & Hebrok, M. 2001). In the islet, beta-cells (-cells) are approximately 70% to 80% of the total islet cells.
\n\t\t\tBeta-cells are responsible for secreting insulin in response to rises in blood nutrient levels during the postprandial state. Glucose is the most important nutrient for insulin secretion. The process by which glucose promotes insulin secretion requires its sensing and metabolism by the beta-cell, a process called glucose-stimulated insulin secretion.
\n\t\t\tGlucose-stimulated insulin secretion is biphasic and pulsatile (Stagner, J.I. et al. 1980). The secretory pulses of beta-cells are associated with synchronous Ca2+ oscillations in response to glucose stimulus (Bergsten, P. et al. 1994), and they have been suggested to be coupled to glycolysis oscillations of the beta cell (Kar, S. & Shankar Ray, D. 2005). Secretory pulses are also regulated and synchronized within the other islet cell types. Insulin and glucagon secretion show asynchronous patterns (Grapengiesser, E. et al. 2006, Stagner, J.I. et al. 1980), whereas somatostatin pulses are synchronized with insulin secretion (Stagner, J.I. et al. 1980).
\n\t\t\t\tGlucose-stimulated insulin secretion also shows a biphasic pattern. Shortly after glucose stimulus, a first burst of insulin secretion occurs, followed by a decrease in the rate of secretion. A second sustained phase of insulin secretion can be observed just after this decrease, which can continue for up to several hours until euglycemia is achieved (Curry, D.L. et al. 1968) (Figure 1).
\n\t\t\t\tAlthough the mechanisms involved in the first phase of insulin secretion (termed the triggering pathway) are well understood, mechanisms regulating the sustained second phase (or the amplifying pathway) are yet to be deciphered, and different players that account for it have been proposed (Henquin, J.C. 2009). Notably, most of them are related to glucose metabolism inside the beta-cell.
\n\t\t\t\tThe first phase of glucose-stimulated insulin secretion is a multistep process that requires transport and oxidation of glucose, electrophysiological changes and fusion of insulin-containing secretory granules with the beta-cell plasma membrane (Figure 1). Glucose enters the cell by facilitated diffusion mediated by glucose transporters (GLUT2 in rodents, GLUT1 in humans). Glucose is then phosphorylated to form glucose-6-phosphate by glucokinase. This enzyme plays a critical role in glucose-stimulated insulin secretion and is considered the glucosensor of the pancreatic beta cell. Due to its kinetic characteristics, glucokinase is a determining factor for glucose phosphorylation (Matschinsky, F.M. 1996) and hence for its metabolism through glycolysis and oxidation.
\n\t\t\t\t\tThe generation of ATP by glycolysis, the Krebs cycle and the respiratory chain leads to closure of the ATP-sensitive K+ channel (KATP), a hetero-octamer comprised of four subunits of the sulphonylurea 1 receptor (SUR1) and four subunits of the inwardly rectifying K+ channel Kir6.2 (Aguilar-Bryan, L. et al. 1998). The closure of KATP channels, permit the background sodium (Na+) entry without balance. These two events depolarize the membrane to a range that allows the opening of voltage-dependent T-type calcium (Ca2+) and sodium (Na+) channels. Na+ and Ca2+ entry further depolarizes the membrane and L-type and maybe other voltage-dependent calcium channels (VDCC) open. Their activation triggers action potentials that increase in intracellular Ca2+ ([Ca2+]i) (Hiriart, M. & Aguilar-Bryan, L. 2008). Together with calcium mobilized from intracellular stores, this Ca2+ increase leads to fusion of insulin-containing secretory granules with the plasma membrane and the release of insulin into the circulation (Rorsman, P. & Renstrom, E. 2003). Following glucose metabolism, the rate-limiting-step for the first phase lies in the rate of signal transduction between sensing the rise in [Ca2+]i and exocytosis of the immediately releasable granules (Straub, S.G. & Sharp, G.W. 2002).
\n\t\t\t\tThe existence of a second phase of insulin secretion was first reported in the 1960s. Curry et. al.(Curry, D.L. et al. 1968) observed that, in total pancreas perfusion with glucose, insulin release showed an early and rapid increase at 2 min after glucose infusion, peaking at 4 min. A second or “slow” phase, characterized by an increasing rate of insulin secretion was sustained during the whole period of glucose infusion. On the other hand, when the pancreas was perfused with tolbutamide, a sulfonylurea that blocks the potassium channels, only the first rapid release peak was observed, suggesting this biphasic insulin secretion is only generated in glucose-stimulated insulin secretion (Curry, D.L. et al. 1968). It was until the 1990s that evidence of mechanisms for glucose-stimulated insulin secretion independent of ionic action (i.e. KATP potassium channel activation) was found (Aizawa, T. et al. 1998, Gembal, M. et al. 1992). Since then, the concept of a rapid first phase glucose-stimulated insulin secretion, caused by a triggering pathway (or KATP-dependent mechanism), followed by a sustained second phase due to an amplifying pathway (or KATP-independent mechanism) has developed (Aizawa, T. et al. 2002, Henquin, J.C. 2000).
\n\t\t\t\t\tBiphasic insulin secretion has been explained by the existence of different pools of insulin-containing granules inside the beta cell (Aizawa, T. & Komatsu, M. 2005, Straub, S.G. & Sharp, G.W. 2004). There is a reserve pool of granules located in the cytoplasm which accounts for approximately 94% of the total granules, and a releasable pool of granules which are docked to the plasma membrane. It has been suggested that the docked granules have different ability to be released and therefore constitute two subsets, the readily releasable pool, and the immediately releasable pool. The granules from the immediately releasable pool are the first to be secreted in response to intracellular Ca2+ increase during the triggering pathway, leading to the first phase of insulin secretion. At the lowest point of secretion in between the two phases, the granules from the readily releasable pool are converted to the immediately releasable pool, an ATP-dependent process termed “priming”. This priming has been suggested to be the rate-limiting step for exocytosis, and the target process for signals involved in the amplifying pathway that leads to the sustained second phase of insulin secretion (Straub, S.G. & Sharp, G.W. 2004) (Figure 1). Given the glucose-stimulated nature of biphasic insulin secretion and the ATP-dependence of priming, most of these signals are proposed to be derived from glucose metabolism. Some of these signals are reviewed in the next section.
\n\t\t\t\tTranscription factors in the beta-cell act in a cooperative manner, forming transcriptional networks, to induce not only insulin expression, but also the expression of other genes
\n\t\t\t\tMechanism of biphasic glucose-stimulated insulin secretion. Glucose enters the cell by glucose transporters (GLUT2 in rodents, GLUT1 in humans) and is then phosphorylated for its metabolism through glycolysis and oxidation. The generation of ATP by glycolysis, the Krebs cycle and the respiratory chain closes the ATP-sensitive K+ channel (KATP), allowing sodium (Na+) entry without balance. These two events depolarizethe membrane and open voltage-dependent T-type calcium (Ca2+) and sodium (Na+) channels. Na+ and Ca2+ entry further depolarizes the membrane and L-type and maybe other voltage-dependent calcium channels (VDCC) open. This activation increases intracellular Ca2+ ([Ca2+]i), which leads to fusion of insulin-containing secretory granules with the plasma membrane and the first phase insulin secretion. A sustained second phase of insulin secretion is held when the granules from the readily releasable pool are converted to the immediately releasable pool, an ATP-dependent process termed “priming”. Most of the signals involved in this process also come from glucose mitochondrial metabolism, comprising the amplifying pathways.
involved in insulin gene regulation and insulin secretion, thus establishing and maintaining beta-cell’s phenotype and function (Lazo-de-la-Vega-Monroy, M.L. & Fernandez-Mejia, C. 2009). Some of these factors include PDX-1, HNF4α, MAFA, FOXA2 and NeuroD1 (Lazo-de-la-Vega-Monroy, M.L. & Fernandez-Mejia, C. 2009).
\n\t\t\t\tPDX-1 is one of the most important transcription factors regulating the insulin gene transcription. This factor is determinant for pancreatic function. -cell-specific knockout studies show that when
PDX1 decrease has also been associated with apoptosis and reduced expression of the anti-apoptotic genes BclXL and Bcl-2 (Johnson, J.D. et al. 2006), defects in post-translational processing of insulin, inhibition of GLP-1 receptor expression (Wang, H. et al. 2005), glucotoxicity (Olson, L.K. et al. 1993) and lipotoxicity (Gremlich, S. et al. 1997, Hagman, D.K. et al. 2005).
\n\t\t\tAs noted earlier, an ATP/ADP ratio increase caused by glucose metabolism in the beta-cells is the mechanism by which the first phase of glucose-stimulated insulin secretion is triggered. However, glucose metabolism can also render a series of signals, or metabolic coupling factors, that may initiate and sustain the second phase of insulin secretion, presumably by favoring mobilization of the insulin granules form the reserve pool and the replenishment of the immediately releasable pool of insulin granules. Some of these metabolic coupling factors participate in mitochondrial shuttles, involving NADPH, pyruvate, malate, citrate, isocitrate, acyl-CoAs, and glutamate (Jitrapakdee, S. et.al. 2010). There are also various signaling pathways that, when activated, may contribute to maintaining or increasing glucose-stimulated insulin secretion, including the CaMKII (Calcium-Calmodulin-Dependent Protein Kinase II), PKA (Protein Kinase A), PKC (Protein Kinase C) and PKG (Protein kinase G) pathways. Notably, most of other insulin secretagogues, namely nutrients, hormones and neurotransmitters, also modulate insulin secretion by these pathways.
\n\t\t\t\tThe role of mitochondria in the second phase of glucose-induced insulin secretion has been established by several studies in cell lines and humans (Jitrapakdee, S. et.al. 2010; Maechler, P. & Wollheim, C.B. 2001). There is even evidence of an uncommon subform of diabetes, mitochondrial diabetes, where mutations in mitochondrial DNA causepancreatic beta-cell dysfunction (Maechler, P. & Wollheim, C.B. 2001).
\n\t\t\t\t\tBesides rendering the initial increase of ATP/ADP ratio, mitochondrial metabolism and anaplerotic metabolites are also involved in sustaining second phase insulin secretion. Pyruvate, the end product of glycolysis, plays an important role in this process, as it participates in several cycles whose final products constitute amplifying signals for insulin secretion. Particularly, NADPH, GTP, Malonyl-CoA, long-chain acyl-CoA, and glutamate have been suggested to sustain insulin secretion, although the exact mechanisms by which they have their effects remain to be elucidated (Jitrapakdee, S. et.al. 2010).
\n\t\t\t\t\tOnce entering the mitochondria, pyruvate may be either converted to Acetyl-CoA by pyruvate dehydrogenase, or carboxylated to oxalacetate by pyruvate carboxylase, and therefore enter the Krebs cycle (Figure 2). Notably, there is a high expression of pyruvate carboxylase in the pancreatic islets comparable to that in gluconeogenic tissues, but islets lack phosphoenolpyruvate carboxykinase (PEPCK), the first enzyme in the glyconeogenic pathway (MacDonald, M.J. 1995). Moreover, several studies have correlated pyruvate carboxylation with insulin secretion (Han, J. & Liu, Y.Q., Hasan, N.M. et al. 2008, Lu, D. et al. 2002, Xu, J. et al. 2008).
\n\t\t\t\t\tOxalacetate from pyruvate carboxylation may be converted to malate, exit the mitochondria, and re-converted to pyruvate, producing NADPH (Pyruvate/malate cycle). Oxalacetate may also condense with acetyl-CoA to form citrate, which either continues in the TCA cycle, or exits the mitochondria, and converts again to oxalacetate and acetyl-CoA by the ATP-citrate lyase (pyruvate/citrate cycle). Oxalacetate may re-enter the pyruvate/malate cycle which will produce NADPH, while acetyl-CoA is carboxylated by Acetyl-CoA carboxylase and form malonyl-CoA, the initial step of fatty acid synthesis (Jitrapakdee, S. et.al. 2010). As the pancreatic islet is not a lipogenic tissue, the fact that acetyl-CoA activity is high in this tissue may indicate that malonyl-CoA can also act as a metabolic coupling factor for insulin secretion (Prentki, M. et al. 1992).
\n\t\t\t\t\tMetabolites from the Krebs cycle can also exit the mitochondria and enter other cycles. Isocitrate, for example, is converted to α-ketoglutarate by the NADP-dependent isocitrate dehydrogenase, rendering NADPH. α-ketoglutarate may re-enter the mitochondria to continue in the TCA cycle, or can be converted to glutamate by the glutamate dehydrogenase (GDH). Glutamate has been suggested to be another metabolic coupling factor for insulin secretion, possibly by entering insulin secretory granules and promoting exocytosis (Maechler, P. & Wollheim, C.B. 1999).
\n\t\t\t\t\tFinally, GTP may be produced by an isoform of the succinyl-CoA synthetase, which catalyzes the conversion of succinyl-CoA to succinate in the TCA cycle. It has been suggested that GTP participates in insulin secretion. In beta-cells, suppression of GTP production by this pathway reduced glucose-induced insulin secretion, independently of changes in NADPH or the ATP/ADP ratio (Kibbey, R.G. et al. 2007).
\n\t\t\t\tAs noted earlier, glucose-stimulated insulin secretion is a Ca2+-mediated process. The increase of cytosolic calcium inside the beta-cell must be sensed and transduced in order to exert a secretory response. One of the candidate proteins involved in this transducing system is CaMK II. CaMK II activation has been correlated with glucose-stimulated insulin secretion. Besides being localized at the insulin secretory granules, CaMKII phosphorylates proteins involved in the secretory machinery, including synapsin I (Matsumoto, K. et al. 1995), MAP-2 (microtubule-associated protein 2) (Krueger, K.A. et al. 1997), VAMP/synaptobrevin(Nielander, H.B. et al. 1995) and others. Insulin release is then suggested to be modulated by CaMK II by mobilizing the secretory granules toward the cell membrane by MAP-2 phosphorylation and by potentially regulating the docking or priming mechanisms via VAMP and synapsin I protein phosphorylation. Since CaM kinase II remains active after glucose stimulation, it is suggested as a mechanism of readily releasable pool replenishment. (Easom, R.A. 1999).
