Clinical syndromes of auto-/hyperimmune basis associated with myelodysplasia.
\\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:{caption:"Highly Cited",originalUrl:"/media/original/117"}},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:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"},{slug:"intechopen-identified-as-one-of-the-most-significant-contributor-to-oa-book-growth-in-doab-20210809",title:"IntechOpen Identified as One of the Most Significant Contributors to OA Book Growth in DOAB"}]},book:{item:{type:"book",id:"759",leadTitle:null,fullTitle:"Osteosarcoma",title:"Osteosarcoma",subtitle:null,reviewType:"peer-reviewed",abstract:"This book is aimed at quickly updating the reader on osteosarcoma, a dreaded primary bone cancer. Progress in management of osteosarcoma has been slow after the evolution of chemotherapy and limb salvage surgery. Research is now directed towards identifying molecular targets for systemic therapy. Availability of chemotherapy drugs and low cost implants in developing world have allowed limb salvage surgery to develop. This book looks at current basic knowledge on osteosarcoma and some of the developments in research which have the potential to change the prognosis.",isbn:null,printIsbn:"978-953-51-0506-0",pdfIsbn:"978-953-51-6964-2",doi:"10.5772/1266",price:119,priceEur:129,priceUsd:155,slug:"osteosarcoma",numberOfPages:184,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"2f4f2676183c2de632e44e5d72bcc778",bookSignature:"Manish Agarwal",publishedDate:"April 11th 2012",coverURL:"https://cdn.intechopen.com/books/images_new/759.jpg",numberOfDownloads:33096,numberOfWosCitations:8,numberOfCrossrefCitations:4,numberOfCrossrefCitationsByBook:2,numberOfDimensionsCitations:17,numberOfDimensionsCitationsByBook:2,hasAltmetrics:0,numberOfTotalCitations:29,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 14th 2011",dateEndSecondStepPublish:"April 11th 2011",dateEndThirdStepPublish:"August 16th 2011",dateEndFourthStepPublish:"September 15th 2011",dateEndFifthStepPublish:"January 13th 2012",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"58420",title:"Dr.",name:"Manish",middleName:"G",surname:"Agarwal",slug:"manish-agarwal",fullName:"Manish Agarwal",profilePictureURL:"https://mts.intechopen.com/storage/users/58420/images/3490_n.jpg",biography:"Dr Manish Agarwal is currently a consultant Orthopedic Oncologist at P.D Hinduja National Hospital, Mumbai. He has pioneered the development of the indigenous tumor megaprosthesis system which is used nationally as well as some centres abroad. He has also pioneered the use of strut allografts for tumor defects and helped expand the tissue bank at Tata Memorial Hospital, Mumbai where he was associate professor for 10 years, and the use of expandable prostheses in India. Along with Non Ferrous technology development corporation (NFTDC, Hyderabad) and IIT Mumbai, he has developed an international class tumor prosthetic system which will shortly undergo clinical trials. He has also done basic research work and phase I trials with traditional herbs for osteosarcoma.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"P. D. Hinduja Hospital and Medical Research Centre",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1073",title:"Bone & Musculoskeletal Oncology",slug:"bone-and-musculoskeletal-oncology"}],chapters:[{id:"35171",title:"Histopathology and Molecular Pathology of Bone and Extraskeletal Osteosarcomas",doi:"10.5772/31431",slug:"histopathology-and-molecular-pathology-of-bone-and-extraskeletal-osteosarcomas",totalDownloads:7922,totalCrossrefCites:1,totalDimensionsCites:7,hasAltmetrics:0,abstract:null,signatures:"Helen Trihia and Christos Valavanis",downloadPdfUrl:"/chapter/pdf-download/35171",previewPdfUrl:"/chapter/pdf-preview/35171",authors:[{id:"87082",title:"Dr.",name:"Helen",surname:"Trihia",slug:"helen-trihia",fullName:"Helen Trihia"},{id:"89731",title:"Dr.",name:"Christos",surname:"Valavanis",slug:"christos-valavanis",fullName:"Christos Valavanis"}],corrections:null},{id:"35172",title:"Imaging Osteosarcoma",doi:"10.5772/34081",slug:"imaging-of-osteosarcoma-review",totalDownloads:7249,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Ali Nawaz Khan, Durr-e-Sabih, Klaus L. Irion, Hamdan AL-Jahdali and Koteyar Shyam Sunder Radha Krishna",downloadPdfUrl:"/chapter/pdf-download/35172",previewPdfUrl:"/chapter/pdf-preview/35172",authors:[{id:"98597",title:"Prof.",name:"Ali Nawaz",surname:"Khan",slug:"ali-nawaz-khan",fullName:"Ali Nawaz Khan"}],corrections:null},{id:"35173",title:"Misdiagnosis and Mistreatment for Osteosarcoma: Analysis of Cause and Its Strategy",doi:"10.5772/32021",slug:"misdiagnosis-and-mistreatment-of-osteosarcoma-analysis-of-the-causes-and-the-solutions-",totalDownloads:2676,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:null,signatures:"Yao Yang and Lin Feng",downloadPdfUrl:"/chapter/pdf-download/35173",previewPdfUrl:"/chapter/pdf-preview/35173",authors:[{id:"89820",title:"Prof.",name:"Yang",surname:"Yao",slug:"yang-yao",fullName:"Yang Yao"}],corrections:null},{id:"35174",title:"Chemotherapy in Osteosarcoma",doi:"10.5772/45726",slug:"chemotherapy-in-osteogenic-sarcoma",totalDownloads:4978,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:null,signatures:"Kapadia Asha, Almel Sachin and Shaikh Muzammil",downloadPdfUrl:"/chapter/pdf-download/35174",previewPdfUrl:"/chapter/pdf-preview/35174",authors:[{id:"152574",title:"Dr.",name:"Muzammil",surname:"Shaikh",slug:"muzammil-shaikh",fullName:"Muzammil Shaikh"}],corrections:null},{id:"35175",title:"Limb Salvage for Osteosarcoma: Current Status with a Review of Literature",doi:"10.5772/45627",slug:"limb-salvage-in-osteosarcoma",totalDownloads:7043,totalCrossrefCites:0,totalDimensionsCites:3,hasAltmetrics:0,abstract:null,signatures:"Manish G. Agarwal and Prakash Nayak",downloadPdfUrl:"/chapter/pdf-download/35175",previewPdfUrl:"/chapter/pdf-preview/35175",authors:[{id:"58420",title:"Dr.",name:"Manish",surname:"Agarwal",slug:"manish-agarwal",fullName:"Manish Agarwal"},{id:"152571",title:"Dr.",name:"Prakash",surname:"Nayak",slug:"prakash-nayak",fullName:"Prakash Nayak"}],corrections:null},{id:"35176",title:"Bone Formation Deregulations Are the Oncogenesis Keys in Osteosarcomas",doi:"10.5772/30693",slug:"involvement-of-osteogenesis-deregulation-in-the-osteosarcoma-tumorogenesis",totalDownloads:1483,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Natacha Entz-Werlé",downloadPdfUrl:"/chapter/pdf-download/35176",previewPdfUrl:"/chapter/pdf-preview/35176",authors:[{id:"83792",title:"Prof.",name:"Natacha",surname:"Entz-Werle",slug:"natacha-entz-werle",fullName:"Natacha Entz-Werle"}],corrections:null},{id:"35177",title:"The Retinoblastoma Protein in Osteosarcomagenesis",doi:"10.5772/32559",slug:"the-retinoblastoma-protein-in-osteosarcomagenesis",totalDownloads:1745,totalCrossrefCites:2,totalDimensionsCites:4,hasAltmetrics:0,abstract:null,signatures:"Elizabeth Kong and Philip W. Hinds",downloadPdfUrl:"/chapter/pdf-download/35177",previewPdfUrl:"/chapter/pdf-preview/35177",authors:[{id:"91925",title:"Prof.",name:"Phil",surname:"Hinds",slug:"phil-hinds",fullName:"Phil Hinds"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"647",title:"Chronic Lymphocytic Leukemia",subtitle:null,isOpenForSubmission:!1,hash:"6ed7cea1e96993e2edc66548c29bb436",slug:"chronic-lymphocytic-leukemia",bookSignature:"Pablo Oppezzo",coverURL:"https://cdn.intechopen.com/books/images_new/647.jpg",editedByType:"Edited by",editors:[{id:"68891",title:"Dr.",name:"Pablo",surname:"Oppezzo",slug:"pablo-oppezzo",fullName:"Pablo Oppezzo"}],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:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],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"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],ofsBooks:[]},correction:{item:{id:"76873",slug:"corrigendum-satellite-control-system-part-i-architecture-and-main-components",title:"Corrigendum: Satellite Control System: Part I - Architecture and Main Components",doi:null,correctionPDFUrl:"https://cdn.intechopen.com/pdfs/76873.pdf\r\n",downloadPdfUrl:"/chapter/pdf-download/76873",previewPdfUrl:"/chapter/pdf-preview/76873",totalDownloads:null,totalCrossrefCites:null,bibtexUrl:"/chapter/bibtex/76873",risUrl:"/chapter/ris/76873",chapter:{id:"72485",slug:"satellite-control-system-part-i-architecture-and-main-components",signatures:"Yuri V. Kim",dateSubmitted:"February 17th 2020",dateReviewed:"April 16th 2020",datePrePublished:"June 15th 2020",datePublished:"April 14th 2021",book:{id:"7030",title:"Satellite Systems",subtitle:"Design, Modeling, Simulation and Analysis",fullTitle:"Satellite Systems - Design, Modeling, Simulation and Analysis",slug:"satellite-systems-design-modeling-simulation-and-analysis",publishedDate:"April 14th 2021",bookSignature:"Tien Nguyen",coverURL:"https://cdn.intechopen.com/books/images_new/7030.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"210657",title:"Dr.",name:"Tien M.",middleName:"Manh",surname:"Nguyen",slug:"tien-m.-nguyen",fullName:"Tien M. Nguyen"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"316140",title:"Dr.",name:"Yuri",middleName:null,surname:"Kim",fullName:"Yuri Kim",slug:"yuri-kim",email:"yurikim@hotmail.ca",position:null,institution:{name:"Canadian Space Agency",institutionURL:null,country:{name:"Canada"}}}]}},chapter:{id:"72485",slug:"satellite-control-system-part-i-architecture-and-main-components",signatures:"Yuri V. Kim",dateSubmitted:"February 17th 2020",dateReviewed:"April 16th 2020",datePrePublished:"June 15th 2020",datePublished:"April 14th 2021",book:{id:"7030",title:"Satellite Systems",subtitle:"Design, Modeling, Simulation and Analysis",fullTitle:"Satellite Systems - Design, Modeling, Simulation and Analysis",slug:"satellite-systems-design-modeling-simulation-and-analysis",publishedDate:"April 14th 2021",bookSignature:"Tien Nguyen",coverURL:"https://cdn.intechopen.com/books/images_new/7030.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"210657",title:"Dr.",name:"Tien M.",middleName:"Manh",surname:"Nguyen",slug:"tien-m.-nguyen",fullName:"Tien M. Nguyen"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"316140",title:"Dr.",name:"Yuri",middleName:null,surname:"Kim",fullName:"Yuri Kim",slug:"yuri-kim",email:"yurikim@hotmail.ca",position:null,institution:{name:"Canadian Space Agency",institutionURL:null,country:{name:"Canada"}}}]},book:{id:"7030",title:"Satellite Systems",subtitle:"Design, Modeling, Simulation and Analysis",fullTitle:"Satellite Systems - Design, Modeling, Simulation and Analysis",slug:"satellite-systems-design-modeling-simulation-and-analysis",publishedDate:"April 14th 2021",bookSignature:"Tien Nguyen",coverURL:"https://cdn.intechopen.com/books/images_new/7030.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"210657",title:"Dr.",name:"Tien M.",middleName:"Manh",surname:"Nguyen",slug:"tien-m.-nguyen",fullName:"Tien M. Nguyen"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"8375",leadTitle:null,title:"Recent Advances in Flood Risk Management",subtitle:null,reviewType:"peer-reviewed",abstract:"This book provides a series of topics on flood risk management from around the world. The first section includes models for improved approaches to flood risk management, the importance of groundwater management in the context of floods (focussing on Taiwan), contingency plan for local communities using flood simulation, deciding on response strategies against the identified flood risk before a flood occurs (illustrated for the Philippines) and models for estimating maximum flood heights (illustrated for Mozambique). The second section examines flood risk management relating to the urban environment, with examples from a coastal city in Saudi Arabia and a housing development in Mexico. The third section relates to flood risk management in the context of agriculture, particularly relating to damage to Asian rice crops.",isbn:"978-1-78923-936-2",printIsbn:"978-1-78923-935-5",pdfIsbn:"978-1-83962-104-8",doi:"10.5772/intechopen.78505",price:119,priceEur:129,priceUsd:155,slug:"recent-advances-in-flood-risk-management",numberOfPages:142,isOpenForSubmission:!1,isSalesforceBook:!1,hash:"c2f3e2f3d1f9b7a5d94177b56a0b13a4",bookSignature:"John Abbot and Andrew Hammond",publishedDate:"April 3rd 2019",coverURL:"https://cdn.intechopen.com/books/images_new/8375.jpg",keywords:null,numberOfDownloads:8667,numberOfWosCitations:11,numberOfCrossrefCitations:6,numberOfDimensionsCitations:14,numberOfTotalCitations:31,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 22nd 2018",dateEndSecondStepPublish:"June 12th 2018",dateEndThirdStepPublish:"August 11th 2018",dateEndFourthStepPublish:"October 30th 2018",dateEndFifthStepPublish:"December 29th 2018",remainingDaysToSecondStep:"4 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:"Edited by",kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"225780",title:"Dr.",name:"John",middleName:null,surname:"Abbot",slug:"john-abbot",fullName:"John Abbot",profilePictureURL:"https://mts.intechopen.com/storage/users/225780/images/system/225780.jpeg",biography:"John Abbot has degrees in chemistry from Imperial College London, the university of British Columbia and McGill University. He subsequently undertook research in kinetic phenomena involving industrial processes at Queens University, Canada and the University of Tasmania. He also holds degrees in law, finance and