\n\t\t\t\tThe guanyl-nucleotide-binding (GTP) protein system or G-protein coupled system plays an important role on insulin secretion. In the beta-cells, two G-protein regulated pathways, the Adenylate cyclase (AC)/PKA, and the phospholipase C (PLC)/PKC pathways, modulate
\n\t\t\t\t\tRegulation of glucose-stimulated insulin secretion by nutrients, hormones and neurotransmitters. Glucose-stimulated insulin secretion may be modulated by several mechanisms. Glucose metabolism increase ATP/ADP ratio and closes ATP-sensitive pottasium channels (KATP), depolarizing the membrane, opening voltage-dependent calcium channels (VDCC), and thus increasing intracellular calcium ([Ca2+]i). Glucose metabolism by the Krebs Cycle also renders a series of metabolic coupling factors that may initiate and sustain insulin secretion. These metabolic coupling factors participate in mitochondrial shuttles, involving NADPH, pyruvate, malate, citrate, isocitrate, acyl-CoAs, and glutamate. Signaling pathways that contribute to maintaining or increasing glucose-stimulated insulin secretion include PKA and PKC. Glucagon, glucagon-Like peptide 1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP) act through PKA pathway, while acetylcholine and cholecystokinine act through the PKC pathway. Fatty acids may contribute to insulin secretion through the PKC pathway through formation of diacylglycerol (DAG) or through protein acylation. Aminoacids may stimulate insulin release by increasing ATP production from the Krebs Cycle, by membrane depolarization, or by participating in intracellular calcium increase. (αKG: alpha-ketoglutarate, ACC: Acetyl CoA Carboxylase, FAS: Fatty Acid Synthase, GDH: Glutamate Dehydrogenase, GTP-SCS: GTP-Succinyl CoA Synthetase, ER: endoplasmic Reticulum, ME: Malic enzyme, MDH: Malate Dehydrogenase, PC: Pyruvate Carboxylase, PHD: Pyruvate Dehydrogenase, PIP2: Phosphatidyl Inositol Biphosphante, IP3:inositol 1,4,5-trisphosphate ).
insulin secretion in response to nutrients and other peripheral signals (Doyle, M.E. & Egan, J.M. 2003). Depending on the type of Gα subunit present, these signals will activate or inhibit Adenylate Cyclase (Gαs and Gαi subunits respectively). Gαq subunits are associated with the phosphatidyl inositol system (Gomperts, B.D. et al. 2003).
\n\t\t\t\t\tWhen the Adenylate Cyclase is activated in the beta-cell, it converts ATP in cyclic AMP (cAMP), which in turn can activate the cAMP-dependent protein kinase (PKA) and the Rap guanine nucleotide exchange factor (GEF) 4 or Epac2. PKA will phosphorylate several proteins, including L-type voltage-dependent calcium channels and proteins from the exocytotic machinery, increasing sustained insulin secretion (Ammala, C. et al. 1993). Epac2 has been shown to favor insulin secretion by increasing the size of the reserve pool and facilitating the recruitment of the granules to the plasma membrane (Shibasaki, T. et al. 2007), mediating pulsatility of insulin secretion (Idevall-Hagren, O. et al. 2010), and binding to the SUR1 subunit of the KATP channels (Zhang, C.L. et al. 2009). The insulin gene itself has cAMP response elements in its promoter that modulate insulin transcription in response to this nucleotide (Melloul, D. et al. 2002).
\n\t\t\t\t\tTherefore, ligands that increase the activity of adenylate cyclase and cAMP have a positive effect on insulin synthesis and secretion (Sharp, G.W. 1979), while ligands that decrease adenylate cyclase activity affect insulin secretion in a negative way (Jones, P.M. & Persaud, S.J. 1998). Hormones and neurotransmitters mostly act on insulin secretion by this pathway (see below).
\n\t\t\t\t\tPhospholipase C (PLC) is the other effector protein regulated by G-protein coupled receptors in the beta-cell. PLC activation cleaves phosphoinositides into two second messengers, inositol 1,4,5-trisphosphate (IP3), involved in Ca2+ release from the endoplasmic reticulum, and diacylglycerol (DAG). DAG is involved in the activation of the Protein kinase C (PKC). PKC phosphorylates the KATP channels and the voltage-dependent Ca2+ channels and mobilize the secretory vesicles (Doyle, M.E. & Egan, J.M. 2003), therefore promoting insulin secretion. Both nutrients and neurotransmitters may act through PKC activation, albeit by different mechanisms. It has been proposed that nutrients may activate atypical isoforms of PKC (-ζ, -ι, and –μ) by a non-identified mechanism independent of DAG, while the typical isoforms (-α, -β, -δ, and -ϵ) of PKC (Protein Kinase C) are activated by DAG (Jones, P.M. & Persaud, S.J. 1998).
\n\t\t\t\tThe cyclic GMP (cGMP)pathway is regulated basically by two factors: calcium and protein kinase G (PKG). Calcium increases the activity of calcium-dependent nitric oxide synthases, a key step in the synthesis of cGMP by soluble guanylyl cyclase(cGC). Calcium may also decrease cGMP synthesis by activating a calcium-dependent phosphodiesterase (PDE1). On the other hand, protein kinase G (PKG), an enzyme activated by cGMP, may phoshporylate different targets and modulate intracellular calcium concentration, primarily closing KATP channels (Soria, B. et al. 2004).
\n\t\t\t\t\tAlthough several studies have pointed to a role of sGC and cGMP on insulin secretion (Laychock, S.G. et al. 1991; Russell, M.A. & Morgan, N. 2010), a precise mechanism of action has not been yet elucidated for this pathway. As phosphorylation of PKG has been identified in rat islets (Jones, P.M. & Persaud, S.J. 1998), this is likely the enzyme mediating cGMP actions on insulin secretion. It has also been shown that PKG activity is necessary to increase ATP content in response to cGMP (Vilches-Flores, A. et al. 2009), and that glucose produces small increases in islet cGMP content (Laychock, S.G. et al. 1991, Schmidt, H.H. et al. 1992).
\n\t\t\t\tBeta-cells may be considered fuel sensors, as they are continually monitoring and responding to nutrient concentration in the circulation in order to secrete insulin and therefore, regulate glucose homeostasis. Given that meals are composed by multiple nutrients, it is important to examine the interplay between glucose-sensing in the beta-cell and other dietary nutrients, such as amino acids, fatty acids and vitamins. Cumulatively, the mixed nutrient sensing generates the metabolic coupling factors working as signals for insulin exocytosis.
\n\t\t\tWhile it would appear that free fatty acids do not stimulate insulin secretion in the absence of glucose, there is a substantial body of evidence that they are essential for glucose-stimulated insulin secretion (Salehi, A. et al. 2005). It has been proposed that, in the presence of glucose, fatty acid oxidation is inhibited, due to formation of malonyl-CoA by acetyl-CoA carboxylase. This permits the accumulation of long-chain acyl-CoA in the cytosol that then stimulate insulin secretion directly or through the formation of other lipid compounds such as diacylglycerol and various phospholipids (Nolan, C.J. et al. 2006). The mechanisms which could be involved in this process are(Yaney, G.C. & Corkey, B.E. 2003): a) activation of protein kinase-C enzymes; b) enhancedfusion of insulin-secretory vesicles with plasma membrane and insulin release; c) modulation of KATP channel activity directly or via complex lipid formation; d) Stimulation of Ca2+-ATPases; e) Protein acylation of GTP-binding proteins; f) Inhibition of lipase activity.
\n\t\t\t\tThe effects of fatty acids on glucose-stimulated insulin secretion are directly correlated with chain length and the degree of unsaturation, where long-chain fatty acids (such as palmitate or linoleate) acutely improve insulin release, however, chronic increase of long-chain fatty acids reduce insulin release in response to glucose stimulation (Newsholme, P. et al. 2007b).
\n\t\t\tIn addition to fatty acid involvement in glucose-stimulated insulin secretion, amino acids derived from dietary proteins and those released from intestinal epithelial cells, in combination with glucose; stimulate insulin secretion,
Glutamine and alanine are quantitatively the most abundant amino acids in blood and extracellular fluids and therefore might be the most relevant to insulin secretion (Newsholme, P. et al. 2010). Alanine increase ATP production in islet beta-cells, an event that has potential to promote the K+ATP channel triggering pathway. Alanine is also one of the electrogenic amino acids, being co-transported with Na+ so that its import depolarizes the plasma membrane and promotes Ca2+ influx, events that trigger insulin secretion (McClenaghan, N.H. et al. 1998). Although glutamine is rapidly transported and metabolized by islets, it does not promote insulin secretion by itself or enhance glucose-stimulated insulin secretion, but can elicit insulin release in the presence of leucine (Newsholme, P. et al. 2007a). It is believed that this is because leucine activates glutamic dehydrogenase, which then increases the capacity of glutamine to contribute to anaplerosis via alpha-ketoglutarate (Newsholme, P. et al. 2007a).
\n\t\t\t\tSimilarly as glucose-stimulated insulin release, leucine acts by generating ATP thought its metabolism, thus causing closure of ATP-sensitive potassium channels, membrane depolarization via opening of the L-voltage-dependent calcium channels, leading to calcium influx and increased cytoplasmic calcium concentrations. Furthermore, leucine acutely stimulates insulin secretion by serving as both metabolic fuel and allosteric activator of glutamate dehydrogenase, resulting in conversion of glutamate to 2-ketoglutarate, a compound that has been proposedto be a common mediator of glucose, amino acid, and organic acid insulin secretion (Odegaard, M.L. et al. 2010). Additionally, transamination of leucine to α-ketoisocaproate and entry into TCA cycle via acetyl-CoA can contribute to ATP generation by increasing the oxidation rate of the amino acid and thus stimulation of insulin secretion.
\n\t\t\t\tOther amino acids also stimulate insulin secretion by elevating cytosolic calcium concentration, although their mechanisms are achieved independently of ATP generation. Positive charged amino acids such as arginine, lysine and histidine, elicit insulin secretion by beta-cell inward transport of positive charge, triggering depolarization of cytoplasm membrane, and influx of extracellular calcium (Newsholme, P. et al. 2010).
\n\t\t\tVitamin A is found in the organism either as retinol, retinal or retinoic acid forms. Retinoic acid is the active form, and the majority of its effects involve the activation of ligand-dependent transcription factors from the superfamily of hormonal nuclear receptors. Two of these receptors are known: the retinoic acid receptors (RARs) and the rexinoid receptors (RXRs). These can bind as heterodimers to specific DNA sequences named Retinoic Acid Response Elements, (RAREs) in the promoters of their target genes, or interact with other receptors such as Vitamin D receptors (VDRs), thyroid hormone receptors and PPARs (Peroxisome Proliferation Activating Receptors).
\n\t\t\t\t\tRetinol is essential for insulin secretion (Chertow, B.S. et al. 1987) and retinoic acid increases insulin secretion in cultured islets (Cabrera-Valladares, G. et al. 1999), presumably by its stimulatory effect on pancreatic glucokinase expression and activity (Cabrera-Valladares, G. et al. 1999). Retinoic acid is also capable of increasing insulin (Cabrera-Valladares, G. et al. 1999) and GLUT2 mRNA (Blumentrath, J. et al. 2001).
\n\t\t\t\tVitamin D is syntethized under the skin thanks to exposure to UVB radiation. It can also be obtained from food in the form of ergocalcipherol (vitamin D2) or cholechalcipherol (vitamin D3). When UVB radiation is absorbed through the skin, 7-dehydrocholesterol reserves form the pre-vitamin D3, which is transformed into vitamin D3 (1,25(OH2)D3 ) in a further process, by the action of the 25(OH2)D3 hydroxylase (Holick, M.F. 2003). Vitamin D acts on Vitamin D receptors (VDRs), which are either in the nucleus or in the membrane, rendering two different mechanisms of action, genomic, and non-genomic (rapid response) (Norman, A.W. et al. 2001)
\n\t\t\t\t\tBoth VDRs (Johnson, J.A. et al. 1994) and 25(OH2)D3 hydroxylase are expressed in the pancreatic beta-cells (Bland, R. et al. 2004), suggesting there may be vitamin D synthesis and effects in these cells. In vitro, 1,25(OH2)Dinduces the biosynthesis of insulin in rat beta-cells (Bourlon, P.M. et al. 1999). It has been suggested that increases in cytosolic Ca2+, a non-genomic effect of vitamin D, can increase insulin secretion (Norman, A.W. 2006). This increase may be modulated by activation of the PKC (Billaudel, B.J. et al. 1995) and PKA (Bourlon, P.M. et al. 1997) signaling pathways (d\'Emden, M.C. et al. 1989).
\n\t\t\t\tBiotin is a water-soluble vitamin that acts as a prosthetic group of carboxylases. Unrelated to this classic role, pharmacological concentrations of biotin regulate gene expression at both the transcriptional and the translational level (Rodriguez-Melendez, R. & Zempleni, J. 2003, Zempleni, J. 2005), and have a wide repertoire of effects on systemic processes such as development (Watanabe, T. 1996), reproduction (Baez-Saldana, A. et al. 2009, Paul, P.K. & Duttagupta, P.N. 1976, Simmins, P.H. & Brooks, P.H. 1983), and metabolism (Dakshinamurti, K. 2005, Fernandez-Mejia, C. 2005).
\n\t\t\t\t\tBiotin exerts beneficial effects on endocrine pancreas physiology. We have found that biotin stimulates insulin and pancreatic glucokinase expression(Romero-Navarro, G. et al. 1999), an enzyme that plays an important role in glucose homeostasis regulating insulin secretion in response to changes in blood glucose concentrations. Our group found that biotin concentrations of 10 to 1000 nM augmented glucokinase activity and mRNA abundance in cultured rat pancreatic islets (Romero-Navarro, G. et al. 1999). A similar stimulatory effect on pancreatic glucokinase was observed in the insulinoma RIN 1046-38 cell line (Borboni, P. et al. 1996). A positive effect of biotin on insulin secretion has been reported (Romero-Navarro, G. et al. 1999, Sone, H. et al. 2000, Sone, H. et al. 1999, Vilches-Flores, A. et al. 2009). Studies by our group (Romero-Navarro, G. et al. 1999, Vilches-Flores, A. et al. 2009) and others (Sone, H. et al. 2000, Sone, H. et al. 1999) have revealed that glucose-stimulated insulin secretion increases in response to acute exposure to pharmacological doses of biotin in either primary cultured islets (Romero-Navarro, G. et al. 1999), perifused pancreas (Sone, H. et al. 1999) or perifused islets (Sone, H. et al. 2000). This effect of biotin on insulin secretion also appears to be dose-dependent (Sone, H. et al. 1999). In isolated pancreatic islets, using blockers and inhibitors of different signaling pathways, we have discovered that the induction of glucokinase mRNA and the increase on insulin secretion by biotin involves guanylate cyclase and PKG activation, which triggers ATP production (Vilches-Flores, A. et al. 2009). The increase of ATP induces insulin secretion via ATP-sensitive potassium channels. Insulin, in an autocrine manner, activates PI3K/Akt signaling, which increases pancreatic glucokinase mRNA expression (Vilches-Flores, A. et al. 2009).
\n\t\t\t\t\tAlthough the acute effect of biotin on
Insulin secretion in response to the plasmatic concentration of glucose can be increased or decreased by several hormones (including insulin itself) and neurotransmitters via activation of their membrane receptors on the beta-cells(Flat, P.R. 1996). The G protein receptors and adenylate cyclase pathway are responsible for mediating most of these effects. The adenylate cyclase pathway may be activated by some neurotransmitters, like acetylcholine, and hormones like GLP-1. GLP-1 is also an important factor for insulin synthesis and secretion, having a trophic effect on the beta-cells as well (Baggio, L.L. & Drucker, D.J. 2007). Other modulating pathways are activated in the beta-cells in response to oxidative stress caused by high glucose levels, like the JNK pathway, which ablates insulin synthesis and interferes with its action (Kaneto, H. et al. 2006).
\n\t\t\tVarious studies have shown an autocrine role of insulin on beta-cell function and survival (Aikin, R. et al. 2006; Navarro-Tableros, V. et al. 2004; Xu, G.G. & Rothenberg, P.L. 1998). In this process, insulin binding to tyrosine-kinase receptors located in the beta-cell promotes the receptor’s autophosphorylation, catalyzing subsequent tyrosine phosphorylation of other proteins like IRS (IRS1 and IRS2). Once phosphorylated, these proteins interact with signaling molecules, which results in a phosphorylation cascade where PI3K, PDK and Akt are sequentially activated. Akt is a serine/threonine kinase which regulates cell survival, proliferation, growth and nutrient metabolism, through phosphorylation of different proteins like GSK3, FOXO and CREB (Song, G. et al. 2005). The activated receptor may act on the Ras signaling pathway, which in turn activates MAP kinases ERK1/2, in this way regulating growth, cellular differentiation and protein synthesis (Kahn, S.E. et al. 2006). In human islets, insulin has a positive effect on insulin production at the transcriptional level, as well as on beta-cell proliferation (Persaud, S.J. et al. 2008).
\n\t\t\tGlucagon is considered the contrarregulatory hormone of insulin, as its systemic actions are contrary to the ones exerted by insulin. Glucagon stimulates glucose production, glycogen degradation, and lipolysis. Paradoxically, it has been shown that glucagon stimulates insulin secretion both in rats (Kawai, K. et al. 1995) and humans (Ahren, B. et al. 1987). Glucagon induces a transient increase in plasma insulin up to 1 mg glucagon concentrations, and this increase is seen before glucose levels rise (Ahren, B. et al. 1987). There is evidence that the positive effect of glucagon on insulin secretion is mediated by activation of glucagon receptors in the beta-cells (Kawai, K. et al. 1995), and this activation may increase cAMP levels, leading to the PKA pathway.
\n\t\t\tIncretins are hormones secreted in the postprandial state by the enteroendocrine cells in the gut. Their main physiological role is to modulate insulin secretion. Two incretins have been described GIP (glucose-dependent insulinotropic peptide) and GLP-1 (glucagon-like peptide-1) (Brubaker, P.L. 2010).
\n\t\t\t\tGLP-1 is released rapidly into the circulation after oral nutrient ingestion, and its secretion occurs in a biphasic pattern starting with an early (within10–15 min) phase that is followed by a longer (30 –60 min) second phase (Herrmann, C. et al. 1995). Incretin-receptor activation leads to activation of adenylate cyclase and elevation of cAMP. Its actions include stimulation of glucose-dependent insulin secretion, induction of beta-cell proliferation, and enhanced resistance to islet cells apoptosis (Brubaker, P.L. 2010). GLP-1 stimulates insulin secretion via mechanisms that include the following: 1) direct inhibition of KATP channels, which leads to beta-cell membrane depolarization; 2) increases in intracellular calcium levels resulting from GLP-1–dependent influx of extracellular calcium through voltage-dependent calcium, channels, activation of nonselective cation channels, and mobilization of intracellular calcium stores; 3) increases in mitochondrial ATP synthesis, which lead to further membrane depolarization; 4) closure of voltage-dependent potassium (Kv) channels and consequent reductions in Kv currents, thereby preventing beta-cell repolarization; and 5) direct effects on beta-cell insulin storage granule exocytosis that occur distal to increases in ATP and intracellular calcium (Baggio, L.L. & Drucker, D.J. 2007).
\n\t\t\t\tBoth GIP and GLP-1 are cleaved and inactivated by the enzyme dipeptidyl peptidase 4 (DPP4). The rapid degradation of GLP-1 by DPP4 has led to the development of degradation-resistant GLP-1–receptor agonists and dipeptidyl peptidase-4 inhibitors, in order to increase the incretin effects. These drugs are currently used for diabetes treatment (Brubaker, P.L. 2010).
\n\t\t\tBesides nutrients, neurohormonal signals such as autonomic innervation can markedly modulate glucose-stimulated insulin secretion. Islets are thoroughly innervated by autonomic nerves, which contain an extensive variety of neuropeptide transmitters. Increased sympathetic activity affects insulin secretion in situations of stress, exercise and trauma. Activation of parasympathetic nerves before and during feeding by the smell, taste and digestive tract, along with incretin hormones derived from the gut are responsible for enhancing insulin response to meals.
\n\t\t\t\tParasympathetic neurotransmitters that stimulate insulin secretion include acetylcholine, vasoactive intestinal polypeptide and gastrin-releasing polypeptide. Sympathetic neurotransmitters inhibit insulin release; these include norepinephrine, galanin and neuropeptide Y. The enteroinsular axis, mediated by incretin hormones, explains why the insulin response to an ingested nutrient load is greater than when the same load is given parenterally. Gastrointestinal hormones such as gastric inhibitory peptide, glucagon-like peptide-1 (7-36) and cholecystokinin exert physiological relevant insulinotrophic effects (Flatt, P.R. 2003). In particular glucagon-like peptide-1 (7-36) has attracted attention by its potential role in the treatment of diabetes (see above).
\n\t\t\t\tThere are at least three potential sites were insulin can be modulated by hormones, peptides and neurotransmitters. Firstly, these may affect the ion channels that regulate membrane potential and calcium influx. Secondly, they may influence the mobilization of intracellular calcium stores, mainly the endoplasmic reticulum, and therefore cytosolic calcium concentration. Thirdly, they may modify the calcium sensibility of the contractile protein interactions that lead to the release of the insulin secretory granules (Flatt, P.R. 2003). The two better known targets of hormones, peptides and neurotransmitters within the beta-cell are related to adenylate cyclase and phospholipase C.
\n\t\t\t\tActivation of adenylate cyclase produces cyclic adenosine monophosphate (cAMP), which inhibits calcium sequestration within intracellular stores. Activation of cAMP-dependent protein kinase (PKA) results in phosphorylation of intracellular proteins that enhance calcium sensitization. PKA also promotes phosphorylation of voltage-dependent calcium channels thereby increasing calcium influx (Flatt, P.R. 2003).
\n\t\t\t\tPhospholipase C activation cleaves phosphatidylinosistol in the membrane producing inositol-1,4,5 triphosphate wich in turn inhibits calcium sequestration into the endoplasmic reticulum, while the adjacent cleavage product, diacylglycerol activates protein kinase C. Similarly to the effects of adenylate cyclase signaling pathway, activation of phospholipase C alters insulin secretion by mechanisms related to calcium sensitivity and protein phosphorylation (Flatt, P.R. 2003).
\n\t\t\tBesides a correct beta-cell function, the organism’s beta-cell mass is also important for maintaining adequate insulin production and secretion. Beta-cell mass is determined by cell number as well as cell size, and it increases progressively during fetal, neonatal and growth periods in the life of an organism, reaching a plateau during adulthood and decaying gradually with age (Ackermann, A.M. & Gannon, M. 2007).
\n\t\t\tDiverse processes participate in increasing and maintaining the beta cell mass, such as neogenesis (newly forming of cells from precursors), proliferation (cell replication), beta-cell size increase (hypertrophy), and apoptosis (cell death) (Ackermann, A.M. & Gannon, M. 2007). Although beta-cell progenitors have been identified in the pancreas (Bonner-Weir, S. et al. 2008, Xu, X. et al. 2008), the participation of neogenesis during post-natal and adult beta cell mass is limited (Dor, Y. et al. 2004), being proliferation (Meier, J.J. et al. 2008) and hypertrophy (Montanya, E. et al. 2000) the mainly responsible mechanisms for post-natal beta cell expansion (Ackermann, A.M. & Gannon, M. 2007). The organism is also capable of modifying beta-cell mass depending on its insulin requirements. In insulin resistance states, such as pregnancy and obesity, beta-cell mass is increased (Rhodes, C.J. 2005) a process driven by proliferation (Ackermann, A.M. & Gannon, M. 2007).
\n\t\t\tThe mechanisms by which adult beta-cell proliferation is driven remain unknown. Nevertheless, some of the factors regulating this process have been identified, such as growth factors (growth hormone, lactogens, insulin, insulin-like growth factors), incretins, cell cycle proteins, and transcription factors (PDX-1) (Ackermann, A.M. & Gannon, M. 2007).
\n\t\t\tAlthough many of the molecular regulators of postnatal beta-cell mass and beta-cell turnover have been identified in rodent models, it has been observed that human beta-cells’ ability to proliferate under the same signals is very restricted compared to rodent ones (Parnaud, G. et al. 2008). Moreover, in humans, beta-cell proliferation has suggested to occur only until early adulthood, as proliferation studies in humans have shown that there is no beta-cell replication after the first 30 years of life (Perl, S. et al. 2010).
\n\t\tOvert hyperglycemia and therefore, the onset of type 1 diabetes occurs when 70-80% of the beta-cell mass is gone. But the progressive loss of beta-cells is suggested to occur slowly over several years (Cnop, M. et al. 2005). This progressive damage may also account for a reduction of the first-phase insulin secretion seen in patients positive to islet cell antibodies but who had not developed hyperglycemia yet (Srikanta, S. et al. 1983). Nevertheless, the rate of beta-cell destruction in type 1 diabetes patients is variable and so can be the first manifestations of the disease. While some patients, mainly children and teenagers, may present ketoacidosis as first sign of diabetes, others (usually adults) could show modest fasting hyperglycemia, which may not evolve to severe hyperglycemia nor ketoacidosis for several years due to remaining function of the beta-cell (ADA 2009).
\n\t\t\tRegardless this variable nature, type 1 diabetes progression after the initiation of the autoimmune response may be divided in two different phases: insulitis and overt diabetes (Mathis, D. et al. 2001) (Figure 3). Apoptosis of the beta-cell is present even in the initiation and, evidently, both in insulitis and diabetes. These observations suggest that the beta-cell has a more important role in the pathophysiology of the disease than previously thought (Eizirik, D.L. et al. 2009, Mathis, D. et al. 2001).
\n\t\t\tIt has been proposed that beta-cell death possibly participates in the initiation of the autoimmune response, particularly in autoantigen presentation (Filippi, C.M. & von Herrath, M.G. 2007; Kaminitz, A. et al. 2007; Mathis, D. et al. 2001). It is known that beta-cells, both in rodents (Finegood, D.T. et al. 1995) and humans (Kassem, S.A. et al. 2000), may undergo physiological periods of apoptosis, particularly during the perinatal period. Moreover, viral infections or inflammatory cytokines may induce accumulation of misfolded proteins, causing ER stress, which can also lead to beta-cell apoptosis (Eizirik, D.L. et al. 2009). Immunological
\n\t\t\tInduction and progression of insulitis. Viral infections or inflammatory processes may lead to beta-cell apoptosis. Apoptotic beta-cells undergoing secondary necrosis may release beta-cell antigens, which would activate the antigen presenting cells. These cells could activate naive T cells in the pancreatic lymph nodes. When T cells reencounter the islet-antigens, they are retained in the islet, releasing inflammatory factors and inducing insulitis. Inflammatory cytokines activate transcription factors NFκβ and STAT-1, which decrease PDX1 and GLUT1 expression, leading to insufficient insulin production and secretion. Activation of NFκβ and STAT-1 also trigger ER stress, apoptotic processes and beta-cell release of citokines, leading to a vicious cycle of inflammation/beta-cell destruction that maintains and eventually amplifies the autoimmune attack.
recognition of antigens released by apoptotic beta-cells undergoing secondary necrosis, particularly in the presence of inflammatory factors such as TNF or interferons, could be an important signal to activate antigen presenting cells, which may then reach the pancreatic lymph nodes and be recognized by T cells (Filippi, C.M. & von Herrath, M.G. 2007). When these T cells reencounter the islet-antigens, they are retained in the islet, triggering the inflammatory process or insulitis (Mathis, D. et al. 2001).
\n\t\t\tBeta-cells also participate in the progression of insulitis (Eizirik, D.L. et al. 2009; Kaminitz, A. et al. 2007). Beta-cells themselves are capable of producing chemokines and cytokines in response to inflammatory factors such as IL-1β and IFNγ (Cardozo, A.K. et al. 2003), a process mediated by activation of the transcription factors NFκβ and STAT-1 (Cardozo, A.K. et al. 2001, Cnop, M. et al. 2005). This cytokines, besides promoting beta-cell death, can contribute to the recruitment and activation immune cells (Eizirik, D.L. et al. 2009). A localized inflammatory process starts within the islet beta-cell milieu, in which immune cells produce more inflammatory cytokines (IL-1β, TNF and interferons) that would activate NFκβ and STAT-1, leading to a vicious cycle of inflammation/beta-cell destruction that maintains and eventually amplifies the autoimmune attack (Eizirik, D.L. et al. 2009, Kaminitz, A. et al. 2007).