business administration. He carried out projects in environmental science as a Professorial Research fellow Central Queensland University from 2009 to 2015. Major flooding events in Queensland in 2011, causing loss of life, extensive property damage and disruption of industry led to developing an interest in the application of neural networks to provide improved medium-term rainfall forecasts for Australia. A series of publications demonstrate that skill of forecasts is significantly superior to official forecasts produced using general circulation models.",institutionString:"University of Tasmania",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"University of Tasmania",institutionURL:null,country:{name:"Australia"}}}],coeditorOne:{id:"259487",title:"Dr.",name:"Andrew",middleName:null,surname:"Hammond",slug:"andrew-hammond",fullName:"Andrew Hammond",profilePictureURL:"https://mts.intechopen.com/storage/users/259487/images/system/259487.jpg",biography:"Dr. Hammond is a Senior Lecturer in Geoscience within the School of Engineering & Technology at Central Queensland University’s Rockhampton Campus, Central Queensland, Australia. He holds undergraduate degrees in Geology and Geography from the University of Tasmania and postgraduate degrees, Master of Applied Science in Pedology from the University of Canterbury, and Ph.D. in Earth Science from Massey University, both in New Zealand. His research interests are basin tectonics and stratigraphy, sedimentology, soil/regolith geology, hydrogeology, geohazards, mining education, and the use and interpretation of geospatial imagery for environmental assessment and land resource management. He has over 30 years\\' geoscience consultancy, research, and teaching experience having worked in a range of geological landscapes within Australia and New Zealand. He held senior research scientist positions in State (Tasmania) and Australian Government agencies and as a researcher in Queensland university research centers.",institutionString:"Central Queensland University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Central Queensland University",institutionURL:null,country:{name:"Australia"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1326",title:"Disaster Management",slug:"disaster-management"}],chapters:[{id:"64220",title:"New Frontiers in Flood Risk Management",slug:"new-frontiers-in-flood-risk-management",totalDownloads:986,totalCrossrefCites:0,authors:[{id:"262657",title:"Prof.",name:"Guangwei",surname:"Huang",slug:"guangwei-huang",fullName:"Guangwei Huang"}]},{id:"64061",title:"Flood Damage Reduction in Land Subsidence Areas by Groundwater Management",slug:"flood-damage-reduction-in-land-subsidence-areas-by-groundwater-management",totalDownloads:1033,totalCrossrefCites:0,authors:[{id:"262443",title:"Prof.",name:"Yeou-Koung",surname:"Tung",slug:"yeou-koung-tung",fullName:"Yeou-Koung Tung"},{id:"267415",title:"Dr.",name:"Yin-Lung",surname:"Chang",slug:"yin-lung-chang",fullName:"Yin-Lung Chang"},{id:"267416",title:"Prof.",name:"Jinn-Chuang",surname:"Yang",slug:"jinn-chuang-yang",fullName:"Jinn-Chuang Yang"},{id:"267417",title:"Prof.",name:"Chehao",surname:"Chang",slug:"chehao-chang",fullName:"Chehao Chang"},{id:"267418",title:"Prof.",name:"Tung-Lin",surname:"Tsai",slug:"tung-lin-tsai",fullName:"Tung-Lin Tsai"}]},{id:"64604",title:"Evidence-Based Contingency Planning to Enhance Local Resilience to Flood Disasters",slug:"evidence-based-contingency-planning-to-enhance-local-resilience-to-flood-disasters",totalDownloads:1446,totalCrossrefCites:2,authors:[{id:"261112",title:"Dr.",name:"Miho",surname:"Ohara",slug:"miho-ohara",fullName:"Miho Ohara"},{id:"264405",title:"Dr.",name:"Badri",surname:"Shrestha",slug:"badri-shrestha",fullName:"Badri Shrestha"},{id:"270525",title:"Mr.",name:"Hisaya",surname:"Sawano",slug:"hisaya-sawano",fullName:"Hisaya Sawano"},{id:"272127",title:"Dr.",name:"Naoko",surname:"Nagumo",slug:"naoko-nagumo",fullName:"Naoko Nagumo"}]},{id:"64508",title:"Fitting a Generalised Extreme Value Distribution to Four Candidate Annual Maximum Flood Heights Time Series Models in the Lower Limpopo River Basin of Mozambique",slug:"fitting-a-generalised-extreme-value-distribution-to-four-candidate-annual-maximum-flood-heights-time",totalDownloads:793,totalCrossrefCites:0,authors:[{id:"260769",title:"Dr.",name:"Daniel",surname:"Maposa",slug:"daniel-maposa",fullName:"Daniel Maposa"}]},{id:"64449",title:"Flood Risk and Vulnerability of Jeddah City, Saudi Arabia",slug:"flood-risk-and-vulnerability-of-jeddah-city-saudi-arabia",totalDownloads:1410,totalCrossrefCites:1,authors:[{id:"259982",title:"Dr.",name:"Mohamed",surname:"Daoudi",slug:"mohamed-daoudi",fullName:"Mohamed Daoudi"},{id:"260410",title:"Dr.",name:"Abdoul Jelil",surname:"Niang",slug:"abdoul-jelil-niang",fullName:"Abdoul Jelil Niang"}]},{id:"65350",title:"Flood Risk Assessment in Housing under an Urban Development Scheme Simulating Water Flow in Plains",slug:"flood-risk-assessment-in-housing-under-an-urban-development-scheme-simulating-water-flow-in-plains",totalDownloads:904,totalCrossrefCites:1,authors:[{id:"4451",title:"Dr.",name:"Judith",surname:"Ramos",slug:"judith-ramos",fullName:"Judith Ramos"},{id:"262117",title:"M.Sc.",name:"Faustino",surname:"De Luna",slug:"faustino-de-luna",fullName:"Faustino De Luna"},{id:"262853",title:"Dr.",name:"Oscar",surname:"Fuentes-Mariles",slug:"oscar-fuentes-mariles",fullName:"Oscar Fuentes-Mariles"},{id:"270618",title:"Dr.",name:"Jesús",surname:"Gracia Sánchez",slug:"jesus-gracia-sanchez",fullName:"Jesús Gracia Sánchez"}]},{id:"63555",title:"Methodology for Agricultural Flood Damage Assessment",slug:"methodology-for-agricultural-flood-damage-assessment",totalDownloads:2101,totalCrossrefCites:2,authors:[{id:"261112",title:"Dr.",name:"Miho",surname:"Ohara",slug:"miho-ohara",fullName:"Miho Ohara"},{id:"264405",title:"Dr.",name:"Badri",surname:"Shrestha",slug:"badri-shrestha",fullName:"Badri Shrestha"},{id:"270525",title:"Mr.",name:"Hisaya",surname:"Sawano",slug:"hisaya-sawano",fullName:"Hisaya Sawano"},{id:"270526",title:"Dr.",name:"Yusuke",surname:"Yamazaki",slug:"yusuke-yamazaki",fullName:"Yusuke Yamazaki"},{id:"270527",title:"Mr.",name:"Yoshio",surname:"Tokunaga",slug:"yoshio-tokunaga",fullName:"Yoshio Tokunaga"}]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"177731",firstName:"Dajana",lastName:"Pemac",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/177731/images/4726_n.jpg",email:"dajana@intechopen.com",biography:"As a Commissioning Editor at IntechOpen, I work closely with our collaborators in the selection of book topics for the yearly publishing plan and in preparing new book catalogues for each season. This requires extensive analysis of developing trends in scientific research in order to offer our readers relevant content. Creating the book catalogue is also based on keeping track of the most read, downloaded and highly cited chapters and books and relaunching similar topics. I am also responsible for consulting with our Scientific Advisors on which book topics to add to our catalogue and sending possible book proposal topics to them for evaluation. Once the catalogue is complete, I contact leading researchers in their respective fields and ask them to become possible Academic Editors for each book project. Once an editor is appointed, I prepare all necessary information required for them to begin their work, as well as guide them through the editorship process. I also assist editors in inviting suitable authors to contribute to a specific book project and each year, I identify and invite exceptional editors to join IntechOpen as Scientific Advisors. I am responsible for developing and maintaining strong relationships with all collaborators to ensure an effective and efficient publishing process and support other departments in developing and maintaining such relationships."}},relatedBooks:[{type:"book",id:"7767",title:"Rainfall",subtitle:"Extremes, Distribution and Properties",isOpenForSubmission:!1,hash:"9f9b3b7d86cb46e2ce3653587805475d",slug:"rainfall-extremes-distribution-and-properties",bookSignature:"John Abbot and Andrew Hammond",coverURL:"https://cdn.intechopen.com/books/images_new/7767.jpg",editedByType:"Edited by",editors:[{id:"225780",title:"Dr.",name:"John",surname:"Abbot",slug:"john-abbot",fullName:"John Abbot"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3054",title:"Approaches to Disaster Management",subtitle:"Examining the Implications of Hazards, Emergencies and Disasters",isOpenForSubmission:!1,hash:"0d6576de4f4c7fc7b8db5e91cba6dc28",slug:"approaches-to-disaster-management-examining-the-implications-of-hazards-emergencies-and-disasters",bookSignature:"John Tiefenbacher",coverURL:"https://cdn.intechopen.com/books/images_new/3054.jpg",editedByType:"Edited by",editors:[{id:"73876",title:"Dr.",name:"John P.",surname:"Tiefenbacher",slug:"john-p.-tiefenbacher",fullName:"John P. Tiefenbacher"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6620",title:"Crisis Management",subtitle:"Theory and Practice",isOpenForSubmission:!1,hash:"f3b12d109006096ab14d339a50fa1860",slug:"crisis-management-theory-and-practice",bookSignature:"Katarina Holla, Michal Titko and Jozef Ristvej",coverURL:"https://cdn.intechopen.com/books/images_new/6620.jpg",editedByType:"Edited by",editors:[{id:"184727",title:"Dr.",name:"Katarina",surname:"Holla",slug:"katarina-holla",fullName:"Katarina Holla"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7712",title:"Natural Hazards",subtitle:"Impacts, Adjustments and Resilience",isOpenForSubmission:!1,hash:"279dba9ff08f763c747d1976a17c8ea4",slug:"natural-hazards-impacts-adjustments-and-resilience",bookSignature:"Ehsan Noroozinejad Farsangi",coverURL:"https://cdn.intechopen.com/books/images_new/7712.jpg",editedByType:"Edited by",editors:[{id:"70678",title:"Dr.",name:"Ehsan",surname:"Noroozinejad Farsangi",slug:"ehsan-noroozinejad-farsangi",fullName:"Ehsan Noroozinejad Farsangi"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10032",title:"Fire Safety and Management Awareness",subtitle:null,isOpenForSubmission:!1,hash:"ba924ac3ec282316ae8ba97882cc4592",slug:"fire-safety-and-management-awareness",bookSignature:"Fahmina Zafar and Anujit Ghosal",coverURL:"https://cdn.intechopen.com/books/images_new/10032.jpg",editedByType:"Edited by",editors:[{id:"89672",title:"Dr.",name:"Fahmina",surname:"Zafar",slug:"fahmina-zafar",fullName:"Fahmina Zafar"}],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:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],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"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"51791",title:"Immune Dysregulation in Myelodysplastic Syndromes: Pathogenetic-Pathophysiologic Aspects and Clinical Consequences",doi:"10.5772/64618",slug:"immune-dysregulation-in-myelodysplastic-syndromes-pathogenetic-pathophysiologic-aspects-and-clinical",body:'\nMyelodysplastic syndromes (MDS) are diseases emerging from somatic mutations of a pluripotent hematopoietic stem cell, affecting its functional capacity for maturation and differentiation, but preserving it alive and capable to escape from apoptotic signals. The affected cell creates a clone, gradually suppressing nonclonal cells, and finally dominating in the bone marrow. Clonal cells are prone to additional genetic events, promoting survival advantage and further impairing differentiation and maturation, thus generating a neoplastic phenotype, with the evolution to acute myelogenous leukemia (AML). Since such genetic events occur serially, but with a variable evolutionary potential, MDS represent probably the best
One rather unexpected aspect of MDS pathophysiology is the strong involvement of the immune system. Soon after the initial description of MDS, many “immune abnormalities” were reported in the literature. The “easy” initial interpretation of the participation of the immune system to the dysplastic clone was quickly changed, in favor of other explanations. But even now, a clear interpretation and a definite treatment strategy for these “abnormalities” have not been established. In this chapter, we describe the spectrum of “
Infections of various etiologies are common among MDS patients and represent one of the major presenting features, but also a leading cause of morbidity and mortality. Beside the usually advanced patient age and comorbidity, the major predisposing factor in many retrospective studies analyzing the frequency and severity of infections is the depth of neutropenia. Functional neutrophil abnormalities have also been reported, such as impaired locomotion and chemotaxis, reduced complement receptor-1 and -3 expressions, and reduced enzymatic armamentarium, resulting in impaired respiratory burst and reduced bactericidal and fungicidal capacity. These defects have been observed in all types of MDS but are more frequent in the higher risk groups [1]. However, severe common and opportunistic infections may be manifested in nonneutropenic patients. In these cases, besides the functional neutrophil impairment, various acquired defects of the adaptive immunity, affecting immunocompetent cell populations have been proposed as predisposing factors. Finally, transfusions, transfusion-induced iron overload, and the newer treatment modalities, such as lenalidomide and hypomethylating agents, may hamper immune functions and contribute to the development of infections.