\n\t\t\tOnce insulitis is established, selective destruction of the beta-cells occur mainly by two proposed mechanisms: a recognition-linked mechanism and activation-linked mechanism. The former involves direct recognition of the beta-cell antigens by cytotoxic T-cells, while the latter is caused by exposure of soluble mediators secreted by T-cells that induce beta-cell death (Cnop, M. et al. 2005, Mathis, D. et al. 2001) such as cytokines, perforin or Fas/Fas ligand interactions, nitric oxide and reactive oxygen species (Cnop, M. et al. 2005, Mathis, D. et al. 2001).
\n\t\t\tInsulitis can be maintained in certain patients without evolving to overt diabetes. Studies in NOD mice have suggested that before the appearance of hyperglycemia, and after insulitis has been triggered, beta-cell function impairment precedes beta-cell apoptosis in response to the autoimmune attack (Strandell, E. et al. 1990). Surprisingly, beta-cell function may be recovered if the islets of these animals are either removed from their inflammatory milieu and cultured
Together with an initial loss of beta-cell function, the inflammatory process found in type 1 diabetes appears to stimulate beta-cell proliferation during the first stage of the disease. An increase in beta-cell mass may maintain metabolic demands for the period before the development of hyperglycemia, but it may also expose more and new epitopes, favoring and increasing the autoimmune destruction (Akirav, E. et al. 2008).
\n\t\t\tGiven the important role of the beta-cell during the initiating and progression stages of insulitis that may lead to type 1 diabetes, current research is being directed toward maintenance and improvement of beta-cell function and mass before and during the inflammatory process, establishing important therapeutic targets. New therapeutic approaches suggest that using combinatory treatments comprising a first immune intervention, followed by stimulation of beta-cell proliferation and function (perhaps with GLP-1-receptor agonists), and maintenance of normal glucose levels, together with the already used immunomodulatory therapy, may help not only to stop the progression of the disease, but even to recover the remaining beta-cell mass and function(Akirav, E. et al. 2008, Weir, G.C. & Bonner-Weir, S. 2010).
\n\t\tType 1 diabetes is one of the most serious chronic diseases of childhood. In spite of all the efforts in finding efficient therapeutic approaches for this disease, insulin keeps being the only effective treatment, as islet transplantation and beta-cell generation from stem cells have shown difficulties in getting donors or generating effective glucose-coupled insulin secreting cells.
\n\t\t\tAs the loss of beta-cells is determinant for the development of overt type 1 diabetes, understanding beta-cell normal physiology, namely insulin secretion, and how it may be affected during the progression of this disease is essential. Moreover, the development of new therapeutic interventions for type 1 diabetes, such as islet transplantation, beta cell maintenance and replacement, or stem cell therapy, require a profound knowledge of how the presence of different nutrients and signals may regulate insulin secretion and beta-cell mass.
\n\t\t\tRecent studies on the different stages of type 1 diabetes have shed light on an important role of beta-cell in the progression of the inflammatory process, and even evidence of reversal of the beta-cell damage present in the disease. These findings may provide tools to propose new integral and combinatorial therapeutic interventions that may aid in fighting this disease.
\n\t\tThis work was supported by grants from CONACyT: 99294-M, and from the Dirección General de Asuntos del Personal Académico: IN221908 Universidad Nacional Autónoma de México. Maria-Luisa Lazo de la Vega-Monroy is recipient of the CONACyT scholarship number CVU/Becario: 217876/207055.
\n\t\tDespite its well-protected position, the liver is the most frequently affected abdominal organ by blunt or penetrating trauma [1, 2]. Over the past decades, the improvements in the assessment and management of hepatic injury have evolved significantly, thus resulting in better outcomes for affected patients [3]. The majority of such injuries develop following high-energy traffic accidents or violent behaviors [4]. Industrial and farming accidents also consist of a significant percentage of liver trauma. Blunt injuries are the majority of cases in Europe, Australia, and Asia, whereas penetrating injuries (stab and gunshot wounds) are most frequently encountered in North America and South Africa [5, 6].
\nBlunt trauma, as a result of traffic accident or fall from a height, may lead to deceleration injury due to the inertia of the liver [4]. The affected sites usually involve the attachments to the diaphragm and abdominal wall. These types of injury typically involve the right lobe, especially the posterior segments, and the caudate lobe, while a vascular injury may also be present with the respective hepatic arteries, portal and hepatic veins being affected [4, 7, 8]. The site of connection between inferior vena cava and hepatic veins is vulnerable to blunt traumas and may lead to serious venous injuries and a significant blood loss. Penetrating injuries are more frequently associated with significant vascular injuries at the liver site inflicted [4]. In this chapter, we aimed to describe the classification and appropriate investigations of liver injuries and elaborate on the use of damage control surgery (DCS) in this setting.
\nThe liver is a wedge-shaped abdominal organ and is located in the right hypochondrium and epigastrium and may extend into the left hypochondrium [9, 10]. It is covered by fibrous Glisson’s capsule and is attached to the surrounding structures and the abdominal wall by several ligaments (falciform, coronary, triangular, hepatoduodenal and hepatogastric ligaments). It is divided into two lobes (right and left) by the falciform ligament, while two “accessory” lobes, the caudate and quadrate lobe, arise from the right lobe. The liver has unique double blood supply from the proper hepatic artery (25%) and portal vein (75%). Venous drainage is achieved through hepatic veins (right, middle, left) to the inferior vena cava.
\nThe Couinaud classification is the most widely used classification for functional liver anatomy [11]. It divides the liver into eight functionally independent segments, which have their own individual vascular supply and biliary drainage (Figure 1) [12]. A branch of the portal vein, hepatic artery, and bile duct are centrally located in each segment, while the vascular outflow to hepatic veins is located peripherally. Due to their functional independence, each segment can be safely resected without damaging the remaining liver parenchyma [13]. Nevertheless, the Couinaud classification system does not take into account the influence of vascular variations and does not provide liver surface landmarks for segment separation [14].
\nLiver functional anatomy – Couinaud classification system.
The liver segments are divided by portal vein branches and hepatic veins and are numbered clockwise [12]. The portal vein bifurcates at hepatic hilum into the left and right branches, which separate the liver into upper and lower segments. The right and left lobes are divided by middle hepatic vein, which runs along the Cantlie’s line from the inferior vena cava to the gallbladder fossa [15] Furthermore, the right hepatic vein divides the right lobe into anterior and posterior segments and left hepatic vein divides the left lobe into medial and lateral parts.
\nThe Caudate lobe (segment 1) is located posteriorly and often drains directly to inferior vena cava, while it can be supplied by both the right and the left portal vein branches, while segments II (superiorly) and III (inferiorly) are located medial to the left hepatic vein [16]. Segment IV (quadrate lobe) is located between the left and middle hepatic veins and is further divided by Bismuth into IVa (superiorly) and IVb (inferiorly) [17]. The anterior segments of the right hemiliver, V (inferiorly) and VIII (superiorly) lie between the middle and right hepatic veins, while the posterior right hemiliver segments, VI (inferiorly) and VII (superiorly), are located lateral to the right hepatic vein.
\nThe American Association for the Surgery of Trauma (AAST) grading scale is widely utilized for the classification of liver injury severity (Table 1) [18, 19]. However, it does not take into consideration the hemodynamic status of patients and the associated injuries. Thus, the World Society of Emergency Surgery (WSES) proposed a novel classification for the proper management of hepatic injuries involving AAST grade (1994 revision), hemodynamic stability, and mechanism of injury (Table 2) [2, 20].
\nAAST grade | \nInjury description | \n
---|---|
I | \nSubcapsular hematoma <10% of surface | \n
Parenchymal laceration or capsular tear <1 cm depth | \n|
II | \nSubcapsular hematoma 10–50% of surface area; intraparenchymal hematoma, <10 cm diameter | \n
Parenchymal laceration 1–3 cm in depth or < 10 cm in length | \n|
III | \nSubcapsular hematoma >50% of surface area or expanding; ruptured subcapsular or parenchymal hematoma; intraparenchymal hematoma >10 cm in diameter | \n
Parenchymal laceration >3 cm in depth | \n|
Any liver vascular injury or active bleeding contained within liver parenchyma | \n|
IV | \nParenchymal disruption 25–75% of hepatic lobe | \n
Active bleeding extending beyond the liver parenchyma into the peritoneum | \n|
V | \nParenchymal disruption >75% of hepatic lobe | \n
Juxtahepatic venous injury including retroheaptic vena cava and major hepatic veins | \n
The American Association for the Surgery of Trauma (AAST) liver injury scale (2018 revision).
Grade is based on highest grade assessment made during imaging, intraoperatively or pathologic specimen.
Advance one grade for multiple injuries up to grade III.
\n | WSES grade | \nAAST grade\n*\n\n | \nMechanism of Injury | \nHemodynamic status | \nCT-scan | \nFirst-line treatment | \n
---|---|---|---|---|---|---|
MINOR | \nI | \nI-II | \nBlunt/penetrating | \nStable | \nYES + local exploration in stab wounds | \nNOM + clinical/laboratory/radiological evaluation | \n
MODERATE | \nII | \nIII | \nBlunt/penetrating | \nStable | \n||
SEVERE | \nIII | \nIV-V | \nBlunt/penetrating | \nStable | \n||
IV | \nI-VI | \nBlunt/penetrating | \nUnstable | \nNO | \nSurgery | \n
The World Society of Emergency Surgery (WSES) classification and management of liver trauma.
American Association for the Surgery of Trauma (AAST) liver injury scale (1994 revision).
NOM: non-operative management.
Minor (WSES grade I) and moderate (WSES grade II) liver injuries concern hemodynamically stable patients after either blunt or penetrating trauma with AAST grade I-II or III lesions, respectively. Severe hepatic injuries include hemodynamically stable, AAST grade IV-VI lesions following penetrating or blunt trauma (WSES grade III) (Figure 2) or any hemodynamically unstable lesion (WSES grade IV).
\nComputed tomography scan demonstrating a severe liver injury.
The importance of the WSES classification and management approach is highlighted by the fact that patients suffering from high-grade AAST lesions, which are hemodynamically stable, can be successfully treated non-operatively [21]. On the contrary, “minor” AAST injuries combined with hemodynamic instability must be treated operatively in order to control the intrabdominal bleeding [20].
\nA liver injury should always be suspected in all patients suffering from a blunt or penetrating thoracoabdominal trauma, especially at the right site. Initial management of these patients should be based on the Advanced Trauma Life Support (ATLS) guidelines with fluid resuscitation and close monitoring being the first priorities [22]. Depending on the underlying injury mechanism, other concurrent injuries should also be evaluated and treated accordingly. The management of multi-trauma patients should take into consideration all the affected organs, and a multidisciplinary team is essential for the optimal treatment approach of these patients.
\nAs far as hepatic trauma is concerned, in hemodynamically unstable patients, despite adequate fluid resuscitation, an immediate operation for bleeding control is indicated, whereas in stable patients, an appropriate workup protocol using ultrasonography or computerized tomography scanning (CT) can be followed. Hemodynamic instability is characterized by the following: heart rate > 120 bpm, systolic blood pressure < 90 mmHg, low urine output, increased respiratory rate (>30 respirations/minute), signs of skin vasoconstriction and altered level of consciousness [22]. Non-operative management necessitates medical centers capable of an accurate injury severity diagnosis, intensive management of patients, and prompt access to diagnostic modalities, interventional radiology, operation theater, and blood–blood products [20, 23].
\nUltrasound plays a significant role in the proper investigation of abdominal injuries. Focused Assessment with Sonography for Trauma (FAST) can be performed immediately at the emergency department and can help assess the pericardium, hepatorenal space (Morison’s pouch), perisplenic space and Douglas pouch to identify the presence of free fluid [22]. More detailed ultrasonography by an experienced radiologist is necessary for a more accurate investigation of liver parenchyma. Ultrasonography has widely replaced diagnostic peritoneal lavage (DPL) and has a high specificity of 95–100% [24]. Nevertheless, ultrasound examination is highly operator-depended and should be performed by experienced clinicians.
\nComputerized tomography (CT) scan is a valuable tool for the evaluation of stable patients with an abdominal injury [25]. A contrast-enhanced, multi-slice CT scan is reported to have a sensitivity and specificity of over 95% for detecting liver injuries [26, 27]. Subscapular and intraparenchymal hematomas, lacerations, and vascular injuries can be recognized. Furthermore, an active hemorrhage can be visualized as an extravasation of contrast medium. A CT scan can also successfully elucidate other abdominal injuries involving the spleen, kidneys, and bowel [26]. Finally, a follow-up CT scan can be utilized for the detection of delayed liver injury complications, including delayed hemorrhage, bile leak, biloma, arteriovenous malformations, and liver abscesses [4, 28].
\nDamage control surgery refers to the immediate steps taken in order to reduce blood loss, the risk of sepsis, morbidity, and mortality instead of a thorough patient workup in the intensive care unit (ICU) [29]. DCS has significantly improved the outcomes of patients presenting at the hospital with severe organ injuries, including liver injuries, and hemodynamic instability due to maneuvers to control the bleeding [1]. Uncontrolled bleeding can lead to coagulopathy secondary to the dilution and depletion of the coagulation factors, hypothermia, and acidosis, the so-called “lethal triad” or “medical bleeding” [21]. The onset of this series of events may necessitate the need for DCS, including temporary (perihepatic) packing of the bleeding sites, where physiological recovery is prioritized over anatomical repair [30].