\nThere are several published cases or small series of patients manifesting pyogenic collections/abscesses, not only at common sites (perianal, splenic, liver), but also at rare and uncommon (pararenal, intramuscular, paracolic, etc.), without the development of strong inflammatory reaction [2, 3]. It has been suggested that mature granulocytes of MDS patients may not produce effective inflammatory reaction to eliminate pathogens, and induce the formation of granulomas or abscesses [1, 2]. MDS patients, even when nonneutropenic, may exhibit delayed healing of infections and have increased intracellular neutrophil collagenase activity, irrespective of WHO or IPSS subgroup [3].
\nOther patients manifest bacterial, viral, and fungal infections, from rare/opportunistic pathogens, before any immunosuppressive or cytotoxic treatment, similar to those encountered among patients with underlying congenital or acquired immunodeficiency. Among such rare bacterial pathogens, coagulase-negative
Only few years after the recognition of MDS as separate entities and the proposal of their first classification system (FAB classification), it was obvious that they were associated with increased frequency of various immune abnormalities, either abnormal laboratory findings, such as organ- and non-organ-specific autoantibodies, or true clinical syndromes or diseases, reflecting severely impaired adaptive immunity.
\nAmong the autoimmune or immune-mediated clinical syndromes, described in association with MDS, Coombs-positive immunohemolytic anemia (AIHA) [4], immune thrombocytopenia (ITP) [5], Evans’ syndrome, autoimmune neutropenia, and pure red cell aplasia (usually drug-related) are included. AIHA is somewhat more common, and is usually of warm type, associated with mild to moderate chronic hemolysis [4]. It can be automatically presented or triggered by red blood cell transfusions. Treatment is mainly based on corticosteroids, but response rate is lower than in the idiopathic cases, and even when a “complete” response is achieved, this cannot be objectively evaluated due to coexistence of the basic disease, which has as a major manifestation anemia, although not clearly hemolytic. When corticosteroids are ineffective or associated with unacceptable toxicity, cyclosporine-A, mofetil mycophenolate, or pulses of vinca alkaloids may be used. In some instances immunosuppressive treatment may be accompanied by trilineage response, improving also neutrophil and platelet counts.
\nImmune thrombocytopenia particularly of chronic type, when manifested in elderly patients may mimic true MDS, particularly when there is additional underlying comorbidity and patients also have anemia of chronic disease. In such instances, the differential diagnosis is difficult and this is clearly an overlapping area of hematological disorders [6]. More complicating is the fact that these two different entities may share some common pathogenetic features, concerning premature megakaryocyte cell death [7]. However, true immune thrombocytopenia with high titers of antiplatelet autoantibodies may be the presenting feature [6, 8] or may complicate the course of a previously diagnosed MDS [9]. In some instances, ITP may precede and MDS may follow some months or years, even after the achievement of complete response of the ITP. Thrombocytopenia has been related to higher amount of glycocalicin and platelet-associated IgG, higher MPV, more advanced disease, and worse prognosis in patients with MDS. The occurrence of ITP has been more frequently reported in chronic myelomonocytic leukemia (CMML) and the del-5q syndrome, whereas relatively severe thrombocytopenia, with mild-moderate or absence of anemia and neutropenia has been reported among patients with isolated del-20q [10]. Retrospective evaluation of 123 patients with CMML revealed the presence of auto-/hyperimmune disorders in 19.5% of them, compared to 3–4% incidence in the general population [11]. CMML has been considered the MDS, most frequently associated with “paraneoplastic” manifestations. Finally, high frequency of hypocomplementemia, often associated with severe cytopenia, particularly in patients with lower risk MDS has been reported, suggesting the possible contribution of autoimmune mechanisms in its pathogenesis [12].
\nDominant position among the immune hyperactivity/autoimmunity syndromes possess the various systemic vasculitides, such as febrile neutrophilic dermatosis (Sweet’s syndrome) [13], other leucocytoclastic vasculitides, and necrotizing panniculitis, most commonly localized in the skin and accompanied by rashes or resulting in extended skin ulcerations. Large vessel arteritis (Takayasu’s disease), aortitis, and other organ-specific vasculitides, such as Wegener’s granulomatosis, have been reported. Additional cutaneous manifestations associated with the occult or prominent presence of an MDS include granulomatous eruptions, pyoderma gangrenosum, erythema nodosum, erythema elevatum diutinum, bullous pemphigoid, cutaneous lupus, Behçet’s disease, dermatomyositis, and Raynaud’s syndrome.
\n\nHematological | \n(Other) Cutaneous syndromes | \n
---|---|
Immunohemolytic anemia | \nErythema nodosum | \n
Immune thrombocytopenia | \nPyoderma gangrenosum | \n
Evans’ syndrome | \nErythema elevatum diutinum | \n
Chronic cold agglutinin disease | \nBullous pemphigoid | \n
Autoimmune neutropenia | \nCutaneous lupus | \n
Pure red cell aplasia | \nGranulomatous eruptions | \n
\n | Raynaud phenomenon | \n
\n | \n\n |
Systemic lupus erythematosus | \n\n | \n
Classical seropositive rheumatoid arthritis | \nFever of unknown origin (disease related) | \n
Seronegative rheumatoid arthritis | \nSarcoidosis – sarcoidotic-type granulomata | \n
Sjögren’s syndrome | \nIridocyclitis – uveitis | \n
Mixed connective tissue disease | \nSterile osteomyelitis | \n
Polymyalgia rheumatica | \nHashimoto’s thyroiditis | \n
Seronegative migratory synovitis | \nAddison disease | \n
Remitting symmetrical synovitis with pitting edema | \nBehcet disease | \n
Eosinophilic fasciitis | \nPericarditis | \n
Relapsing polychondritis | \nPleural effusions | \n
Polymyosistis | \nChronic autoimmune hepatitis | \n
Dematomyosistis | \nInflammatory bowel disease | \n
\n | Ulcerative colitis | \n
\n | \nAutoimmune pancreatitis | \n
Sweet’s syndrome | \nPulmonary alveolar proteinosis | \n
Leucocytoclastic vasculitis | \nBronchiolitis obliterans organizing pneumonia | \n
Periarteritis nodosa | \nNephrotic syndrome | \n
Wegener granulomatosis | \nSegmental glomerulosclerosis | \n
Large vessel arteritis (Takayasu disease) | \nPeripheral demyelinating polyneuropathy | \n
Aortitis | \nExpressive aphasia | \n
Necrotizing panniculitis | \n\n |
Clinical syndromes of auto-/hyperimmune basis associated with myelodysplasia.
Fever of unknown origin in the absence of any known underlying condition has been described in association with MDS and may be accompanied by mild lymphadenopathy and sarcoidic-type noncaseating granulomata, high serum ferritin, and polyclonal hyper-γ-globulinemia. Various rheumatic manifestations may also be associated with an MDS and some patients are diagnosed following an initial presentation of a typical rheumatic disease. Remitting seronegative symmetrical synovitis with pitting edema has been reported as an initial presentation of MDS, with subsequent manifestation of relapsing polychondritis. Besides the more frequent than expected classical rheumatoid arthritis and systemic lupus erythematosus, seronegative migratory synovitis, various seropositive and seronegative polyarthritic syndromes, polymyositis, polymyalgia rheumatica, eosinophilic fasciitis, Sjögren’s syndrome, and mixed connective tissue disease have also been reported.
\nLess common syndromes are noninfectious serosal effusions, usually pleural, but sometimes also pericarditis, chronic autoimmune hepatitis, Hashimoto’s thyroiditis, Addison’s disease, inflammatory bowel disease, glomerulonephritis and nephrotic syndrome, focal and segmental glomerulosclerosis, chronic autoimmune pancreatitis, ulcerative colitis, and various syndromes reflecting immune-based inflammatory processes of the CNS, such as seizures, expressive aphasia and paresis, and peripheral demyelinating polyneuropathy [14]. Finally, noninfectious pulmonary infiltrates, sometimes typical for alveolar proteinosis and bronchiolitis obliterans organizing pneumonia (BOOP), in the absence of previous allogeneic transplantation have also been reported. Table 1 summarizes the various auto-/hyperimmune syndromes, sometimes called “paraneoplastic,” associated with MDS.
\n\nOf particular interest is the syndrome of relapsing polychondritis, which, besides the presentation as an idiopathic autoimmune syndrome, has almost exclusively been reported in association with MDS and very rarely with other diseases. Thus, among newly diagnosed polychondritis, without any evidence for a hematological disorder, BM examination may reveal the presence of an as yet undiagnosed MDS [15]. Polychondritis is manifested as painful inflammation of the cartilaginous areas of the body, such as the external ear, the basal area of the nose and the nasal septum, the synovial cartilage, and the tracheal and bronchial cartilaginous rings. Symptomatic period may persist for many days or some weeks, followed by resolution, but symptoms reappear after weeks or months. The cartilage is finally destroyed, resulting in anatomical malformation and functional disturbances. The syndrome may be associated with fever, renal, cardiovascular, or ocular manifestations, as well as by symptoms, related to organ-specific dysfunction, not clearly containing cartilaginous tissue [16]. Pathogenesis is clearly immune-based and may reflect immunological reaction against some marrow stromal elements, which also exist in the cartilaginous tissue. Prompt intervention with corticosteroids accelerates resolution of the inflammatory reaction and may reduce tissue destruction and malformations.
\nAutoimmune diseases have been reported on average in 10–30% of MDS patients, in all age groups and disease subtypes sometimes more frequently among females and in patients with higher risk MDS or CMML [9, 17]. In some early studies, the frequency of true autoimmune diseases among series of MDS patients was not found increased compared to non-MDS subjects of similar age. Moreover, the detection of various autoantibodies, directed against erythrocytic, neutrophilic, and platelet components, in the serum of MDS patients has been disputed, whether it really represents an immune abnormality, and has been attributed to the advanced patient age to thorough searching processes or to alloimmunization from the frequent transfusions. It has been suggested, although not proved, that similar results could be obtained from multiply transfused non-MDS patients of advanced age [18]. In another study, patients exhibiting immune abnormalities were younger and had mainly therapy-related MDS with complex chromosomal aberrations [9]. Among the reported cases with available cytogenetics, trisomy 8 cases are rather overrepresented, but in the majority of described series of patients no clear preponderance of any demographic, cytogenetic, or histological feature was found [19]. In some studies, the frequency of autoimmune diseases is higher, but there is the possibility of misinterpretation of dysplastic bone marrow changes attributed to the advanced patient age or to the underlying autoimmune disease as indicative of primary MDS [17]. In a large French multicenter retrospective analysis of 123 MDS patients, exhibiting systemic inflammatory and autoimmune diseases (SIADs), vasculitic syndromes were more frequently encountered among CMML, and a comparison of this group with 665 patients without such manifestations revealed that patients exhibiting SIADs were younger, male, without RARS, with higher risk disease, and a poor karyotype, but without survival difference [20].
\nAutoimmune manifestations may not be a single clinical syndrome, but a clustering of two or more autoimmune or immune-based conditions may occur in the same patient. Autoantibodies most frequently found are either organ-specific or non-organ-specific, such as rheumatoid factor, antinuclear antibodies, antineutrophil cytoplasmic (cANCA), or antineutrophil perinuclear antibodies (pANCA), the last two been associated with various vasculitides. Interferon regulatory factor-1 (IRF-1) mRNA expression was found 10-folds increased in MDS patients with autoimmune manifestations, in sharp difference to those without, and to normal controls. It was therefore suggested that absence of IRF-1 expression may be a protective mechanism preventing autoimmunity in MDS [21]. However, from the prognostic point of view although patients with autoimmune manifestations have similar overall survival compared to patients without those with higher IRF-1 expression have longer survival [22].
\nThere is no agreement whether autoimmune manifestations influence prognosis. This is because the severity of autoimmune diseases and conditions, supervened by a MDS, may be substantially diverse and prevent their evaluation as an additional prognostic factor. The majority of retrospective studies tend to demonstrate a survival advantage for patients not exhibiting (auto)immune abnormalities as compared to those who did [23]; however, other studies did not show any difference [9]. In a Japanese study, patients with immune abnormalities had more frequent infections, faster leukemic transformation, and shorter survival. Autoimmune diseases usually respond partially or temporarily to immunosuppressive treatment, but they may relapse and follow the basic disease activity [18]. In other instances they may persist throughout the course of the MDS and demand unaffordable corticosteroid doses to be controlled. In any case, autoimmune diseases remit permanently with allogeneic stem cell transplantation. Remission of autoimmune manifestations has been associated with improved survival, although in some studies it may accelerate evolution to AML. Furthermore, achievement of remission and return to the MDS stage may induce relapse of the autoimmune condition and in general the manifestation of autoimmunity follows the dysplastic phase and disappear during evolution to AML [24].