\nThe earliest report on perihepatic packing to prevent uncontrolled bleeding from injuries to the liver dates back to 1908 by James Pringle [31], while later in 1913, Halstead described the use of a rubber sheet between the injured liver and the gauze packs [32]. Despite the improvements in outcomes, perihepatic packing was sparsely described in the literature [33] until Stone et al. [34] reported a survival rate of 76% in patients managed with “truncated laparotomy” compared to 7% in patients managed with definitive surgical repair. Rotondo et al. [35] introduced the term “damage control laparotomy” and demonstrated that this approach could improve survival in hemorrhaging trauma patients (requiring transfusion of >10 units of packed red blood cells) with multiple visceral penetrating injuries and major vessel injuries. The authors described the three steps of their approach, and the same research group later modified it by introducing a fourth pre-operative phase (Table 3) [36]. Since then, DCS has been successfully implemented for the management of major liver injury with optimal outcomes. The use of angioembolization in more recent series has been proposed as the logical augmentation of damage control approaches to control bleeding, but particularly in the case of high-grade injuries, it may lead to major hepatic necrosis [37].
\nDamage control (DC) Phase | \nDescription | \n
---|---|
DC0 | \n\n
| \n
DCI | \n\n
| \n
DCII | \n\n
| \n
DCIII | \n\n
| \n
The four Phases of damage control for exsanguinating penetrating abdominal injury by Johnson et al.
As mentioned earlier, DCS can play a vital role in the setting of the “lethal triad” and thus metabolic acidosis (pH <7.2), hypothermia (<34°C), and coagulopathy (prolonged activated partial thromboplastin time and prothrombin time > two times normal) constitute absolute indications for DCS. Uncontrolled major intra-abdominal bleeding, association with extra-abdominal injury, >10 units of blood transfusion, and hemodynamic instability (low blood pressure and tachycardia) are relative indications for DCS [29].
\nDC0 constitutes the first phase of the DCS process and takes place in the pre-hospital setting and in the emergency room. The most crucial aspects of this phase are injury pattern recognition in order to determine which patients will most likely benefit from DCS according to the absolute and relative indications, and the “scoop and run” concept to truncate scene times. The administration of blood products and tranexamic acid in the pre-hospital setting has been increasingly used [38, 39]. Given the significant improvements in trauma resuscitation strategies aiming at rapid bleeding control, management of coagulopathy, and diversion away from the over-resuscitation with crystalloids, the use of DCS may be required to a lesser extent in the future [40–42]. There is a growing body of evidence that the use of a high plasma to packed red blood cell ratio can lead to a decrease in hemorrhage-related mortality [43]. French lyophilized plasma – manufactured by the French Military Blood Institute – is a universal therapeutic viro-inactivated plasma that can be reconstituted in <6 min at the point-of-care and is compatible with any blood type [44]. Data suggest that French lyophilized plasma can be used more rapidly correct for the trauma-induced coagulopathy compared to fresh frozen plasma, particularly in the military setting [45]. Its role against normal saline in the management of post-traumatic coagulopathy prevention and correction in the pre-hospital civilian setting is currently under investigation (PREHO-PLYO study) [46], and it is awaited to revolutionize the current state of practice for the management of severe trauma, including liver injury.
\nOnce the patients reach the emergency room, immediate assessment by the trauma team and damage control resuscitation is vital. The surgical and critical care teams should strive towards obtaining vascular access with two large-bore catheters, inserting nasogastric tube and urinary catheter (unless there is blood at the urethral meatus, high riding prostate or prevalent perineal hematoma), rapid induction of anesthesia, drainage of the chest (if needed), intravenous broad-spectrum antibiotics and tetanus prophylaxis (if indicated), rapid rewarming and prevention of further hypothermia, and expedited transport to the operating room for DCS [30].
\nDCI starts with the exploratory laparotomy, which aims to control bleeding and limit contamination, and ends with the temporary closure of the abdominal wall. After the patient is positioned in a “cruciform” lie, the patient is prepped from chin to mid-thighs and a vertical midline incision from the xiphoid process to the pubic symphysis is made [30]. If the suspicion for a severe fracture of the pelvis is high, the incision should be limited just below the umbilicus to facilitate continuous tamponade of the suspected pelvic hematoma. If the patient is unstable, the incision should not be delayed if arterial or venous lines are not in place; these can be inserted during the operation.
\nIf the observed intra-abdominal bleeding is not considered to be major, compression on its own or the use of topical hemostatic agents, bipolar devices or electrocautery, argon beam coagulation, omental patching or even simple suturing of the liver parenchyma may be adequate to control the hemorrhage [2, 20, 47–49]. In the case of massive intra-abdominal hemorrhage, more aggressive maneuvers should be adopted, including perihepatic packing and manual compression, or even hepatic vascular isolation (i.e., intrahepatic balloon tamponade) [50, 51]. Injuries to the portal vein should be primarily repaired, while ligation of the portal vein should be considered only as an alternative – provided that the proper hepatic artery is intact – due to the increased risk of hepatic necrosis or massive intestinal edema [47]. Data suggest preferring liver packing or resection over portal vein ligation if only lobar or segmental branches of the portal vein are injured [2, 47, 52]. However, portal vein ligation is safer than arterial ligation regarding biliary complications or hepatic necrosis, and may even prepare the liver for staged extended liver resection [53]. If the surgeon comes across a proper hepatic artery injury, they should shoot for a primary repair; otherwise, selective hepatic artery ligation should be preferred, and if the common or right hepatic artery is to be ligated, cholecystectomy should follow to prevent gallbladder necrosis [1, 52]. When arterial control or the Pringle maneuver is inadequate to control the hemorrhage, the surgeon should suspect that there might be an aberrant hepatic artery [47]. If the bleeding arises from the area behind the liver, the injury is most likely to be found on the hepatic or retro-hepatic caval vein [2, 47, 54]. Inserting vascular shunts (i.e., atrio-caval shunt) might also be useful to control hemorrhage [29, 47]. In case of persistent bleeding and hemodynamic instability, resuscitative endovascular balloon occlusion of the aorta in the zone I and of the vena cava at the level of the retro-hepatic vena cava can serve as a bridge to more definitive procedures [47]. Liver resection should be avoided at this phase, but if absolutely necessary, non-anatomic resections should be preferred [2, 47, 48, 52], while resection of a hemorrhaging spleen or kidney can be performed, if needed in order to stop the bleeding [29]. Angioembolization should be advocated for either stable patients after the initial surgical hemostatic attempt or adjunctively in case of suspected uncontrolled bleeding despite the surgical hemostatic attempt [2, 47, 55]; data also suggest that its routine implementation immediately after DCS can significantly improve survival in grade IV or V liver injury [56]. Regarding contamination control, intrahepatic abscesses can be managed with percutaneous drainage, and bilomas may either resolve spontaneously or should also be managed with percutaneous drainage potentially with adjunct therapeutic endoscopic retrograde cholangiopancreatography and stent placement [47]. Abdominal wall closure is the final step before transitioning to DCII (transfer to the ICU) and should be only temporary without fascial closure to avoid abdominal compartment syndrome [30].
\nDCII involves taking the patient to the ICU postoperatively, where the goal is to restore the biochemical and physiological derangements. Managing fluid administration to bring the patient back to hemodynamic stability is often achieved through invasive monitoring (i.e., transthoracic echocardiography, transesophageal Doppler, pulmonary artery catheterization, etc.) [30]. Securing adequate oxygenation and aggressive rewarming of the patient are also necessary. The management of coagulopathy is crucial for survival, and the use of rotational thromboelastometry and other tests to assess how the coagulation cascade works along with massive blood transfusion practices have led to an improvement in outcomes and a decrease in blood transfusion requirements [30, 57]. Prevention of potentially fatal complications commonly seen in the ICU, including infection, adult respiratory distress syndrome, and deep vein thrombosis, is also important for patient survival [29]. This is the perfect opportunity for treating physicians to perform a complete reassessment of the patient and a “tertiary survey”, including imaging studies that may help identify previously unknown injuries.
\nDCIII involves definite repair of the injuries once the patient is stabilized and has returned to his “physiologic normality” and commonly takes place within 24–72 hours after admission to the ICU. The patient is taken back to the operating room for re-exploration and packing removal (preferably after 48 hours) [21]. That is also the stage when an anatomic liver resection may be performed (Figure 3), along with the removal of devitalized tissue or vascular shunts, anastomosis of vessels or bowel, or even a feeding jejunostomy. The phase ends with the permanent closure of the abdominal wall. This should be performed with the approximation of the fascial edges if gentle adduction permits; if this is not possible due to retroperitoneal or bowel wall edema, then the abdominal wall should be again only temporarily closed with the fascia left open. In that scenario, the patient is taken back to the ICU and provided the patient is hemodynamically stable, administration of diuretics to decrease the bowel edema should be considered [30]. This situation should then be managed with washouts and re-inspection of the abdomen regularly, while primary closure should be completed within seven days, particularly in the absence of signs of infection. Other abdominal closure alternatives should be considered if this is not possible. This will lead to a large ventral hernia that will require repair at some future time point [30].
\nSurgical management of severe liver injury with active bleeding.
Immediate resuscitation and DCS play a critical role in the outcomes of trauma patients in general, and particularly in those with severe liver injuries where the exsanguination of large amounts of blood is common. The decrease in the time from the scene to hospital and taking, the implementation of massive transfusion protocols, and the improvements in the approaches to control bleeding and contamination intraoperatively by leaving major resections for a later phase have revolutionized the outcomes after liver trauma over the past decades. The advents of pre-hospital care are awaited to change the need for DCS in the future.
\nIntechOpen books are available online by accessing all published content on a chapter level.
",metaTitle:"Access policy",metaDescription:"IntechOpen books are available online by accessing all published content on a chapter level",metaKeywords:null,canonicalURL:null,contentRaw:'[{"type":"htmlEditorComponent","content":"All IntechOpen published chapters are available OPEN ACCESS can be read without the requirement for registration of any kind, immediately upon publication, without any barrier.
\\n\\nThe HTML version, as well as the PDF version of publications dated before 2012 that are accessible through a reader, are available to readers with no restriction.
\\n\\nThe full content of chapters can be read, copied and printed from the link location of the chapter and these actions are not limited or restricted in any way.
\\n\\nRegistration is requested only to download the PDF of the chapter. There are no subscription fees and there is no charge to user groups.
\\n\\nIntechOpen chapters are distributed under CC BY 3.0 licences allowing users to “copy, use, distribute, transmit and display the work publicly and to make and distribute derivative works, in any digital medium for any responsible purpose, subject to proper attribution of authorship...” and there is no non-commercial restriction.
\\n\\nAuthors may post published works to any repository or website with no delay, and Authors and Editors of IntechOpen books have direct access to the PDF of the full book.
\\n\\nAll published content can be crawled for indexing. Full text and metadata may be accessed with instructions publicly posted.
\\n\\nAll IntechOpen books are indexed in CLOCKSS and preservation of access to published content is clearly indicated.
\\n\\nPolicy last updated: 2021-02-26
\\n"}]'},components:[{type:"htmlEditorComponent",content:"All IntechOpen published chapters are available OPEN ACCESS can be read without the requirement for registration of any kind, immediately upon publication, without any barrier.
\n\nThe HTML version, as well as the PDF version of publications dated before 2012 that are accessible through a reader, are available to readers with no restriction.
\n\nThe full content of chapters can be read, copied and printed from the link location of the chapter and these actions are not limited or restricted in any way.
\n\nRegistration is requested only to download the PDF of the chapter. There are no subscription fees and there is no charge to user groups.
\n\nIntechOpen chapters are distributed under CC BY 3.0 licences allowing users to “copy, use, distribute, transmit and display the work publicly and to make and distribute derivative works, in any digital medium for any responsible purpose, subject to proper attribution of authorship...” and there is no non-commercial restriction.
\n\nAuthors may post published works to any repository or website with no delay, and Authors and Editors of IntechOpen books have direct access to the PDF of the full book.
\n\nAll published content can be crawled for indexing. Full text and metadata may be accessed with instructions publicly posted.
\n\nAll IntechOpen books are indexed in CLOCKSS and preservation of access to published content is clearly indicated.