\nIn the largest retrospective epidemiologic and prognostic analysis of about 1400 patients, 28% exhibited hyper/autoimmune manifestations and the most prominent was hypothyroidism associated with Hashimoto’s thyroiditis (12% of the total population or 44% of the autoimmune syndromes), followed by immune thrombocytopenia (12%), rheumatoid arthritis (10%), and psoriasis (7%). Autoimmune conditions were more frequent among females with lower risk disease, and less transfusion dependent. The probability for AML transformation was lower and the median survival significantly higher for patients with autoimmune diseases (60 versus 45 months), and in multivariate analysis, adjusted for age and IPSS, the manifestation of an autoimmune syndrome was an independent favorable prognostic factor [23].
\nMany investigational studies have focused on various parameters of adaptive immunity in MDS. In the majority of patients, peripheral blood lymphopenia, mainly CD4+ cell lymphopenia, and to a lesser degree or at all, CD8+ cell reduction, frequently resulting in reduction or inversion of the CD4/CD8 cell ratio has been recognized. These findings have not been associated with specific FAB subtypes or any other clinical or laboratory feature [10, 20]. Many studies have confirmed the previous findings, particularly in patients with RAEB, and demonstrated severe functional T-cell impairment in terms of sluggish reaction to mitogenic stimuli and increased radiosensitivity, reflecting impaired DNA repair, implying that these defects might impact on patient hematopoiesis [25].
\nAn initial approach for the interpretation of the numerical imbalance of T-cell subsets was that they might be attributed to multiple red blood cell transfusions, since in some early studies a correlation of the severity of T-lymphocyte abnormalities with transfusion intensity was reported [26]. However, it soon became clear that T-lymphocyte imbalance was present already at baseline, before any medical intervention, and therefore this finding might most probably be a disease feature. T cells of MDS patients synthesize lower amounts of the TH1 direction cytokines interleukin-2 (IL-2) and interferon-gamma (IFN-γ), following mitogenic stimulation, respond inadequately to IL-2 and cooperate inefficiently with B lymphocytes in the induction of immunoglobulin production [24–28]. Studies of NK cell function have always reported reduced cytotoxic and cytolytic activity against cellular targets, as well as impaired both complement-dependent (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) [27]; however, in many other more recent studies, no abnormality in NK cells has been identified. We have investigated several immune function parameters at baseline on the same population of 81 patients with various MDS subtypes and we have shown that patients with RAEB had more profound CD3+ and CD4+ lymphopenia, and significantly lower and sometimes inverted CD4/CD8 cell ratio. We have also shown that CD3+ and CD8+ cell lymphopenia were associated with more frequent infections, higher AML evolution rate, and shorter overall survival [28]. A Japanese group confirmed decreased CD8+ cells in RA patients and inverted bone marrow CD4/CD8 cell ratio, with increased activated CD8+CD11α+ cells in all patients. RAEB patients had decreased marrow total T cells and all MDS patients had decreased marrow CD4+CD45RA+ naïve- and increased CD4+CD45RO+ memory T-helper cells, probably indicating impaired immune surveillance permitting the undisturbed evolution of the dysplastic clone. The prognostic significance of the numerical T-cell abnormalities on the above-mentioned issues was confirmed by other groups [19, 29]. Evaluation of lymphocyte subsets in bone marrow biopsies with specific immunostaining has not demonstrated any quantitative or qualitative T- and NK-cell abnormality, but only revealed increased B lymphocytes in patients with higher risk disease and it has been suggested that identification of >3% B lymphocytes in the marrow biopsy is an adverse prognostic feature [30].
\nFAB | \nReaction | \n\n | Total Erythema (mm) / Positive Antigens (mean) | \nComposite score | \n|
---|---|---|---|---|---|
\n | (+/-) | \n(+) % | \n\n | \n | \n |
RA | \n8/12 | \n66.7 | \n11.9/3.00 | \n18.2 ± 2.7 | \n0.160 | \n
RARS | \n4/10 | \n40.0 | \n8.6/2.40 | \n12.1 ± 1.9 | \n\n | \n
RAEB | \n10/16 | \n62.5 | \n11.2/2.43 | \n16.1 ± 2.2 | \n\n | \n
RAEBt | \n2 / 8 | \n25.0 | \n6.3/2.25 | \n10.7 ± 1.5 | \n\n | \n
CMML | \n5 / 8 | \n62.5 | \n8.8/2.87 | \n14.8 ± 0.7 | \n\n | \n
Total | \n29/54 | \n53.7 | \n9.8/2.59 | \n14.8 ± 1.0 | \n0.0003 | \n
Controls | \n16/18 | \n88.9 | \n17.4/4.11 | \n25.8 ± 2.4 | \n\n |
Results of the skin reaction to Multitest CMI® in patients with MDS
Patients with MDS-RA and with aplastic anemia exhibit Th1 and Tc1 polarization of their immune activation [31]. Later this was confirmed also for patients with refractory cytopenia with multilineage dysplasia (RCMD) and was correlated with very high serum and marrow IFN-γ and tumor necrosis factor-α (TNF-α) levels, and high degree of apoptosis. Higher Th1/Th2 and Tc1/Tc2 ratios have been observed in patients with lower risk IPSS and normal karyotype, but not in aneuploid karyotypes. Th1 polarization may not be a uniform finding in MDS patients, but concerns only a subgroup of RCMD with prominent CD8+ lymphopenia [32].
\nActivated T lymphocytes do not belong to the dysplastic/leukemic clone and express HLA-DR, CD25, CD45RO, and CD57, but not CD28 and CD62L. This antigenic profile is independent of disease subtype, prognostic classification, kind of cytogenetic abnormality, or any other feature [33]. Interestingly, both patients with lower risk MDS and those with aplastic anemia have increased T-lymphocyte counts and B lymphocytopenia compared to patients with high-risk MDS and to controls, but lower risk MDS patients exhibit stronger and uniform Th1/Tc1 polarization than those with aplastic anemia [34]. Moreover, bone marrow NK T-cell infiltrates express the activated effector T-cell phenotype CD8+CD57+CD28−CD62L− and the NK C-lectin-family receptors NKG2D and CD244. These infiltrates represent oligoclonal expansions of autoreactive T cells, as this can be demonstrated by TCR clonality assays and are more prominently identified in the bone marrow than in the peripheral blood [35].
\nMDS patients also exhibit impairment of delayed cutaneous T-cell hypersensitivity, as this can be demonstrated with various skin patch tests, challenging reaction to common antigens. Most importantly, they may lose immunologic memory against potentially important antigens, such as tuberculin and
Further understanding of the immune dysregulation of MDS was achieved through investigation of the regulatory T cells (T-regs). T-regs are a specific subset of helper T cells, inducing immune tolerance and moderating the intensity of immune reactions. Many autoimmune and neoplastic diseases are associated with T-reg impairment, favoring uncontrolled immune activation and attenuation of immune surveillance against tumor growth. An increase of polyclonal/nonclonal T cells in higher risk MDS, and a significant correlation of T-reg number, with the percentage of marrow blasts, the IPSS and progression to AML has been reported [37]. T-regs, characterized as CD4+ CD25high+FOXP3+ or CD4+CD25high+CD127low cells, were found increased in lower risk MDS but they were not correlated with any known disease feature or lab finding [38]. Investigation of the T-reg kinetics, function, and trafficking has revealed that in early MDS, peripheral blood and marrow T-regs are normal in number but dysfunctional, exhibiting lower CXCR4 expression and impaired marrow homing. In contrast, at late MDS or at leukemic transformation, T-regs increase and become functional and migrating. Effective treatment partially restores the number, but disease relapse is again associated with T-reg expansion. Thus, T-regs may share a pathophysiological role in MDS, since impaired suppressor function results in autoimmune phenomena, whereas in more advanced stages, their expansion favors clonal development and leukemic transformation [39]. It has been suggested that absolute number of a T-reg subpopulation, the “effector regulatory T cells,” characterized as CD4+FOXP3+CD25+CD127lowCD45RA−CD27− cells, could be used as a prognostic factor in lower risk MDS predicting severity of anemia, AML transformation, and overall survival [40].
\nOther interesting T-cell subsets are the IL-17 producing helper T cells, the so-called Th17 cells and the Th22 cells. Th17 cells were found substantially increased in patients with lower risk MDS and their number was inversely correlated with that of T-regs. T-regs, although suppressive for other T-cell populations, do not affect Th17 cell number. Thus, the Th17/T-reg cell ratio has been found very high in lower risk disease and has been proposed as a marker of “effective” immunosuppression, high degree of apoptosis, and higher risk for autoimmunity, as well as an indicator for application of immunosuppressive treatment [41]. In contrast, helper T cells producing IL-22 (Th22 cells), involved in the pathogenesis of inflammatory reaction and autoimmunity, were found increased in patients with advanced MDS and their number was correlated with the mRNA levels of proinflammatory cytokines [42].
\nFinally, peripheral blood Tγδ lymphocytes, possessing a TCR with rearranged gamma/delta chains, and particularly Vγ9Vδ2 T cells, the major Tγδ-cell subset, which represent an important subpopulation for antitumor activity, were found reduced in patients with MDS and the reduction was greater in patients exhibiting autoimmune manifestations. Although Tγδ cells were not clonal, they reacted poorly to IL-2, and bromohalohydrin, a specific mitogen for these cells, induced mitogenic responses in only 60% of the MDS studied, unrelated to any specific disease feature. However, when activated, they exerted normal antileukemic effects against leukemic blasts. Therefore, the impaired number and function of this T-cell subpopulation may play a role in clonal expansion and disease progression of MDS [43].
\nAlthough B lymphocytes in MDS patients do not demonstrate the spectrum of abnormalities detected in T cells, since their production and function is governed by T cells, their aberration actually reflects the functional integrity of T cells. Information for B lymphocytes is fewer and often conflicted. In many studies, decreased proportion and peripheral blood absolute B lymphocytopenia, frequently accompanied by hypogammaglobulinemia and recurrent infections has been reported [27, 44]. These findings are mostly confined to patients with lower risk disease and are associated with T-lymphocyte imbalance and reduced numbers of bone marrow B cells and B-cell precursors.
\nAnalysis of the marrow CD34+ cell differentiation toward B lymphocytes in patients with low-risk MDS has revealed low expression of B-lineage differentiation genes and reduced production of B-cell precursors, a finding proposed to be used as a hallmark of low-risk disease [45]. An additional factor contributing to B lymphocytopenia is that bone marrow B-, but not T lymphocytes, exhibit increased apoptosis, similar to that observed in nonlymphoid cells. Increased B-cell apoptosis could not be considered a clonal “property,” since it was found neither in leukemic nor in normal marrows [44]. This was also confirmed on trephine biopsies of patients with high-risk MDS only, and the percentage of B lymphocytes was inversely correlated with prognosis [30]. Bone marrow flow cytometry analysis has shown increased proportion of CD34+CD45low B-cell precursors in patients with RA and RARS, and lower values in those with RAEB, whereas in AML B-cell precursors were not found at all, probably reflecting differentiation incapability of the CD34+ cells. Indeed, an inverse correlation of CD34+CD45low+ B cells with marrow blasts and a positive one with hemoglobin was found. Abnormal expression pattern of B-cell differentiation antigens, with hypoexpression of CD79α and TdT has also been reported, implying a possible role of the MDS marrow microenvironment in the maturation process of B lymphocytes [46].
\nRegarding the origin of B- and T lymphocytes, available data are again conflicting. In the majority of clonal studies, neither T- nor B lymphocytes or NK cells were found to originate from the dysplastic clone. Some studies have shown clonal origin of the B lymphocytes in a proportion of MDS patients, and in a Japanese study, the majority of patients with RA and those with immunological abnormalities exhibited clonal B lymphocytes [47]. Clonal origin was also found in 5% of the CD20+/CD22+ B cells of patients with trisomy 8. By using interphase FISH on sorted marrow cells, 13% of the CD5+CD19+ lymphocytes were clonal, implying that a part of the B lymphocytes in some patients may be clonal and that these cells may contribute to the manifestation of immune abnormalities [48].
\nB lymphocytes of MDS patients express low number of HLA-DR molecules (HLA class-II antigens) and are either deficient of EBV receptors or they carry abnormal Fcγ and C3d receptors, which cannot be used by EBV viral particles to enter and activate B cells. B-lymphocyte cultures produce increased amounts of IL-6 and IL-10, following mitogenic stimulation. IL-6 is overproduced even without mitogenic stimuli. Finally, B lymphocytes of patients manifesting immune abnormalities have lower number of cell surface Fas ligand receptors, a finding possibly indicating their resistance to apoptosis.
\nNot surprisingly several quantitative serum γ-globulin and immunoglobulin abnormalities have been described in MDS patients, such as polyclonal hyper-γ-globulinemia, monoclonal M-spikes, or hypo-γ-globulinemia. Monoclonal components have been found significantly higher than in normal age-matched population [49]. It has been suggested that dysplastic monocytes might exert unspecific immune stimulation on B- and T lymphocytes through increased IL-1 production favoring the development of monoclonal B-cell populations and producing M-spikes.