\n\nPolicy last updated: 2021-02-26
\n"}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"6700",title:"Dr.",name:"Abbass A.",middleName:null,surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. Hashim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6700/images/1864_n.jpg",biography:"Currently I am carrying out research in several areas of interest, mainly covering work on chemical and bio-sensors, semiconductor thin film device fabrication and characterisation.\nAt the moment I have very strong interest in radiation environmental pollution and bacteriology treatment. The teams of researchers are working very hard to bring novel results in this field. I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55578/images/4574_n.png",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. From 2004 to 2011, he was a Research Assistant with the Communications Engineering Department at the University of Málaga. In 2011, he became an Assistant Professor in the same department. From 2012 to 2015, he was with Ericsson Spain, where he was working on geo-location\ntools for third generation mobile networks. Since 2015, he is a Marie-Curie fellow at the Denmark Technical University. His current research interests include the areas of mobile communication systems and channel modeling in addition to atmospheric optical communications, adaptive optics and statistics",institutionString:null,institution:{name:"University of Malaga",country:{name:"Spain"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:5828},{group:"region",caption:"Middle and South America",value:2,count:5289},{group:"region",caption:"Africa",value:3,count:1765},{group:"region",caption:"Asia",value:4,count:10555},{group:"region",caption:"Australia and Oceania",value:5,count:909},{group:"region",caption:"Europe",value:6,count:15952}],offset:12,limit:12,total:119464},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{sort:"dateEndThirdStepPublish",topicId:"20"},books:[{type:"book",id:"10956",title:"Pulsed Lasers",subtitle:null,isOpenForSubmission:!0,hash:"88bd906b149fc3d1c5d6fdbd9916826c",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10956.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10672",title:"Nonlinear Optics",subtitle:null,isOpenForSubmission:!0,hash:"cfe87b713a8bee22c19361b86b03d506",slug:null,bookSignature:"Dr. Boris I. Lembrikov",coverURL:"https://cdn.intechopen.com/books/images_new/10672.jpg",editedByType:null,editors:[{id:"2359",title:"Dr.",name:"Boris",surname:"Lembrikov",slug:"boris-lembrikov",fullName:"Boris Lembrikov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10674",title:"Topics on Quantum Information Science",subtitle:null,isOpenForSubmission:!0,hash:"d7481712cff0157cd8f849cba865727d",slug:null,bookSignature:"Prof. Sergio Curilef and Dr. Angel Ricardo Plastino",coverURL:"https://cdn.intechopen.com/books/images_new/10674.jpg",editedByType:null,editors:[{id:"125424",title:"Prof.",name:"Sergio",surname:"Curilef",slug:"sergio-curilef",fullName:"Sergio Curilef"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10921",title:"Plasma Science and Technology",subtitle:null,isOpenForSubmission:!0,hash:"c45670ef4b081fd9eebaf911b2b4627b",slug:null,bookSignature:"Dr. Aamir Shahzad",coverURL:"https://cdn.intechopen.com/books/images_new/10921.jpg",editedByType:null,editors:[{id:"288354",title:"Dr.",name:"Aamir",surname:"Shahzad",slug:"aamir-shahzad",fullName:"Aamir Shahzad"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10852",title:"Electromagnetic Compatibility",subtitle:null,isOpenForSubmission:!0,hash:"f5d2cce3a2adbd5d108d3301ee97025b",slug:null,bookSignature:"Dr. Ahmed Kishk",coverURL:"https://cdn.intechopen.com/books/images_new/10852.jpg",editedByType:null,editors:[{id:"150146",title:"Dr.",name:"Ahmed",surname:"Kishk",slug:"ahmed-kishk",fullName:"Ahmed Kishk"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:29},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:8},{group:"topic",caption:"Business, Management and Economics",value:7,count:4},{group:"topic",caption:"Chemistry",value:8,count:9},{group:"topic",caption:"Computer and Information Science",value:9,count:10},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:10},{group:"topic",caption:"Engineering",value:11,count:29},{group:"topic",caption:"Environmental Sciences",value:12,count:4},{group:"topic",caption:"Immunology and Microbiology",value:13,count:4},{group:"topic",caption:"Materials Science",value:14,count:7},{group:"topic",caption:"Mathematics",value:15,count:3},{group:"topic",caption:"Medicine",value:16,count:51},{group:"topic",caption:"Neuroscience",value:18,count:3},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:3},{group:"topic",caption:"Physics",value:20,count:4},{group:"topic",caption:"Psychology",value:21,count:4},{group:"topic",caption:"Robotics",value:22,count:2},{group:"topic",caption:"Social Sciences",value:23,count:4},{group:"topic",caption:"Technology",value:24,count:1},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:2}],offset:12,limit:12,total:5},popularBooks:{featuredBooks:[{type:"book",id:"9893",title:"Automation and Control",subtitle:null,isOpenForSubmission:!1,hash:"09ba24f6ac88af7f0aaff3029714ae48",slug:"automation-and-control",bookSignature:"Constantin Voloşencu, Serdar Küçük, José Guerrero and Oscar Valero",coverURL:"https://cdn.intechopen.com/books/images_new/9893.jpg",editors:[{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7016",title:"Cardiovascular Risk Factors in Pathology",subtitle:null,isOpenForSubmission:!1,hash:"7937d2c640c7515de372282c72ee5635",slug:"cardiovascular-risk-factors-in-pathology",bookSignature:"Alaeddin Abukabda, Maria Suciu and Minodora Andor",coverURL:"https://cdn.intechopen.com/books/images_new/7016.jpg",editors:[{id:"307873",title:"Ph.D.",name:"Alaeddin",middleName:null,surname:"Abukabda",slug:"alaeddin-abukabda",fullName:"Alaeddin Abukabda"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9873",title:"Strategies of Sustainable Solid Waste Management",subtitle:null,isOpenForSubmission:!1,hash:"59b5ceeeedaf7449a30629923569388c",slug:"strategies-of-sustainable-solid-waste-management",bookSignature:"Hosam M. Saleh",coverURL:"https://cdn.intechopen.com/books/images_new/9873.jpg",editors:[{id:"144691",title:"Prof.",name:"Hosam M.",middleName:"M.",surname:"Saleh",slug:"hosam-m.-saleh",fullName:"Hosam M. Saleh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9154",title:"Spinal Deformities in Adolescents, Adults and Older Adults",subtitle:null,isOpenForSubmission:!1,hash:"313f1dffa803b60a14ff1e6966e93d91",slug:"spinal-deformities-in-adolescents-adults-and-older-adults",bookSignature:"Josette Bettany-Saltikov and Gokulakannan Kandasamy",coverURL:"https://cdn.intechopen.com/books/images_new/9154.jpg",editors:[{id:"94802",title:"Dr.",name:"Josette",middleName:null,surname:"Bettany-Saltikov",slug:"josette-bettany-saltikov",fullName:"Josette Bettany-Saltikov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10405",title:"River Basin Management",subtitle:"Sustainability Issues and Planning Strategies",isOpenForSubmission:!1,hash:"5e5ddd0f2eda107ce19c4c06a55a8351",slug:"river-basin-management-sustainability-issues-and-planning-strategies",bookSignature:"José Simão Antunes Do Carmo",coverURL:"https://cdn.intechopen.com/books/images_new/10405.jpg",editors:[{id:"67904",title:"Prof.",name:"José Simão",middleName:null,surname:"Antunes Do Carmo",slug:"jose-simao-antunes-do-carmo",fullName:"José Simão Antunes Do Carmo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7030",title:"Satellite Systems",subtitle:"Design, Modeling, Simulation and Analysis",isOpenForSubmission:!1,hash:"b9db6d2645ef248ceb1b33ea75f38e88",slug:"satellite-systems-design-modeling-simulation-and-analysis",bookSignature:"Tien Nguyen",coverURL:"https://cdn.intechopen.com/books/images_new/7030.jpg",editors:[{id:"210657",title:"Dr.",name:"Tien M.",middleName:"Manh",surname:"Nguyen",slug:"tien-m.-nguyen",fullName:"Tien M. Nguyen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8472",title:"Bioactive Compounds in Nutraceutical and Functional Food for Good Human Health",subtitle:null,isOpenForSubmission:!1,hash:"8855452919b8495810ef8e88641feb20",slug:"bioactive-compounds-in-nutraceutical-and-functional-food-for-good-human-health",bookSignature:"Kavita Sharma, Kanchan Mishra, Kula Kamal Senapati and Corina Danciu",coverURL:"https://cdn.intechopen.com/books/images_new/8472.jpg",editors:[{id:"197731",title:"Dr.",name:"Kavita",middleName:null,surname:"Sharma",slug:"kavita-sharma",fullName:"Kavita Sharma"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10201",title:"Post-Transition Metals",subtitle:null,isOpenForSubmission:!1,hash:"cc7f53ff5269916e3ce29f65a51a87ae",slug:"post-transition-metals",bookSignature:"Mohammed Muzibur Rahman, Abdullah Mohammed Asiri, Anish Khan, Inamuddin and Thamer Tabbakh",coverURL:"https://cdn.intechopen.com/books/images_new/10201.jpg",editors:[{id:"24438",title:"Prof.",name:"Mohammed Muzibur",middleName:null,surname:"Rahman",slug:"mohammed-muzibur-rahman",fullName:"Mohammed Muzibur Rahman"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10413",title:"A Collection of Papers on Chaos Theory and Its Applications",subtitle:null,isOpenForSubmission:!1,hash:"900b71b164948830fec3d6254b7881f7",slug:"a-collection-of-papers-on-chaos-theory-and-its-applications",bookSignature:"Paul Bracken and Dimo I. Uzunov",coverURL:"https://cdn.intechopen.com/books/images_new/10413.jpg",editors:[{id:"92883",title:"Prof.",name:"Paul",middleName:null,surname:"Bracken",slug:"paul-bracken",fullName:"Paul Bracken"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9515",title:"Update in Geriatrics",subtitle:null,isOpenForSubmission:!1,hash:"913e16c0ae977474b283bbd4269564c8",slug:"update-in-geriatrics",bookSignature:"Somchai Amornyotin",coverURL:"https://cdn.intechopen.com/books/images_new/9515.jpg",editors:[{id:"185484",title:"Prof.",name:"Somchai",middleName:null,surname:"Amornyotin",slug:"somchai-amornyotin",fullName:"Somchai Amornyotin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8148",title:"Investment Strategies in Emerging New Trends in Finance",subtitle:null,isOpenForSubmission:!1,hash:"3b714d96a68d2acdfbd7b50aba6504ca",slug:"investment-strategies-in-emerging-new-trends-in-finance",bookSignature:"Reza Gharoie Ahangar and Asma Salman",coverURL:"https://cdn.intechopen.com/books/images_new/8148.jpg",editors:[{id:"91081",title:"Dr.",name:"Reza",middleName:null,surname:"Gharoie Ahangar",slug:"reza-gharoie-ahangar",fullName:"Reza Gharoie Ahangar"}],equalEditorOne:{id:"206443",title:"Prof.",name:"Asma",middleName:null,surname:"Salman",slug:"asma-salman",fullName:"Asma Salman",profilePictureURL:"https://mts.intechopen.com/storage/users/206443/images/system/206443.png",biography:"Professor Asma Salman is a blockchain developer and Professor of Finance at the American University in the Emirates, UAE. An Honorary Global Advisor at the Global Academy of Finance and Management, USA, she completed her MBA in Finance and Accounting and earned a Ph.D. in Finance from an AACSB member, AMBA accredited, School of Management at Harbin Institute of Technology, China. Her research credentials include a one-year residency at the Brunel Business School, Brunel University, UK. Prof. Salman also served as the Dubai Cohort supervisor for DBA students under the Nottingham Business School, UK, for seven years and is currently a Ph.D. supervisor at the University of Northampton, UK, where she is a visiting fellow. She also served on the Board of Etihad Airlines during 2019–2020. One of her recent articles on “Bitcoin and Blockchain” gained wide visibility and she is an active speaker on Fintech, blockchain, and crypto events around the GCC. She holds various professional certifications including Chartered Fintech Professional (USA), Certified Financial Manager (USA), Women in Leadership and Management in Higher Education, (UK), and Taxation GCC VAT Compliance, (UK). She recently won an award for “Blockchain Trainer of the Year” from Berkeley Middle East. Other recognitions include the Women Leadership Impact Award by H.E First Lady of Armenia, Research Excellence Award, and the Global Inspirational Women Leadership Award by H.H Sheikh Juma Bin Maktoum Juma Al Maktoum.",institutionString:"American University in the Emirates",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"American University in the Emirates",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"2160",title:"MATLAB",subtitle:"A Fundamental Tool for Scientific Computing and Engineering Applications - Volume 1",isOpenForSubmission:!1,hash:"dd9c658341fbd264ed4f8d9e6aa8ca29",slug:"matlab-a-fundamental-tool-for-scientific-computing-and-engineering-applications-volume-1",bookSignature:"Vasilios N. Katsikis",coverURL:"https://cdn.intechopen.com/books/images_new/2160.jpg",editors:[{id:"12289",title:"Prof.",name:"Vasilios",middleName:"N.",surname:"Katsikis",slug:"vasilios-katsikis",fullName:"Vasilios Katsikis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:5334},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"9893",title:"Automation and Control",subtitle:null,isOpenForSubmission:!1,hash:"09ba24f6ac88af7f0aaff3029714ae48",slug:"automation-and-control",bookSignature:"Constantin Voloşencu, Serdar Küçük, José Guerrero and Oscar Valero",coverURL:"https://cdn.intechopen.com/books/images_new/9893.jpg",editors:[{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7016",title:"Cardiovascular Risk Factors in Pathology",subtitle:null,isOpenForSubmission:!1,hash:"7937d2c640c7515de372282c72ee5635",slug:"cardiovascular-risk-factors-in-pathology",bookSignature:"Alaeddin Abukabda, Maria Suciu and Minodora Andor",coverURL:"https://cdn.intechopen.com/books/images_new/7016.jpg",editors:[{id:"307873",title:"Ph.D.",name:"Alaeddin",middleName:null,surname:"Abukabda",slug:"alaeddin-abukabda",fullName:"Alaeddin Abukabda"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9873",title:"Strategies of Sustainable Solid Waste Management",subtitle:null,isOpenForSubmission:!1,hash:"59b5ceeeedaf7449a30629923569388c",slug:"strategies-of-sustainable-solid-waste-management",bookSignature:"Hosam M. Saleh",coverURL:"https://cdn.intechopen.com/books/images_new/9873.jpg",editors:[{id:"144691",title:"Prof.",name:"Hosam M.",middleName:"M.",surname:"Saleh",slug:"hosam-m.