\nInvestigating the significance of serum protein electrophoresis in 158 patients, we noticed a normal pattern in 36% (mainly in RA and RARS) and only in 8% of CMML. A normal baseline pattern was associated with longer survival, independently of the IPSS and FAB classification. An acute phase reaction (alpha2-globulins >10 g/l) was seen in 17% at baseline, developed in additional 24% in the course of the disease, but in 80% of the patients transformed to AML and was associated with shorter survival. Hypo-γ-globulinemia was found in 6%, mainly RARS, was not related to frequent infections, and in RAEB it was associated with decreased marrow cellularity, deeper cytopenias, and longer survival. Polyclonal hyper-γ-globulinemia was found in 41% of patients (particularly RAEB-t, CMML) and monoclonal proteins in 16 cases (10%) more commonly in CMML and 2.5 times more frequently than in a control population of similar age. An additional 18% of the patients exhibited discrete M-components among polyclonal spectrum of γ-globulins. This finding has not yet been described and its significance is unclear [50].
\nPatients with MDS exhibit severe functional NK-cell impairment, but sometimes also numerical abnormalities. Cytotoxic NK-T cells, phenotypically characterized as CD3+CD8+CD16+, are usually normal or decreased but IFN-γ production is normal or increased. NK cells, characterized as CD3−CD8−CD11b+HNK1+ CD56+CD57+ cells, have been found normal, rarely decreased, but sometimes even increased [51]. The NK activity of MDS patients is almost always decreased compared to healthy controls [27, 51], although immunophenotypically NK cells are indistinguishable. In general, CD8+ T-cell function and the defective NK activity in MDS have been strongly and inversely correlated with bone marrow blast cell percentage, marrow cellularity, and serum sIL-2R levels [51]. Alloantigen- or mitogen-induced cell-mediated cytotoxicity [27] as well as IFN-α and IL-2 production following NK cell activation is also impaired and the preincubation of NK cells with IFN-α may partially increase NK activity [52]. There are conflicting data regarding the origin of NK cells. By using FISH on FACS-sorted cells of patients with monosomy 7, monosomic signs in CD3−CD56+ cells were detected in 3 out of 4 [53]. In another study, between 20 and 50% but not all the NK cells were clonal, demonstrating a kind of “chimerism” by clonal and nonclonal NK cells in the majority of patients.
\nMany groups investigated whether IFN-α treatment could induce blast/clonal cell clearance, through augmentation of the NK activity. In one study on 38 patients with RAEB, following 3-month treatment with IFN-α, NK activity and NK cell number and function was increased, but these alterations were not associated with any meaningful clinical response. NK cells exhibited normal tumor cell binding capacity, but inability of releasing cytotoxic factors, possibly suggesting intrinsic functional defects [52]. Another group did not confirm any quantitative defect and found normal expression of the activating receptors NKp46, NKp30, and NKG2D, but a depressed cytolytic activity. Incubation with IL-2 upregulated the NKp46 expression, but did not enhance NK-cell cytotoxicity but induced higher rate of apoptosis [53]. A strong correlation of the NK activity with higher IPSS, abnormal karyotype, excess of blasts and marrow hypercellularity, and downregulation of the NKG2D receptor has also been reported [54]. The Nordic MDS study Group showed that decreased expression of DNAM1 and NKG2D receptors on marrow NK cells was inversely correlated with blast percentage and suggested that DNAM1 plays a pivotal role in NK-mediated cell killing [55].
\nIL-12, alone or combined with IL-2, induces variable and unpredictable response to NK cells. Some patients (mainly with RA) exhibit a response closer to normal, while others respond poorly. The combination of IL-2 and IL-12 increases IFN-γ and TNF-α production in a synergistic way. IL-12 alone is not so stimulatory, and the combination of IL-2+IL-12 generates stimulation, similar to that obtained by IL-2 alone. Indeed, priming of peripheral blood mononuclear cells (PBMC) with IL-12 increased their cytotoxicity against autologous leukemic blasts to almost normal levels and significantly reduced WT1 mRNA expression, used as a marker of residual leukemic burden, except in patients with overt, high-bulk AML. Thus,
In a study from Düsseldorf, the authors recognized a small subgroup of high-risk patients, with almost absent peripheral blood NK cells, but intact populations of NK T cells. A larger subgroup with normal number but poor function of NK cells was characterized by reduced intracellular granzyme-B and perforin levels. This subgroup restored almost completely NK-cell function, following mitogen or cytokine stimulation. NK cells were mainly immature but exhibited normal mature/activated (CD56bright+CD107+) immunophenotype and a restricted repertoire of KIR receptors. It is therefore suggested that the dysfunctional NK cells lead to inefficient/insufficient immune surveillance and clonal expansion [57]. The Pittsburgh Group reported different marrow frequencies of NK and NK T cells in MDS and AML. In MDS they did not find numerical impairment of the NK-cell population, but a significant decrease in mature CD56dimCD16+CD57bright cells, which had great prognostic significance for survival [58]. Other groups have reported increased intracellular granzyme-B levels in the NK cells of MDS patients [59].
\nThe immune-activated status of MDS patients lead to overproduction and elevated serum levels of many cytokines. We were the first group to report elevated serum soluble interleukin-2 receptors (sIL-2R) and tumor necrosis factor-α levels in 42 MDS patients confirming an abnormal immune stimulatory status. Although the difference in TNF-α levels between early and advanced MDS was not significant, patients with advanced MDS had significantly higher serum sIL-2R levels compared to those with early MDS [60].
Serum IL-6 levels were found elevated in the majority of MDS patients and serum GM-CSF levels in less than half of them, although these cytokines were undetectable in normal subjects. Higher IL-6 concentrations were found in patients with advanced subtypes, were inversely correlated with the severity of the anemia and positively with peripheral blood and bone marrow blast cell percentages, and may increase further following chemotherapy. IL-6, IL-7, MCSF, TGFβ, and IL-1β are constitutively produced by marrow stromal cells of patients with MDS and AML, but not from stromal cells of normal subjects, and IL-6 gene transcription could be induced by exogenous addition of IL-1β confirming a cytokine network dysregulation [62]. Serum IL-8 levels were also found elevated, but they dropped under chemotherapy or during remission.
\nA Dutch group measured serum levels of seven cytokines in 75 MDS patients and found detectable levels of G-CSF in the majority of them, and increased IL-3 and IL-6 levels in a minority of patients but not in controls [63]. Serum TNF-α levels have been correlated with the severity of anemia, poor performance status, leucocytosis and monocytosis, higher β2-microglobulin and lower albumin levels, liver and renal impairment, and shorter survival [62–64]. TNF-α levels <10 pg/ml have been associated with achievement of higher remission rate and longer PFS Progression Free and overall survival, whereas lower TNF-α and IL-1β levels could predict response to treatment with erythropoietin [64]. Thus, TNF-α represents the most important circulating and measurable cytokine, from the pathogenetic and the prognostic point of view. In general, serum levels of type-1 cytokines (IL-1β, IL-7, IL-8, IL-12, RANTES, and IFN-γ) [64, 65] are found elevated in lower risk MDS, whereas inhibitory factors (IL-10, sIL-2R) are elevated in higher risk disease.
\nThe group of Mayo Clinic evaluated plasma levels of 30 different cytokines in 78 patients, and showed that although levels of 19 cytokines differed significantly from controls, in multivariate analysis, only levels of IL-6, IL-7, and CXCL10 had independent prognostic value for survival. Indeed, patients with normal levels of all these three cytokines had a median survival of 76 months compared to only 25 months for patients with elevated levels of at least one of them. For IL-6 levels in particular, a strong association with inferior leukemia-free survival, independent from other prognostic factors, was found [66].
\nFinally, a Spanish group, among other findings, demonstrated an inverse correlation of the CD3+, CD4+, and CD8+ populations with age, as well as an inverse correlation of serum IL-10 levels with the number of CD8+ cells, disease progression, and overall survival [67]. In another study, investigating the association of IL-10 gene polymorphisms with the development and the features of MDS, the highly IL-10-expressing genotype
A basic property of the immunocompetent cells is the recognition of the “self” and the orchestration of an immune response against the “nonself” or the “altered self,” and when self-recognition is impaired, an autoimmune disorder emerges. An initial interpretation for the frequent autoimmune disorders and other immune abnormalities of MDS patients was that they might probably reflect clonal origin of B- and T lymphocytes. Later, however, it was demonstrated that, in the majority of cases, B- and T lymphocytes are nonclonal, but T-lymphocyte abnormalities may influence disease course. Various T-lymphocyte subsets exert complex immunoregulatory activities on other T-cell populations, B lymphocytes, and monocytes. Mixed lymphocyte cultures are performed with the coculture of a pure T-cell population (responder cells), upon which a kinetically inactive, but cell-surface intact, non-T cell population (stimulant cells) affects, thus generating a mixed lymphocyte reaction. MLRs represent dynamic
The proliferative reaction (MLR) is mediated through recognition of structural antigenic domains of the cell surface of non-T cells, and particularly HLA class-II antigens. The stimulating capacity of the non-T-cell population is abrogated when cell membrane structure is destroyed, either following mechanical stress or treatment with proteolytic enzymes. Moreover, the stimulatory capacity is not a soluble factor and non-T- or B-lymphocyte supernatants do not retain any stimulatory activity on T lymphocytes [69], whereas preincubation of the non-T-cell population with anti-HLA-DR monoclonal antibodies completely abrogates the AMLR and substantially depresses the Allo-MLR. The stimulatory potential of other membrane determinants on the MLRs was identified in a similar way. Such molecules are HLA class I (HLA-A, -B, and -C) for the Allo-MLR, CD3-Ti complex for any type of MLR, and probably additional minor antigenic determinants of the MHC. Stimulating capacity of the non-T-cell population is dependent on the various mononuclear cell constituents included. B lymphocytes are stronger stimulants than NK cells and null lymphocytes. Activated B lymphocytes, surface IgM(+) B lymphocytes, and B lymphoblasts are better stimulants than resting- and IgM(−) B lymphocytes, and this property is independent of their content in EBV-DNA or the origin from a mitogen-enriched culture. The role of monocytes is contradictory, since inactive monocytes enhance autologous reactivity, whereas the admixture of monocytes in the responder T-cell population results in severe impairment of both AMLR and Allo-MLR.
\nMLRs share the characteristic features of an orchestrated immune reaction showing immunologic memory and specificity. When T lymphocytes, previously exposed to autologous non-T cells and obtained the seventh day of culture, are re-exposed to the same non-T-cell population, they demonstrate their peak proliferation earlier, on the third day of culture (secondary AMLR), thanks to previously engrafted immunologic memory. The same has been confirmed for the Allo-MLR, because when in the secondary culture the allogenic stimuli are different, then different responder T-cell population is activated and the reaction shows the kinetic of the primary MLR. There are different autoreactive and alloreactive T-cell populations. The number of alloreactive T cells is 5–40 times higher than autoreactive, and represents 1/400–1/150 of the total peripheral blood T lymphocytes, whereas autoreactive constitute 1/5000–1/2200 of them.
\nThe basic function of the MLRs is the production of suppressor “activity” or of suppressor/cytotoxic T cells. The main part of the responder population are CD4+ helper/inducer T lymphocytes and treatment of this population with an anti-CD4 monoclonal antibody, practically abrogates all types of MLR. Conversely, treatment with an anti-CD8 antibody quantitatively decreases the strength of both types of MLR. Thus, from the relative content of the two major T-cell subpopulations AMLR has two different phases. Responder CD4+ T lymphocytes undergo a proliferative reaction upon sensation of autologous signals (self-MHC antigens: autoreactive T cells). CD4+ cell proliferative reaction is peaked on the third and fourth day of the culture, when helper T-cell population dominates. This reaction is followed by a secondary activation of the suppressor CD8+ T cells, which is quantitatively stronger, is peaked on the sventh and eighth day of the culture and inhibits any further proliferation of the autoreactive T cells. This serially fulfilled lymphocyte reaction is mediated through the production of IL-2 by the CD4+ T cells. In the Allo-MLR the responder population (alloreactive T cells) is activated through the recognition of the MHC alloantigens and is consisted of both helper and suppressor T lymphocytes. Allo-MLR is always stronger than AMLR. Deficiency of AMLR and of Allo-MLR has been reported in various diseases and conditions, a list of which is provided in Table 3.
\nConnective tissue disorders | \nAutoimmune diseases | \n
---|---|
Rheumatoid arthritis | \nImmunohemolytic anemia | \n
Still\'s disease | \nImmune thrombocytopenic purpura | \n
Systemic Lupus Erythematosus | \nHenoch-Schoenlein puprpura | \n
Dermatomyosistis/polymyositis | \nInsulin-dependent diabetes mellitus | \n
Sjogren\'s syndrome | \nHashimoto\'s thyroiditis | \n
Ankylosing spondylitis | \nChronic active hepatitis | \n
\n | Inflammatory bowel disease | \n
\n | \nPrimary biliary cirrhosis | \n
Infectious mononucleosis | \nMyasthenia gravis | \n
Chronic mucocutaneous candidiasis | \nMultiple sclerosis | \n
Acquired immunodeficiecy syndrome | \nArthropathic psoriasis | \n
Chronic Hepatitis C | \n\n |
Chronic periodontitis | \n\n | \n
\n | Allergic asthma | \n
\n | \nAtopic dermatitis | \n
Breast cancer | \nHay fever | \n
Lung cancer | \nFood allergy | \n
Colon cancer | \n\n |
Head and neck cancer | \n\n | \n
Gastric cancer | \nSarcoidosis | \n
Bladder cancer with schistosomiasis | \nDown\'s syndrome | \n
Kaposi\'s sarcoma | \nCongenital immunodeficiency | \n
Myelodysplastic syndromes | \nIdiopathic portal hypertension | \n
\n | Ataxia-telangiectasia | \n
\n | \nCongenital hyper-IgM syndrome | \n
Chronic lymphocytic leukemia | \nMixed cryoglobulinemia | \n
Hairy cell leukemia | \nHemophilic patients treated with fVIII concentrates | \n
Hodgkin\'s lymphoma | \nTransplanted patients | \n
B-cell non-Hodgkin\'s lymphoma | \nPatients in chronic hemodialysis | \n
Peripheral T-cell lymphoma | \nAdvanced age | \n
Multiple myeloma | \n\n |
Diseases with an abnormal autologous mixed lymphocyte reaction.
Besides the immunoregulatory cell circuits, generated following “autorecognition” in the AMLR, helper and suppressor T lymphocytes exert regulatory function in normal hematopoiesis. T lymphocytes obtained at the early phase of the AMLR (third day) have promoting activity on the formation of early (bursts) and late erythroid colonies (CFU-E) and this activity is similar to that obtained by PHA-activated T lymphocytes. This activity, initially termed
Cytotoxic activity, generated in the MLRs, is also directed against autologous and allogeneic B lymphocytes, monocytes, and cells with an altered antigenic profile, either neoplastic or not. Generation of cytotoxic activity against tumor cells as a result of immune activation is of tremendous clinical significance. In AMLR and Allo-MLR the neoplastic cells may represent the stimulant cell population, whereas responder populations might be both the suppressor/cytotoxic CD3+CD16+ NK-T cells and the CD3-CD16+CD56+ NK cells. Activation of these populations results in increased proliferation and the adoption of an activated profile. Thus, cytotoxic T cells generated in AMLR may play an important role in antitumor surveillance [70].
\nAMLR and Allo-MLR were found significantly reduced on 12 MDS patients and the amount of IL-2 produced during these reactions was severely depressed. Exogenous addition of IL-2 partially restored the strength of the reactions, which, however, continued to be substantially reduced compared to normal controls. To investigate which cell population was primarily affected, the authors compared the strength of Allo-MLR by using allogeneic non-T cells from both normal controls and other MDS patients against T cells from MDS patients. They also tested Allo-MLR of T lymphocytes from healthy controls against non-T cells obtained either from normal subjects or from MDS patients. Allo-MLR of T cells from MDS patients was substantially improved with the use of normal allogeneic non-T cells, but did not reach the normal range. Conversely, Allo-MLR of T cells from normal subjects was severely deficient when stimulant non-T cells had been obtained from MDS patients compared to the reaction against non-T cells from normal subjects. Therefore, it appears that in MDS there is an impaired stimulating capacity of the non-T-cell population consisting of B lymphocytes, monocytes, and immature myeloid cells [26]. Almost concurrently the presence of “leukemia-inhibitory activity” (LIA) of peripheral blood non-T cells of MDS patients mainly obvious in patients with an excess of blasts, but also in some patients without an excess of blasts (RA-RARS) was reported. Moreover, the majority of the patients without an excess of blasts, whose serum contained LIA, evolved quickly to RAEB/AML. This “activity” of higher risk MDS patients could be eluted from culture of PBMC in FCS-enriched media with the addition of GM-CSF and IL-4 [71]. Cells responsible for the induction of suppression/inhibition of cell growth are clonal macrophages, transformed in culture to “giant macrophages” or dendritic cells. The mediator of suppression was a soluble factor, other than IFN-γ or TNF-α, identified as acidic isoferritin [72].
\nWe investigated the MLRs in 20 MDS patients in paired experiments with sex- and age-matched controls at baseline, before the administration of any interventional treatment. To express the strength of reactions we used the
FAB group | \nN | \n(Mean ± SEM) cpm | \n(Mean ± SEM) S.I. | \np | \nAMLR patient/AMLR control | \n
---|---|---|---|---|---|
RA | \n4 | \n2068 ± 205 | \n2.64 ± 0.33 | \n\n | \n0.58 ± 0.09 | \n
RAS | \n5 | \n2301 ± 206 | \n2.77 ± 0.18 | \n\n | \n0.63 ± 0.06 | \n
RAEB | \n8 | \n1837 ± 310 | \n1.90 ± 0.07 | \n\n | \n0.40 ± 0.03 | \n
CMML | \n3 | \n2562 ± 177 | \n3.39 ± 0.21 | \n\n | \n0.51 ± 0.08 | \n
\n | \n20 | \n2108 ± 154 | \n2.49 ± 0.15 | \n0.51 ± 0.04 | \n|
20 | \n4396 ± 404 | \n5.31 ± 0.32 | \n\n | \n | |
\n | \n\n |
Results of the autologous mixed lymphocyte reaction in patients with MDS (counts per min and stimulation index, S.I.) Bold letters/numbers indicate statistically significant differences.
To evaluate the capability of the stimulant cell population, Allo-MLR was performed against non-T cells originating either from another MDS patient or from a healthy control. Moreover, to evaluate the capability of the responder cells, Allo-MLR of the healthy controls was performed against non-T cells from MDS patients or from other controls. In all cases, Allo-MLR against normal non-T cells was substantially higher, and on average threefold as strong as AMLR and Allo-MLR against “dysplastic” non-T cells was weaker, but always stronger than AMLR of the same person. The difference between these two types of controls’ Allo-MLR was significant (S.I.: 7.90 ± 0.89 versus 14.12 ± 1.59,
\n | \n | Normal non-T cells | \n\n | \n | \n | Dysplastic non-T cells | \n\n | \n | \n |
---|---|---|---|---|---|---|---|---|---|
FAB Group | \nN | \n× ±SEM | \n\n | p | \nN | \n× ±SEM | \np | \n||
\n | \n | cpm | \nS.I. | \n\n | \n | cpm | \nS.I. | \n\n | \n |
RA | \n4 | \n3562 ± 334 | \n4.79 ± 0.64 | \n3 | \n2532 ± 407 | \n3.01 ± 0.23 | \nn.s. | \n||
RAS | \n5 | \n4569 ± 702 | \n5.86 ± 0.87 | \n4 | \n3859 ± 685 | \n4.89 ± 1.16 | \nn.s. | \n||
RAEB | \n8 | \n2643 ± 328 | \n3.04 ± 0.25 | \n7 | \n1865 ± 563 | \n2.21 ± 0.49 | \nn.s. | \n||
CMML | \n3 | \n4215 ± 695 | \n5.93 ± 0.62 | \n0.070 | \n1 | \n3380 | \n4.47 | \n– | \n|
All Pts | \n20 | \n3544 ± 312 | \n4.53 ± 0.41 | \n15 | \n2697 ± 389 | \n3.63 ± 0.21 | \n|||
Controls | \n20 | \n11,355 ± 1459 | \n14.12 ± 1.59 | \n\n | 12 | \n6558 ± 869 | \n7.90 ± 0.89 | \n\n | |
RAEB vs. all other MDS (S.I.) | \n3.04 ± 0.29 | \n\n | \n | 5.52 ± 0.47 | \n
Allogeneic mixed lymphocyte reaction in patients with myelodysplastic syndromes – counts per min and stimulation index (S.I.) Bold letters/numbers indicate statistically significant differences.
Similar results were obtained by the Czech group who found significantly decreased MLRs with lower TNF-α and IFN-γ production in the supernatants of patients with RA compared to the MLRs of RARS patients. They also found less affected the allo-MLR against normal non-T cells, and identified as more defective the second (effector) phase of the reaction [74]. Therefore, in the MLRs of MDS patients there is an impairment of both the responder (T cells) and the stimulant population (non-T cells). The responder population reacts poorly to autologous and allogeneic stimuli and exhibits a profile of immune tolerance, which is clearer in the high-risk patients. Moreover, the stimulant population provides insufficient stimuli for reaction to the T cells, since it also depresses the alloreactivity of normal T lymphocytes. The possible, if any, clinical consequences of these findings are practically unknown or remain only speculative.
\n“Inhibitory activity” derived from serum and PBMC culture’s supernatants of MDS patients has earlier been described and associated with poor prognosis [71]. Normal PBMC inhibit autologous hematopoietic cell colony formation in short-term cultures, as did also PBMC of patients with RA, but they induced a clear inhibitory activity later on day 10. Responsible cells are probably cytotoxic T and NK cells, which may react against the clone and suppress the growth of clonal cells at early stages of the disease. If this suppressor function develops early and is effective, clonal growth may be arrested. Nevertheless, NK cells of MDS patients usually exhibit impaired function and sometimes are clonal. However, since suppressor activity is achieved through various soluble cytokines and mainly through TNF-α, it is not quite specific and may also affect nonclonal cells, resulting in hematopoietic suppression, as this is observed in hypoplastic MDS and aplastic anemia. Indeed, lymphocyte culture supernatants from MDS patients exert suppressive activity on the growth of normal hematopoietic progenitors [75].
\nThis form of cytotoxicity was also identified in high-risk MDS and in AML, and was attributed to possible infection of leukemic cells by an oncogenic virus. However, viral infection is not necessary for the generation of an immune reaction, since clonal cells contain and sometimes express on their membrane many abnormal or mutated proteins, possibly representing neoantigens capable to induce lymphocytotoxic reactions by CD8+ T cells. Autoantigens are hardly found in MDS and may only be speculative but have been identified in some other marrow failure syndromes, such as aplastic anemia and paroxysmal nocturnal hemoglobinuria. As possible antigens, the Wilms Tumor protein (WT1), moesin, a cytoskeleton protein, KIF20B (kinesin), desmoplakin, and proteinase-3, an enzyme of blast-cell granules, have been indicated [76]. T lymphocytes of some MDS/AML patients stimulated
A challenging hypothesis is that the adaptive immunity may rather “react” than be impaired following various cellular interactions, and this immune “reaction,” or at least such cellular interactions, might be a part of the pathogenesis of MDS. This “reaction” also may represent a defensive mechanism of the immune system against the dysplastic/neoplastic clone and is orchestrated specifically against clonal bone marrow cells. Specific CD8+ suppressor/cytotoxic T cells recognizing progenitor cells with trisomy 8 have been identified in MDS patients with this abnormality. Clonal inhibition is achieved via MHC class I recognition and through induction of FAS-mediated apoptosis [78]. The possible contributing role of an altered marrow microenvironment in the development of such immune alterations is also tempting.
\nThe presence of increased number of immunocompetent T lymphocytes with an activated cytotoxic immunophenotype CD8+CD25+CD28-CD57+ has been reported in the marrows of patients with aplastic anemia and MDS. These cells do not to directly influence the severity of peripheral blood cytopenias [79]. In our study on 41 patients, the percentage of activated marrow suppressor/cytotoxic T lymphocytes was inversely correlated with marrow cellularity and blast cell percentage, and positively with Fas antigen expression on CD34+ clonal progenitor cells [80]. The cytotoxic reaction against marrow CD34+ cells of MDS patients has a well-defined signal transduction pathway in the T cells and can be augmented
We also investigated the behavior of the clonal CD34+ progenitors as stimulant population in mixed cultures with autologous T lymphocytes as responder cells, in other words the immune reaction when T cells are in close contact with clonal stem cells. We compared this type of reaction (autologous progenitor cell mixed lymphocyte reaction—APLR) with the classical types of MLRs. APLR reflects the strength of the immune reaction against the clone in a background of established relative immune tolerance. We tested APLR in 20 MDS patients and 10 healthy controls. We noticed significant differences in the strength of the reaction between patients and controls, as well as between the various subtypes of MDS. Results are shown in Table 6. Among normal subjects APLR was rather a mild proliferative reaction, less than half strong as AMLR and about six- to sevenfold weaker than Allo-MLR. Among MDS patients, APLR was significantly stronger than in controls (
FAB Group | \nN | \ncpm (Mean ± SEM) | \nStim. Index (Mean ± SEM) | \np | \nAPLR pt/APLR control | \n
---|---|---|---|---|---|
RA | \n4 | \n2334 ± 382 | \n2.88 ± 0.41 | \n0.173 | \n1.21 ± 0.11 | \n
RAS | \n5 | \n2365 ± 385 | \n2.77 ± 0.18 | \n0.109 | \n1.34 ± 0.13 | \n
RAEB | \n8 | \n7502 ± 1194 | \n10.35 ± 2.46 | \n3.92 ± 0.74 | \n|
CMML | \n3 | \n3488 ± 556 | \n4.55 ± 0.25 | \n1.43 ± 0.12 | \n|
All patients | \n20 | \n4582 ± 735 | \n6.09 ± 1.27 | \n2.39 ± 0.85 | \n|
Controls | \n10 | \n1866 ± 308 | \n2.21 ± 0.31 | \n\n | \n |
RAEB | \n8 | \n7502 ± 1194 | \n10.35 ± 2.46 | \n\n | \n |
Other MDS | \n12 | \n\n | 3.26 ± 0.95 | \n\n |
Autologous progenitor cell mixed lymphocyte reaction (APLR) Counts per min and stimulation index Bold letters/numbers indicate statistically significant differences.