-saleh",fullName:"Hosam M. Saleh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9154",title:"Spinal Deformities in Adolescents, Adults and Older Adults",subtitle:null,isOpenForSubmission:!1,hash:"313f1dffa803b60a14ff1e6966e93d91",slug:"spinal-deformities-in-adolescents-adults-and-older-adults",bookSignature:"Josette Bettany-Saltikov and Gokulakannan Kandasamy",coverURL:"https://cdn.intechopen.com/books/images_new/9154.jpg",editors:[{id:"94802",title:"Dr.",name:"Josette",middleName:null,surname:"Bettany-Saltikov",slug:"josette-bettany-saltikov",fullName:"Josette Bettany-Saltikov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10405",title:"River Basin Management",subtitle:"Sustainability Issues and Planning Strategies",isOpenForSubmission:!1,hash:"5e5ddd0f2eda107ce19c4c06a55a8351",slug:"river-basin-management-sustainability-issues-and-planning-strategies",bookSignature:"José Simão Antunes Do Carmo",coverURL:"https://cdn.intechopen.com/books/images_new/10405.jpg",editors:[{id:"67904",title:"Prof.",name:"José Simão",middleName:null,surname:"Antunes Do Carmo",slug:"jose-simao-antunes-do-carmo",fullName:"José Simão Antunes Do Carmo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7030",title:"Satellite Systems",subtitle:"Design, Modeling, Simulation and Analysis",isOpenForSubmission:!1,hash:"b9db6d2645ef248ceb1b33ea75f38e88",slug:"satellite-systems-design-modeling-simulation-and-analysis",bookSignature:"Tien Nguyen",coverURL:"https://cdn.intechopen.com/books/images_new/7030.jpg",editors:[{id:"210657",title:"Dr.",name:"Tien M.",middleName:"Manh",surname:"Nguyen",slug:"tien-m.-nguyen",fullName:"Tien M. Nguyen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8472",title:"Bioactive Compounds in Nutraceutical and Functional Food for Good Human Health",subtitle:null,isOpenForSubmission:!1,hash:"8855452919b8495810ef8e88641feb20",slug:"bioactive-compounds-in-nutraceutical-and-functional-food-for-good-human-health",bookSignature:"Kavita Sharma, Kanchan Mishra, Kula Kamal Senapati and Corina Danciu",coverURL:"https://cdn.intechopen.com/books/images_new/8472.jpg",editors:[{id:"197731",title:"Dr.",name:"Kavita",middleName:null,surname:"Sharma",slug:"kavita-sharma",fullName:"Kavita Sharma"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10201",title:"Post-Transition Metals",subtitle:null,isOpenForSubmission:!1,hash:"cc7f53ff5269916e3ce29f65a51a87ae",slug:"post-transition-metals",bookSignature:"Mohammed Muzibur Rahman, Abdullah Mohammed Asiri, Anish Khan, Inamuddin and Thamer Tabbakh",coverURL:"https://cdn.intechopen.com/books/images_new/10201.jpg",editors:[{id:"24438",title:"Prof.",name:"Mohammed Muzibur",middleName:null,surname:"Rahman",slug:"mohammed-muzibur-rahman",fullName:"Mohammed Muzibur Rahman"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10413",title:"A Collection of Papers on Chaos Theory and Its Applications",subtitle:null,isOpenForSubmission:!1,hash:"900b71b164948830fec3d6254b7881f7",slug:"a-collection-of-papers-on-chaos-theory-and-its-applications",bookSignature:"Paul Bracken and Dimo I. Uzunov",coverURL:"https://cdn.intechopen.com/books/images_new/10413.jpg",editors:[{id:"92883",title:"Prof.",name:"Paul",middleName:null,surname:"Bracken",slug:"paul-bracken",fullName:"Paul Bracken"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9515",title:"Update in Geriatrics",subtitle:null,isOpenForSubmission:!1,hash:"913e16c0ae977474b283bbd4269564c8",slug:"update-in-geriatrics",bookSignature:"Somchai Amornyotin",coverURL:"https://cdn.intechopen.com/books/images_new/9515.jpg",editors:[{id:"185484",title:"Prof.",name:"Somchai",middleName:null,surname:"Amornyotin",slug:"somchai-amornyotin",fullName:"Somchai Amornyotin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"9559",title:"Teamwork in Healthcare",subtitle:null,isOpenForSubmission:!1,hash:"0053c2ff8d9ec4cc4aab82acea46a41e",slug:"teamwork-in-healthcare",bookSignature:"Michael S. Firstenberg and Stanislaw P. Stawicki",coverURL:"https://cdn.intechopen.com/books/images_new/9559.jpg",editedByType:"Edited by",editors:[{id:"64343",title:null,name:"Michael S.",middleName:null,surname:"Firstenberg",slug:"michael-s.-firstenberg",fullName:"Michael S. Firstenberg"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7016",title:"Cardiovascular Risk Factors in Pathology",subtitle:null,isOpenForSubmission:!1,hash:"7937d2c640c7515de372282c72ee5635",slug:"cardiovascular-risk-factors-in-pathology",bookSignature:"Alaeddin Abukabda, Maria Suciu and Minodora Andor",coverURL:"https://cdn.intechopen.com/books/images_new/7016.jpg",editedByType:"Edited by",editors:[{id:"307873",title:"Ph.D.",name:"Alaeddin",middleName:null,surname:"Abukabda",slug:"alaeddin-abukabda",fullName:"Alaeddin Abukabda"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9873",title:"Strategies of Sustainable Solid Waste Management",subtitle:null,isOpenForSubmission:!1,hash:"59b5ceeeedaf7449a30629923569388c",slug:"strategies-of-sustainable-solid-waste-management",bookSignature:"Hosam M. Saleh",coverURL:"https://cdn.intechopen.com/books/images_new/9873.jpg",editedByType:"Edited by",editors:[{id:"144691",title:"Prof.",name:"Hosam M.",middleName:"M.",surname:"Saleh",slug:"hosam-m.-saleh",fullName:"Hosam M. Saleh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9893",title:"Automation and Control",subtitle:null,isOpenForSubmission:!1,hash:"09ba24f6ac88af7f0aaff3029714ae48",slug:"automation-and-control",bookSignature:"Constantin Voloşencu, Serdar Küçük, José Guerrero and Oscar Valero",coverURL:"https://cdn.intechopen.com/books/images_new/9893.jpg",editedByType:"Edited by",editors:[{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10405",title:"River Basin Management",subtitle:"Sustainability Issues and Planning Strategies",isOpenForSubmission:!1,hash:"5e5ddd0f2eda107ce19c4c06a55a8351",slug:"river-basin-management-sustainability-issues-and-planning-strategies",bookSignature:"José Simão Antunes Do Carmo",coverURL:"https://cdn.intechopen.com/books/images_new/10405.jpg",editedByType:"Edited by",editors:[{id:"67904",title:"Prof.",name:"José Simão",middleName:null,surname:"Antunes Do Carmo",slug:"jose-simao-antunes-do-carmo",fullName:"José Simão Antunes Do Carmo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9515",title:"Update in Geriatrics",subtitle:null,isOpenForSubmission:!1,hash:"913e16c0ae977474b283bbd4269564c8",slug:"update-in-geriatrics",bookSignature:"Somchai Amornyotin",coverURL:"https://cdn.intechopen.com/books/images_new/9515.jpg",editedByType:"Edited by",editors:[{id:"185484",title:"Prof.",name:"Somchai",middleName:null,surname:"Amornyotin",slug:"somchai-amornyotin",fullName:"Somchai Amornyotin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9021",title:"Novel Perspectives of Stem Cell Manufacturing and Therapies",subtitle:null,isOpenForSubmission:!1,hash:"522c6db871783d2a11c17b83f1fd4e18",slug:"novel-perspectives-of-stem-cell-manufacturing-and-therapies",bookSignature:"Diana Kitala and Ana Colette Maurício",coverURL:"https://cdn.intechopen.com/books/images_new/9021.jpg",editedByType:"Edited by",editors:[{id:"203598",title:"Ph.D.",name:"Diana",middleName:null,surname:"Kitala",slug:"diana-kitala",fullName:"Diana Kitala"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7030",title:"Satellite Systems",subtitle:"Design, Modeling, Simulation and Analysis",isOpenForSubmission:!1,hash:"b9db6d2645ef248ceb1b33ea75f38e88",slug:"satellite-systems-design-modeling-simulation-and-analysis",bookSignature:"Tien Nguyen",coverURL:"https://cdn.intechopen.com/books/images_new/7030.jpg",editedByType:"Edited by",editors:[{id:"210657",title:"Dr.",name:"Tien M.",middleName:"Manh",surname:"Nguyen",slug:"tien-m.-nguyen",fullName:"Tien M. Nguyen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10413",title:"A Collection of Papers on Chaos Theory and Its Applications",subtitle:null,isOpenForSubmission:!1,hash:"900b71b164948830fec3d6254b7881f7",slug:"a-collection-of-papers-on-chaos-theory-and-its-applications",bookSignature:"Paul Bracken and Dimo I. Uzunov",coverURL:"https://cdn.intechopen.com/books/images_new/10413.jpg",editedByType:"Edited by",editors:[{id:"92883",title:"Prof.",name:"Paul",middleName:null,surname:"Bracken",slug:"paul-bracken",fullName:"Paul Bracken"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9154",title:"Spinal Deformities in Adolescents, Adults and Older Adults",subtitle:null,isOpenForSubmission:!1,hash:"313f1dffa803b60a14ff1e6966e93d91",slug:"spinal-deformities-in-adolescents-adults-and-older-adults",bookSignature:"Josette Bettany-Saltikov and Gokulakannan Kandasamy",coverURL:"https://cdn.intechopen.com/books/images_new/9154.jpg",editedByType:"Edited by",editors:[{id:"94802",title:"Dr.",name:"Josette",middleName:null,surname:"Bettany-Saltikov",slug:"josette-bettany-saltikov",fullName:"Josette Bettany-Saltikov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"1150",title:"Orthopedics",slug:"orthopedics",parent:{title:"Surgery",slug:"surgery"},numberOfBooks:29,numberOfAuthorsAndEditors:689,numberOfWosCitations:342,numberOfCrossrefCitations:184,numberOfDimensionsCitations:483,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicSlug:"orthopedics",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"9154",title:"Spinal Deformities in Adolescents, Adults and Older Adults",subtitle:null,isOpenForSubmission:!1,hash:"313f1dffa803b60a14ff1e6966e93d91",slug:"spinal-deformities-in-adolescents-adults-and-older-adults",bookSignature:"Josette Bettany-Saltikov and Gokulakannan Kandasamy",coverURL:"https://cdn.intechopen.com/books/images_new/9154.jpg",editedByType:"Edited by",editors:[{id:"94802",title:"Dr.",name:"Josette",middleName:null,surname:"Bettany-Saltikov",slug:"josette-bettany-saltikov",fullName:"Josette Bettany-Saltikov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9522",title:"Tibia Pathology and Fractures",subtitle:null,isOpenForSubmission:!1,hash:"a458a39d8281ed7fda0548fbb75927a2",slug:"tibia-pathology-and-fractures",bookSignature:"Dimitrios D. Nikolopoulos, George K. Safos and John Michos",coverURL:"https://cdn.intechopen.com/books/images_new/9522.jpg",editedByType:"Edited by",editors:[{id:"228477",title:"Dr.",name:"Dimitrios D.",middleName:null,surname:"Nikolopoulos",slug:"dimitrios-d.-nikolopoulos",fullName:"Dimitrios D. Nikolopoulos"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9350",title:"Knee Surgery",subtitle:"Reconstruction and Replacement",isOpenForSubmission:!1,hash:"78aa92dc594a2cc0f60f28b640b28c10",slug:"knee-surgery-reconstruction-and-replacement",bookSignature:"João Bosco Sales Nogueira, José Alberto Dias Leite, Leonardo Heráclio Do Carmo Araújo and Marcelo Cortez Bezerra",coverURL:"https://cdn.intechopen.com/books/images_new/9350.jpg",editedByType:"Edited by",editors:[{id:"215718",title:"M.Sc.",name:"João Bosco Sales",middleName:null,surname:"Nogueira",slug:"joao-bosco-sales-nogueira",fullName:"João Bosco Sales Nogueira"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7975",title:"Limb Amputation",subtitle:null,isOpenForSubmission:!1,hash:"4cf345d93bc54587899c69ce6d3b07f2",slug:"limb-amputation",bookSignature:"Masaki Fujioka",coverURL:"https://cdn.intechopen.com/books/images_new/7975.jpg",editedByType:"Edited by",editors:[{id:"53197",title:"Prof.",name:"Masaki",middleName:null,surname:"Fujioka",slug:"masaki-fujioka",fullName:"Masaki Fujioka"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7087",title:"Tendons",subtitle:null,isOpenForSubmission:!1,hash:"786abac0445c102d1399a1e727a2db7f",slug:"tendons",bookSignature:"Hasan Sözen",coverURL:"https://cdn.intechopen.com/books/images_new/7087.jpg",editedByType:"Edited by",editors:[{id:"161402",title:"Dr.",name:"Hasan",middleName:null,surname:"Sözen",slug:"hasan-sozen",fullName:"Hasan Sözen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7548",title:"Meniscus of the Knee",subtitle:"Function, Pathology and Management",isOpenForSubmission:!1,hash:"a82a659a178c693e15f88dcfb8fb2782",slug:"meniscus-of-the-knee-function-pathology-and-management",bookSignature:"Taiceer Abdulwahab and Karl Almqvist",coverURL:"https://cdn.intechopen.com/books/images_new/7548.jpg",editedByType:"Edited by",editors:[{id:"204153",title:"Dr.",name:"Taiceer",middleName:null,surname:"Abdulwahab",slug:"taiceer-abdulwahab",fullName:"Taiceer Abdulwahab"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8676",title:"Hip Surgeries",subtitle:null,isOpenForSubmission:!1,hash:"35280afd3082f1a6b3c10bdc0ae447f6",slug:"hip-surgeries",bookSignature:"Nahum Rosenberg",coverURL:"https://cdn.intechopen.com/books/images_new/8676.jpg",editedByType:"Edited by",editors:[{id:"68911",title:"Dr.",name:"Nahum",middleName:null,surname:"Rosenberg",slug:"nahum-rosenberg",fullName:"Nahum Rosenberg"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6585",title:"Total Hip Replacement",subtitle:"An Overview",isOpenForSubmission:!1,hash:"fc19d9c4ee5073fbab74a0e2aed20ba2",slug:"total-hip-replacement-an-overview",bookSignature:"Vaibhav Bagaria",coverURL:"https://cdn.intechopen.com/books/images_new/6585.jpg",editedByType:"Edited by",editors:[{id:"37266",title:"Dr.",name:"Vaibhav",middleName:null,surname:"Bagaria",slug:"vaibhav-bagaria",fullName:"Vaibhav Bagaria"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6755",title:"Recent Advances in Arthroscopic Surgery",subtitle:null,isOpenForSubmission:!1,hash:"5c122c5b88bdc03c130d34ad2ac2d722",slug:"recent-advances-in-arthroscopic-surgery",bookSignature:"Hiran Wimal Amarasekera",coverURL:"https://cdn.intechopen.com/books/images_new/6755.jpg",editedByType:"Edited by",editors:[{id:"67634",title:"Dr.",name:"Hiran",middleName:"Wimal",surname:"Amarasekera",slug:"hiran-amarasekera",fullName:"Hiran Amarasekera"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6337",title:"Update in Management of Foot and Ankle Disorders",subtitle:null,isOpenForSubmission:!1,hash:"8b2f0af3f51f43cce1e3e36375ea3220",slug:"update-in-management-of-foot-and-ankle-disorders",bookSignature:"Thanos Badekas",coverURL:"https://cdn.intechopen.com/books/images_new/6337.jpg",editedByType:"Edited by",editors:[{id:"66087",title:"Dr.",name:"Thanos",middleName:null,surname:"Badekas",slug:"thanos-badekas",fullName:"Thanos Badekas"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6340",title:"Essentials of Hand Surgery",subtitle:null,isOpenForSubmission:!1,hash:"17716f5af3207a5039578a6d8e795cdf",slug:"essentials-of-hand-surgery",bookSignature:"Alexandro Aguilera Salgado",coverURL:"https://cdn.intechopen.com/books/images_new/6340.jpg",editedByType:"Edited by",editors:[{id:"162339",title:"Dr.",name:"Alexandro",middleName:null,surname:"Aguilera Salgado",slug:"alexandro-aguilera-salgado",fullName:"Alexandro Aguilera Salgado"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6145",title:"Primary Total Knee Arthroplasty",subtitle:null,isOpenForSubmission:!1,hash:"18df110af120b1a8e88e0a1ded2aba75",slug:"primary-total-knee-arthroplasty",bookSignature:"Alessandro Rozim Zorzi and João Batista de Miranda",coverURL:"https://cdn.intechopen.com/books/images_new/6145.jpg",editedByType:"Edited by",editors:[{id:"80871",title:"M.D.",name:"Alessandro Rozim",middleName:null,surname:"Zorzi",slug:"alessandro-rozim-zorzi",fullName:"Alessandro Rozim Zorzi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:29,mostCitedChapters:[{id:"26862",doi:"10.5772/27413",title:"Titanium as a Biomaterial for Implants",slug:"titanium-as-a-biomaterial-for-implants",totalDownloads:15801,totalCrossrefCites:40,totalDimensionsCites:94,book:{slug:"recent-advances-in-arthroplasty",title:"Recent Advances in Arthroplasty",fullTitle:"Recent Advances in Arthroplasty"},signatures:"Carlos Oldani and Alejandro Dominguez",authors:[{id:"70012",title:"Dr.",name:"Carlos",middleName:null,surname:"Oldani",slug:"carlos-oldani",fullName:"Carlos Oldani"},{id:"73445",title:"MSc.",name:"Alejandro",middleName:"Anibal",surname:"Dominguez",slug:"alejandro-dominguez",fullName:"Alejandro Dominguez"}]},{id:"50915",doi:"10.5772/63266",title:"Doped Bioactive Glass Materials in Bone Regeneration",slug:"doped-bioactive-glass-materials-in-bone-regeneration",totalDownloads:2861,totalCrossrefCites:7,totalDimensionsCites:19,book:{slug:"advanced-techniques-in-bone-regeneration",title:"Advanced Techniques in Bone Regeneration",fullTitle:"Advanced Techniques in Bone Regeneration"},signatures:"Samit Kumar Nandi, Arnab Mahato, Biswanath Kundu and Prasenjit\nMukherjee",authors:[{id:"60514",title:"Dr.",name:"Samit",middleName:null,surname:"Nandi",slug:"samit-nandi",fullName:"Samit Nandi"}]},{id:"26863",doi:"10.5772/26362",title:"The Bearing Surfaces in Total Hip Arthroplasty – Options, Material Characteristics and Selection",slug:"the-bearing-surfaces-in-total-hip-arthroplasty-options-material-characteristics-and-selection",totalDownloads:8987,totalCrossrefCites:9,totalDimensionsCites:16,book:{slug:"recent-advances-in-arthroplasty",title:"Recent Advances in Arthroplasty",fullTitle:"Recent Advances in Arthroplasty"},signatures:"Hamid Reza Seyyed Hosseinzadeh, Alireza Eajazi and Ali Sina Shahi",authors:[{id:"66361",title:"Dr.",name:"Alireza",middleName:null,surname:"Eajazi",slug:"alireza-eajazi",fullName:"Alireza Eajazi"},{id:"74857",title:"Dr.",name:"Hamid Reza",middleName:null,surname:"Seyyed Hosseinzadeh",slug:"hamid-reza-seyyed-hosseinzadeh",fullName:"Hamid Reza Seyyed Hosseinzadeh"},{id:"173207",title:"Dr.",name:"Alisina",middleName:null,surname:"Shahi",slug:"alisina-shahi",fullName:"Alisina Shahi"}]}],mostDownloadedChaptersLast30Days:[{id:"70683",title:"Restoration of Cervical and Lumbar Lordosis: CBP® Methods Overview",slug:"restoration-of-cervical-and-lumbar-lordosis-cbp-methods-overview",totalDownloads:644,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"spinal-deformities-in-adolescents-adults-and-older-adults",title:"Spinal Deformities in Adolescents, Adults and Older Adults",fullTitle:"Spinal Deformities in Adolescents, Adults and Older Adults"},signatures:"Paul A. Oakley, Ibrahim M. Moustafa and Deed E. Harrison",authors:[{id:"308067",title:"Dr.",name:"Paul A.",middleName:null,surname:"Oakley",slug:"paul-a.-oakley",fullName:"Paul A. Oakley"},{id:"308068",title:"Dr.",name:"Deed E.",middleName:null,surname:"Harrison",slug:"deed-e.-harrison",fullName:"Deed E. Harrison"},{id:"311314",title:"Prof.",name:"Ibrahim M.",middleName:null,surname:"Moustafa",slug:"ibrahim-m.-moustafa",fullName:"Ibrahim M. Moustafa"},{id:"410567",title:"Dr.",name:"Paul A.",middleName:null,surname:"Oakley",slug:"paul-a.-oakley",fullName:"Paul A. Oakley"},{id:"410568",title:"Dr.",name:"Ibrahim M.",middleName:null,surname:"Moustafa",slug:"ibrahim-m.-moustafa",fullName:"Ibrahim M. Moustafa"},{id:"410569",title:"Dr.",name:"Deed E.",middleName:null,surname:"Harrison",slug:"deed-e.-harrison",fullName:"Deed E. Harrison"}]},{id:"55812",title:"Postural Restoration: A Tri-Planar Asymmetrical Framework for Understanding, Assessing, and Treating Scoliosis and Other Spinal Dysfunctions",slug:"postural-restoration-a-tri-planar-asymmetrical-framework-for-understanding-assessing-and-treating-sc",totalDownloads:5776,totalCrossrefCites:0,totalDimensionsCites:1,book:{slug:"innovations-in-spinal-deformities-and-postural-disorders",title:"Innovations in Spinal Deformities and Postural Disorders",fullTitle:"Innovations in Spinal Deformities and Postural Disorders"},signatures:"Susan Henning, Lisa C. Mangino and Jean Massé",authors:[{id:"204825",title:"Dr.",name:"Susan",middleName:null,surname:"Henning",slug:"susan-henning",fullName:"Susan Henning"},{id:"206242",title:"Dr.",name:"Lisa C",middleName:null,surname:"Mangino",slug:"lisa-c-mangino",fullName:"Lisa C Mangino"},{id:"206245",title:"Dr.",name:"Jean",middleName:null,surname:"Massé",slug:"jean-masse",fullName:"Jean Massé"}]},{id:"75596",title:"The Use of a Dynamic Elastomeric Fabric Orthotic Intervention in Adolescents and Adults with Scoliosis",slug:"the-use-of-a-dynamic-elastomeric-fabric-orthotic-intervention-in-adolescents-and-adults-with-scolios",totalDownloads:75,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"spinal-deformities-in-adolescents-adults-and-older-adults",title:"Spinal Deformities in Adolescents, Adults and Older Adults",fullTitle:"Spinal Deformities in Adolescents, Adults and Older Adults"},signatures:"Martin Matthews and James Wynne",authors:[{id:"198503",title:"Mr.",name:"Martin",middleName:"John",surname:"Matthews",slug:"martin-matthews",fullName:"Martin Matthews"},{id:"338865",title:"Mr.",name:"James H.",middleName:null,surname:"Wynne",slug:"james-h.-wynne",fullName:"James H. Wynne"}]},{id:"54481",title:"Pelvic Osteotomies for Developmental Dysplasia of the Hip",slug:"pelvic-osteotomies-for-developmental-dysplasia-of-the-hip",totalDownloads:1732,totalCrossrefCites:2,totalDimensionsCites:2,book:{slug:"developmental-diseases-of-the-hip-diagnosis-and-management",title:"Developmental Diseases of the Hip",fullTitle:"Developmental Diseases of the Hip - Diagnosis and Management"},signatures:"Chunho Chen, Ting-Ming Wang and Ken N. Kuo",authors:[{id:"189672",title:"M.D.",name:"Chunho",middleName:null,surname:"Chen",slug:"chunho-chen",fullName:"Chunho Chen"},{id:"189675",title:"Dr.",name:"Tingming",middleName:null,surname:"Wang",slug:"tingming-wang",fullName:"Tingming Wang"},{id:"189859",title:"Prof.",name:"Ken N",middleName:null,surname:"Kuo",slug:"ken-n-kuo",fullName:"Ken N Kuo"}]},{id:"65013",title:"Management of Flexor Tendon Injuries in Hand",slug:"management-of-flexor-tendon-injuries-in-hand",totalDownloads:941,totalCrossrefCites:0,totalDimensionsCites:1,book:{slug:"tendons",title:"Tendons",fullTitle:"Tendons"},signatures:"Tawheed Ahmad, Summaira Jan and Saima Rashid",authors:[{id:"276868",title:"Dr.",name:"Tawheed",middleName:null,surname:"Ahmad",slug:"tawheed-ahmad",fullName:"Tawheed Ahmad"},{id:"283320",title:"Dr.",name:"Summaira",middleName:null,surname:"Jan",slug:"summaira-jan",fullName:"Summaira Jan"},{id:"283321",title:"Dr.",name:"Saima",middleName:null,surname:"Rashid",slug:"saima-rashid",fullName:"Saima Rashid"}]},{id:"62382",title:"Crush Injuries of the Hand Part II: Clinical Assessment, Management and Outcomes",slug:"crush-injuries-of-the-hand-part-ii-clinical-assessment-management-and-outcomes",totalDownloads:1014,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"essentials-of-hand-surgery",title:"Essentials of Hand Surgery",fullTitle:"Essentials of Hand Surgery"},signatures:"Roohi Sharifah Ahmad and Pho Robert Wan Heng",authors:[{id:"214913",title:"Prof.",name:"S.A.",middleName:null,surname:"Roohi",slug:"s.a.-roohi",fullName:"S.A. Roohi"},{id:"217121",title:"Prof.",name:"Robert",middleName:null,surname:"Pho",slug:"robert-pho",fullName:"Robert Pho"}]},{id:"61241",title:"Complications of Total Hip Replacement",slug:"complications-of-total-hip-replacement",totalDownloads:736,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"total-hip-replacement-an-overview",title:"Total Hip Replacement",fullTitle:"Total Hip Replacement - An Overview"},signatures:"Chang Park and Irfan Merchant",authors:[{id:"227863",title:"Mr.",name:"Chang",middleName:null,surname:"Park",slug:"chang-park",fullName:"Chang Park"},{id:"234643",title:"Mr.",name:"Irfan",middleName:null,surname:"Merchant",slug:"irfan-merchant",fullName:"Irfan Merchant"}]},{id:"69978",title:"Valgus Deformity Correction in Total Knee Replacement: An Overview",slug:"valgus-deformity-correction-in-total-knee-replacement-an-overview",totalDownloads:459,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"knee-surgery-reconstruction-and-replacement",title:"Knee Surgery",fullTitle:"Knee Surgery - Reconstruction and Replacement"},signatures:"Melvin J. George",authors:[{id:"210622",title:"Dr.",name:"Melvin",middleName:null,surname:"George",slug:"melvin-george",fullName:"Melvin George"}]},{id:"56116",title:"Epidemiology of Sarcopenia and Frailty",slug:"epidemiology-of-sarcopenia-and-frailty",totalDownloads:1764,totalCrossrefCites:2,totalDimensionsCites:4,book:{slug:"frailty-and-sarcopenia-onset-development-and-clinical-challenges",title:"Frailty and Sarcopenia",fullTitle:"Frailty and Sarcopenia - Onset, Development and Clinical Challenges"},signatures:"Harnish P Patel, Esther Clift, Lucy Lewis and Cyrus Cooper",authors:[{id:"83886",title:"Dr.",name:"Harnish",middleName:null,surname:"Patel",slug:"harnish-patel",fullName:"Harnish Patel"},{id:"125686",title:"Prof.",name:"Cyrus",middleName:null,surname:"Cooper",slug:"cyrus-cooper",fullName:"Cyrus Cooper"},{id:"206190",title:"Mrs.",name:"Esther",middleName:null,surname:"Clift",slug:"esther-clift",fullName:"Esther Clift"},{id:"206191",title:"Mrs.",name:"Lucy",middleName:null,surname:"Lewis",slug:"lucy-lewis",fullName:"Lucy Lewis"}]},{id:"59498",title:"Cruciate-Retaining Total Knee Arthroplasty",slug:"cruciate-retaining-total-knee-arthroplasty",totalDownloads:750,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"primary-total-knee-arthroplasty",title:"Primary Total Knee Arthroplasty",fullTitle:"Primary Total Knee Arthroplasty"},signatures:"Vittorio Calvisi, Alessandro Paglia, Norman Ciprietti and Remo\nGoderecci",authors:[{id:"218908",title:"Prof.",name:"Vittorio",middleName:null,surname:"Calvisi",slug:"vittorio-calvisi",fullName:"Vittorio Calvisi"},{id:"218967",title:"Dr.",name:"Remo",middleName:null,surname:"Goderecci",slug:"remo-goderecci",fullName:"Remo Goderecci"},{id:"218968",title:"Dr.",name:"Alessandro",middleName:null,surname:"Paglia",slug:"alessandro-paglia",fullName:"Alessandro Paglia"},{id:"218970",title:"Dr.",name:"Norman",middleName:null,surname:"Ciprietti",slug:"norman-ciprietti",fullName:"Norman Ciprietti"}]}],onlineFirstChaptersFilter:{topicSlug:"orthopedics",limit:3,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[{type:"book",id:"10176",title:"Microgrids and Local Energy Systems",subtitle:null,isOpenForSubmission:!0,hash:"c32b4a5351a88f263074b0d0ca813a9c",slug:null,bookSignature:"Prof. Nick Jenkins",coverURL:"https://cdn.intechopen.com/books/images_new/10176.jpg",editedByType:null,editors:[{id:"55219",title:"Prof.",name:"Nick",middleName:null,surname:"Jenkins",slug:"nick-jenkins",fullName:"Nick Jenkins"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:8,limit:8,total:1},route:{name:"profile.detail",path:"/profiles/311630/j-m-miranda1",hash:"",query:{},params:{id:"311630",slug:"j-m-miranda1"},fullPath:"/profiles/311630/j-m-miranda1",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var t;(t=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(t)}()