Our results have been confirmed by Chamuleau et al., who demonstrated increased non-MHC-restricted autologous cytotoxicity against clonal marrow precursors in eight patients with lower risk MDS, possibly indicating immune surveillance against clonal expansion although they have not provided clinical data on its significance [59]. Suppression may not be restricted against the dysplastic clone and may also affect nonclonal (normal) hematopoiesis. Lymphocyte-depleted long-term bone marrow cultures from patients with lower risk MDS also generated some nonclonal hematopoietic colony growth, which was abrogated when T lymphocytes were present in the culture system [82]. Autologous lymphocytes were particularly cytotoxic in patients with hypoplastic MDS, trisomy 8, or bearing the DR15 allele [84]. The suppressive role of autologous T lymphocytes has been very nicely demonstrated in a patient with MDS and cyclic hematopoiesis, in whom, the percentage of marrow CD3+ lymphocytes was inversely correlated with neutrophil and platelet count during the various phases of ineffective hematopoiesis [85].
\nCorrelation of AMLR to APLR in each subject tested with MLRs. By correlating AMLR to APLR an almost complete, discrete compartmentalization of the three main subject groups was found. Normal controls exhibited higher AMLR than APLR, patients with lower risk MDS had lower, both types of MLRs, whereas patients with an excess of marrow blasts showed impaired AMLR and very increased APLR.
The strong MLR against autologous clonal CD34+ progenitors observed in patients with RAEB was inversely correlated with marrow cellularity. All four patients with a strong APLR had marrow cellularity of <35% and marrow blast cell percentage of 5–10% (RAEB-1). These patients, although severely pancytopenic and transfusion dependent, had a delayed evolution to AML or they did not progressed at all. In two of them who progressed, marrow cellularity was increased and in a new APLR, performed at the time of AML progression, lymphocyte activation against autologous blasts had been abrogated [86]. Thus, it appears that lymphocyte activation in patients with RAEB is rather inversely correlated with leukemic burden, but immunologic memory for this reaction is maintained and patients who lose their immune activation during leukemic transformation may regain it following the achievement of remission. Moreover, maintenance of remission is completely dependent on the presence of autologous cytotoxicity against leukemic cells, mainly exerted by NK cells. This cytotoxic reaction is disappeared upon relapse of the leukemia [87]. Unfortunately, immune activation against clonal cells is not the rule and T cells in MDS (particularly Tγδ cells) may respond poorly, if not at all, even following IL-2 stimulation, despite normal IL-2R expression, demonstrating impaired immune surveillance against the clone [51]. Indeed, the Czech group did not find any significant lymphocyte activation in eight out of nine patients tested and confirmed the nonclonal origin of the T cells [71].
\nClonal dendritic cells can also induce T-cell stimulation in AML. Proliferative reaction against these cells is high but results in the generation of cytotoxic T lymphocytes with low activity against autologous or allogeneic nonleukemic targets [88]. Dendritic cells of MDS patients in Allo-MLR systems are poor stimulators for both normal and MDS-derived T cells, indicating an impaired antigen presenting capacity. These cells, generated from CD34+ cells, although immunophenotypically normal, were significantly decreased as were also the populations or circulating myeloid- and plasmacytoid-derived dendritic cells, confirming ineffective “dendritopoiesis” [89] and produce less IL-12 and more IL-10 in response to LPS and IFN-γ showing qualitative and quantitative defects of cytokine production.
\nBlast cells exert direct suppressor activity on the activation, TH1 polarization and proliferation of T lymphocytes. This activity is mediated through protein substances transcribed via the NF-AT and NF-kB signals by inhibition of transition from G0 to G1 phase [90]. Upon NK cells, leukemic cells induce impaired killing capacity, reduced TNF-α and IFN-γ production, reduced CD107α degranulation, downregulation of the NKp46- and upregulation of the NKG2A receptor expression, effects directed via IL-10, and favoring clonal escape and expansion [91]. In other instances, however, blast cells induce lymphocyte activation, as previously described, with the production of IL-2, IL-4, IL-10, IL-13, and IFN-γ. Lymphocyte culture supernatants, when further activated with IL-2, generate strong cytotoxic LAK and NK cells inducing lysis of autologous and allogeneic leukemic cells [92]. In the majority of cases, immune effector function of NK-T and NK cells, observed in some patients with MDS, are abolished on leukemic transformation.
\nFrom the pathogenetic point of view it appears that an initial, harmful event (viral, drug, irradiation, etc.), affecting the pluripotent hematopoietic stem cell compartment in the bone marrow, may antigenically alter a minor population of these cells. Even when the consequences of the harmful event are negligible and maturation and differentiation processes might remain almost intact, it is possible that an immunologic reaction could be initiated. This reaction is directed against the even minimally modulated hematopoietic progenitor cell population. Indeed, the strength of the autologous cytotoxic immune reaction, frequently accompanying the emergence of a dysplastic clone, is not related to the complexity/severity of the cytogenetic abnormalities, and a minor genetic damage may induce a strong reaction. Conversely, complex chromosomal aberrations and other gross genetic damage, leading to hematopoietic failure, may induce a weak or not any immune reaction. This reaction may be less specific and may also generate cytotoxicity, not only against the affected cells, but also to the unaffected/normal hematopoietic progenitors, inducing apoptosis and resulting in stem-cell depletion and hematopoietic failure. Soluble factors (cytokines) released by the activated lymphocytes might also harm accessory/stromal cells. This cascade of events usually leads to aplastic anemia. When the initial harmful event induces deeper genetic damage in a pluripotent stem cell and this cell, although genetically altered, succeeds in escaping from apoptotic cell death may generate an abnormal (dysplastic) clone. Clonal cells continue to trigger the immunocompetent cells, but the latter although activated cannot eliminate the clonal cells, which continue to escape, gradually expand, and suppress the unaffected/normal stem cell compartment through at least two mechanisms:
(1)\tImmune effector cytotoxic cells can destroy more easily the nonclonal/normal progenitor cells as a result of clonal cell escape from the immune attack.
(2)\tSecondary genetic alterations occurring gradually provide growth advantage to the clonal cells.
Thus, immune activation may perpetuate and when cytotoxic activity is ineffective and incapable to eliminate clonal cells, it becomes an “immunologic abnormality.” The more effective the immune activation, the higher the degree of apoptosis induced, affecting more and more marrow cellularity and creating a syndrome mostly similar to aplastic anemia. Therefore, the decreased marrow cellularity observed in some marrow failure syndromes might be considered an “adverse event” of an effective immune reaction capable to restrict the growth of the abnormal/mutated/genetically altered clonal cell population. On rare occasions, the intensive immune activation, augmented by an infection or a blood transfusion, may be capable to completely eradicate the dysplastic clone leading to spontaneous complete remission even after evolution to AML. In contrast, when immune activation is ineffective, clonal expansion and evolution continues unimpededly until the stage of AML. At this stage, either passively, due to high “antigenic burden,” or actively, through mechanisms, induced by the leukemic cells, immune tolerance or immune paralysis is established abrogating further immune reaction [93]. In rare instances, even after evolution, immune activation may be maintained and result in an oligoblastic/hypoplastic AML. Conversely, when immune activation is abolished early or when the dysplastic/neoplastic clone achieves in earning immune tolerance, the evolution might be uneventful and lead to a hypercellular AML.
\nAbout 10–15% of MDS patients at initial presentation have a hypoplastic marrow (cellularity ≤30%). These patients exhibit more severe cytopenias, various degrees of trilineage dysplasia, more prominent immune abnormalities, and usually a normal karyotype or single chromosomal abnormalities. Although hypoplastic MDS share many similarities with aplastic anemia, different molecular mechanisms of marrow damage have been identified between them and other/nonhypoplastic MDS. Among them development of oligoclonal expansion of cytotoxic T lymphocytes, overexpression of TRAIL- and Fas ligand-induced apoptosis, underexpression of Flice-like inhibitory protein long isoform (FLIPL), and increased production of IFN-γ and TNF-α are included. Patients with hypolastic MDS have more stable clinical course and lower evolution rates in relation to patients with nonhypoplastic disease of the same FAB/WHO categories. They show good response to treatment with corticosteroids, cyclosporine-A, antithymocyte globulin, or alemtuzumab, and to various combinations of the above. Overall survival varies and if patients will not succumb to a severe infection, they may retain a prolonged leukemia-free survival [94, 95].
\nSuppressor/cytotoxic autoimmune reactions are more frequently identified among lower risk MDS, have specificity against the pluripotent or an early committed, usually erythropoietic progenitor cell, and are associated with higher degree of marrow apoptosis. In the majority of cases, the autoimmune process includes the production of specific antierythroblastic antibodies without the positivity of direct antiglobulin test. The production of such IgG autoantibodies can be provoked
Increased marrow apoptosis is a dominant feature of MDS and affects all hematopoietic cell compartments from the more immature-undifferentiated to the mature and recognizable cells. The apoptotic rate of CD34+ cells in normal subjects has been calculated at about 1%, whereas in MDS, it ranges from 3 to 15%. Higher apoptotic rate is usually found in patients with early MDS and in few patients with an excess of blasts [98]. Apoptotic rate may vary in the same patient at different time points reflecting also the evolution of mutational status of the clonal cells. Specific cytogenetic abnormalities, such as trisomy 8 have been associated with higher degree of apoptosis. Apoptosis is a multifactorial process in MDS with a possible contribution of the immune effector cells. Clonal cells’ death could create abnormal structures with potentially (auto)antigenic properties and apoptosis can represent the causative factor of the initiation of autologous cytotoxic immune reaction. Indeed, increased apoptotic cell rate has been associated with higher marrow cytotoxic T-cell infiltration and in many instances by oligoclonal T cells in MDS patients, who also express the TIA-1 antigen on their hematopoietic cells [99]. The proapoptotic marrow microenvironment triggers stromal cells to produce IL-32, which in turn induces further TNF-α transcription, thus establishing a vicious cycle. IL-32 expression has been found many folds higher in the stromal cells of MDS patients, rendering this cytokine a specific stromal cell marker for MDS [100].
\nAlthough immune activation plays the dominant pathogenetic role for the generation of marrow failure in aplastic anemia, in MDS this cannot be easily identified in every individual patient. In other words, it is not identifiable which part of the hematopoietic failure results from the clonal disorder
Corticosteroids are the most widely used immunosuppressive treatment administered to patients with MDS and autoimmune diseases [17, 20]. Response rates vary broadly and the required dose depends on the type of autoimmune disease, MDS subtype, chronicity of the condition, and other factors. Although symptom resolution may be fast, autoimmune disease may relapse during tapering, demanding higher doses, which may not be tolerable by elderly patients. Thus, corticosteroids usually lead to partial or transient response and second-line treatment with other agents is necessary. Steroids may also benefit hematopoiesis, improving cytopenias and reducing RBC transfusion needs. Responses are mainly seen in patients with lower risk IPSS, with a specific profile, but also by some patients with RAEB [102] and may be long-lasting and maintained with small maintenance steroid doses.
\nCyclosporin-A (Cy-A) is the second more widely used immunosuppressive agent and has also been used in combination with cytotoxic chemotherapy as a modulator of multidrug resistance, which is commonly found in higher risk MDS and in AML following MDS. Cy-A is effective even at lower doses, aiming to achieve serum levels lower than those desirable in aplastic anemia and in allogeneic stem cell transplantation and therefore is well-tolerated and induces durable remissions [103, 104]. Retrospective evaluation of 50 patients showed a hematological improvement and particularly an erythroid response in 60%. Better response was achieved by patients with hypoplastic marrow, favorable karyotype, or carrying the DRB1*1501 allele [105]. The NIH group has reported more frequent expression of the HLA-DR2/HLA-DR15 allele in patients with MDS and aplastic anemia compared to a control population and an association of the expression of this allele with a favorable response to immunosuppression [106]. Cy-A added to T-lymphocyte cultures decreases IFN-γ- but not Fas-L production and lead to abrogation of the inhibitory activity of the supernatant on hematopoietic colony formation. However, the growth of secondary colonies continues to be decreased due to low number of pluripotent CD34+ progenitors.
\nProbably the most effective immunosuppressive treatment is antithymocyte globulin (ATG), which has been given to MDS patients with any marrow cellularity [101, 104]. Hematopoietic improvement is achieved following elimination of the autoreactive cytotoxic T cells and may result in restoration of the dysplastic marrow and peripheral blood morphology. In many instances cytogenetic complete remission has also been reported, whereas in others, hematologic remission is not accompanied by cytogenetic remission. In these cases, most probably immune activation mainly suppresses nonclonal hematopoiesis without significantly disturbing the dysplastic clone. Finally, rapid evolution to AML or increase of marrow blasts despite hematological improvement has occasionally been reported following treatment with Cy-A or ATG [107]. In these cases, immune activation may effectively suppress clonal cells and its abrogation has favored the unimpeded clonal expansion and evolution. Mofetil mycophenolate (MMF) or alemtuzumab can be used when corticosteroids and/or Cy-A are ineffective or contraindicated, or when severe adverse effects emerge, but the experience with these agents is limited. The main drawback of immunosuppression is that combined with the usually coexisting neutropenia substantially increases the risk for common and opportunistic infections, even when all prophylactic measures are applied. Cy-A, in particular, may further impair previously existed renal failure and may induce various adverse events as a result of pharmacodynamic interactions to patients concommittantly treated with many other drugs.
\nImmune-stimulating treatment, targeting NK-/NK-T cells and aiming to generate cytotoxic T-cell activity and eliminate the dysplastic clone, has been associated with rather disappointing results. A promising message is that newer immunomodulating drugs, such as lenalidomide, appear to increase NK T cells and improve their function, including cytokine production, although this is not the major mechanism of action of the drug [108]. Hypomethylating agents, currently used particularly in higher risk patients, when effective and leading to complete response may also benefit autoimmune or hyperimmune clinical syndromes associated with MDS. It has also been suggested that 5-azacytidine has an independent immune-modulating activity and that remissions of the auto-/hyperimmune syndrome may occur independently of the induction of hematological and cytogenetic response, and might also be effective in cases in which other immunosuppressive treatments have been proved ineffective [109].
\nThe injudicious use of immunosuppressive treatment in MDS may become a trench knife [110]. Patients exhibiting overactive immune response, but clonal hematopoiesis, even when sharing a hypoplastic bone marrow, might need even more effective immune activation to wear down the dysplastic clone. Similarly, patients with an established clonal disease, but without any immune activation, could potentially gain benefit with the administration of immune stimulation in an effort to eliminate the clone. On the other hand, abrogation of an overactive immune stimulation should be attempted when this activation suppresses primarily the residual normal/nonclonal hematopoiesis and minimally disturbs the development of the abnormal/dysplastic clone. When immune activation/reaction status cannot be identified and/or quantified, in the middle of established dysplastic hematopoiesis, a course of moderately strong immunosuppressive treatment with corticosteroids and/or cyclosporine could be administered, and in cases of a favorable response, careful tapering of the drugs should be tested in an effort to maintain the obtained response.
\nThe argan tree, being a xerophile species, observed on the semiarid and arid climate has specific ecological characteristics and many interests (forest, forage, and fruit). Argan oil is essentially rich in unsaturated fatty acids and saturated fatty acids. As for the secondary metabolism, it contains polyphenols, tocopherol, sterol, and alcohol, and this explains its benefits in treating heart diseases and skin infections and in general its therapeutic uses and medication as a food supplement [1, 2]. Argan oil has a high level of oleic and linoleic acids and antioxidant compounds, which has an impact on cardiovascular disease [3]. Minor compounds of argan oil, such as sterols, may be involved in its cholesterol-lowering effect [4]. The antidiabetic effect of argan oil has been claimed for a long time in traditional medicine; however the mechanism of regulation of the level of glucose in the blood remains unknown [5]. The antihypertensive effect of argan oil and its mechanism of action have been studied by Berrougui et al. [6]. The purpose of this present work is the comparison between two provenances of argan tree, an endemic variety that grows in southwestern Tindouf located in Algerian Sahara and the other introduced to Mostaganem located in Mediterranean area (Figure 1).
Distribution of the argan tree in Tindouf and northwest Africa [
A mature fruit of Algerian argan (
The extraction was carried out by a Soxhlet apparatus, according to the standard technique [8]; the technique consists in using an organic solvent (hexane). 25 g of almond seeds powder are placed in a cartridge, and then the cartridge is closed by cotton and placed in the Soxhlet extractor. A flask is weighed empty and then filled with 200 ml of solvent. This flask is inserted into the extractor and placed in a sand bath set at a boiling point of the solvent. The extraction is carried out for 3 h and 6 h, then the solvent is removed by distillation, and the oil which remains in the flask is dried at a temperature of 105°C for a few minutes. The volatile compounds were extracted by the solid-phase microextraction (SPME) method; this technique does not require the use of solvents or complicated apparatus, and it is based essentially on the adsorption phenomenon based on a balance between the matrix and coating of the fiber. The identification and quantification of aromatic compounds were performed by gas chromatography-mass spectrometry (GC-MS) (Figure 2).
Fruit, seed, and almond argan oil.
The chemical parameters were detected according to ISO standards [9, 10]. Total sugars were measured according to the method of Dubois et al. [11].
Equipment related to the results presented inTable 1: 50 mg of the almonds of each sample and put in a vial, distilled water is added until at 50 ml. Introduce 1 ml of the solution to be assayed into a tube of each sample and then 1 ml of the phenol solution (5%). The tubes are carefully shaken, and then 5 ml of concentrated sulfuric acid “H2SO4” are added using a graduated pipette. After standing for 30 min in the dark, the absorbance (OD) measurements are made at 490 nm in the case of hexoses. The calibration of the spectrophotometer (UV-vis spectrophotometer) is done with a blank solution containing 1 ml of distilled water, 1 ml of 5% phenol, and 5 ml of H2SO4.
Parameters | Tindouf argan | Mostaganem argan |
---|---|---|
Relative density | 0.83 ± 0.02 | 0.91 ± 0.03 |
Refractive index | 1.4642 ± 0.08 | 1.4612 ± 0.04 |
Acid number | 2.244 ± 0.01 | 2.524 ± 0.09 |
Index saponification | 179.55 ± 0.8 | 185.60 ± 0.5 |
Ester index | 177.306 ± 0.3 | 183.076 ± 0.5 |
pH | 4.62 ± 0.07 | 4.43 ± 0.02 |
Humidity | 2 ± 0.001% | 4.33 ± 0.002% |
Phosphatide | 11.4 ± 0.06% | 13.8 ± 0.02% |
Extraction yield (3 h) | 25.727 ± 0.08% | 25.727 ± 0.02% |
Extraction yield (6 h) | 25.727 ± 0.07% | 41.67 ± 0.04% |
Total sugar | 8.19 ± 0.04% | 4.86 ± 0.06% |
Fat | 38.61 ± 0.3% | 41.67 ± 0.5% |
Ash | 2.4 ± 0.03% | 1.4 ± 0.01% |
Nitrogen content | 1.045 ± 0.001% | 0.602 ± 0.00% |
Protein | 6.53 ± 0.04% | 3.76 ± 0.005% |
Chemical and physical parameters of argan oil of two taxa, Tindouf and Mostaganem argan.
The mineral material was determined by 5 g of the almonds of each region placed in the capsules and placed in the muffle furnace with a temperature of 900°C for 2 h and then metered in desiccators until it was cooled and finally weighed. The protein content is carried out in three stages: mineralization, distillation, and titration; in each flask 3 g of sample from each region are introduced, and 1.5 g of the catalyst is added with some glass bead, then 20 ml of sulfuric acid are poured in. A concentrated 50 ml of distilled water and 45 ml of sodium hydroxide solution (40%) are added for 3 min. The end of the apparatus is leveled in a tarpaulin containing 20 ml of boric acid (4%) which fixes the solution. The titration is carried out with a 0.1 N sulfuric acid solution in the presence of a colored indicator (methyl red) until a pink turn is obtained. For the determination of the fat, introduce 50 g of the sample from each region into the cartridge, place it in the Soxhlet, and weigh the empty flask and fill it with hexane (300 ml). After 6 h of extraction, determine the moisture by the loss of sample water (oil), take two capsules, put in each capsule 3 g of the oil, and placed in an oven at a temperature of 105°C for 2 h of drying. For the determination of the refractive index, calibrate the refractometer apparatus with distilled water. Then, one or two drops of each oil sample are placed on the prism, and the dark zone is moved in the middle for the separation cloth of the light and dark beach.
Determination of PH and acid number, 2 g of the sample and introduce it into the flask or flask. Add 5 ml of ethanol and some drops of phenolphthalein solution (or phenol red) as an indicator, and titrate the liquid with the potassium hydroxide solution contained in the burette to the color curve where the volume V is recorded. For the determination of saponification index, in a flask introduce 2 g of the sample, and add with a burette 25 ml of potassium hydroxide solution and fragments of pumice or porcelain. Fit the glass tube or refrigerant, and place the balloon on the boiling water bath. Allow to cool, disassemble the tube, and add 20 ml of water then 5 drops of phenolphthalein solution. The ester number is the number of milligrams of potassium hydroxide necessary for the neutralization of the acids released by the hydrolysis of the esters contained in 1 g of argan oil. Hydrolysis of the esters by heating in the presence of an ethanoic solution, determination of the excess of alkali by a standard solution of hydrochloric acid. For the determination of phosphatide content, introduce 25 g of oil and 200 ml of acetone in a flask, then leave the mixture at a temperature of 4°C for 2 hours, then filter the mixture on the paper previously weighed and dry this paper at a temperature of 100°C up to 150°C, and finally put in the desiccator and weigh.
Analysis was performed as described by Baccouri et al. [12]. Each oil sample was spiked with 4-methyl-2-pentanone (internal standard) to a final concentration of 6.7 μg/kg. Then 1.5 g was introduced into a 10 ml vial fitted with a silicone septum. The vial was immersed in a water bath at 40°C, and the oily solution is maintained under magnetic stirring. After 2 min, a divinylbenzene/carboxen/polydimethylsiloxane (DVB/CAR/PDMS) fiber (50/30 μm, 2 cm long from Supelco Ltd., Bellefonte, PA) was exposed to the sample headspace for 30 min [13] and immediately desorbed for 2 min at 260°C in the gas chromatograph in splitless condition. All the analyses were performed in triplicate.
GC-MS analysis was performed with a Shimadzu GC-2010 gas chromatograph equipped with a Shimadzu QP-2010 Plus quadrupole mass spectrometer (Shimadzu Corporation, Kyoto, Japan) and a DB-WAXETR capillary column (30 m × 0.25 mm, 0.25 mm film thickness, J&W Scientific Inc., Folsom, CA, USA). Due to the high boiling point of the oily compounds, direct injection to GC-MS apparatus is impossible, and pre-preparation has to be done. We used increased temperatures. Detection was carried out by electron impact mass spectrometry in total ion current (TIC) mode, using ionization energy of 70 eV. The identification of volatile compounds was confirmed by the injection of pure standards. Compounds for which pure standards were not available were identified on the basis of mass spectra and retention indices available in the literature. The relative concentration (μg kg−1 of oil) of the identified compounds was calculated by relating the areas of the internal standard of each compound.
The amount of total phenolics was assayed spectrophotometrically by means of the modified Folin-Ciocalteu method [14, 15]. Briefly, 2.5 ml of 10-fold diluted Folin-Ciocalteu reagent, 2 ml of 7.5% aqueous sodium carbonate solution, and 0.5 ml of phenolic extract were mixed well. After 15 min of heating at 45°C, the absorbance was measured at 765 nm with a UV-visible spectrophotometer (UV-1700 Pharmaspec, Shimadzu, Milan, Italy) [16].
The hydrogen-donating ability of the crude extract and radical scavenging activity (RSA) of argan fruit parts were investigated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH•) radical scavenging assay (RSA) [17, 18]. All operations were done in the dark or dim light [19]. For control purpose, the absorbance of the DPPH• without samples was measured.
The inhibition percentage (IP) of the DPPH• by the extracts was calculated according the formula IP = [(
The TAA in crude extracts was determined according to the Trolox equivalent antioxidant capacity (TEAC) assay following the original analytical procedure described by Re et al. [20] with slight modifications. ABTS radical cation (ABTS•+) was produced by reacting a 7 mM ABTS stock solution with 2.45 mM potassium persulfate (final concentration). For the study, the ABTS•+ stock solution was diluted with ethanol to an absorbance of 0.70 (±0.02) at 734 nm and equilibrated at 30°C. Sample solutions of 30 μL (or standard) were mixed with ABTS•+ solution 3 ml. Absorbance readings were taken at 30°C exactly 6 min after initial mixing. An appropriate solvent blank was obtained by mixing an absolute ethanol of 30 μL with ABTS•+ solution of 3 ml and monitored its absorbance at 6 min. All determinations were carried out in triplicate. The ABTS•+ scavenging effect (% Inhibition) was calculated by the equation % Inhibition = [(
Significant differences among different oils were tested by the one-way analysis of variance and the Duncan test for mean comparison. Statistical analyses were performed using the software package Statistica version 7. Results were reported as mean ± standard deviation (
We noted a small difference in the extraction yield of almonds for both Tindouf and Mostaganem taxa, respectively (25.727–29.272%), after the 3 h duration, while they have a difference of 38.63–41.67% for the duration of 6 h. The percentages of the total sugar of Mostaganem taxa kernels (4.86%) are equal to almost half of the percentage of Tindouf taxa total sugars (8.19%). The sample of Tindouf taxa kernels contains a significant ash (2.4%) compared to the Mostaganem taxa sample (1.4%). The protein content of Tindouf almonds (6.35%) is high compared to the Mostaganem taxa (3.76%). As for the amount of fat, it is brought closer together between the two samples; the kernel gives a significant amount of (40%). Concerning the physicochemical characteristics of argan oil, according to our results we notice that argan oil is not miscible with ethanol for both samples. A difference in the moisture content between the argan oil of the Mostaganem taxa (4.33%) and the Tindouf taxa (2%), and the relative density, by comparison the Tindouf oil (0.83) is lower than Mostaganem (0.91). On the other hand, for the refractive index of argan oil, we record the same values 1.46) with an acid pH. Regarding the other indices, the acidity index of the oil of Mostaganem taxa is equal to 2.5245 and that of Tindouf is 2.2440; the saponification index of the oil of Mostaganem is 185.6 and that of Tindouf is 179.55 (Table 2).
Compound | Tindouf argan | Mostaganem argan | |
---|---|---|---|
Butanoic | 1.2 ± 0.2d | 1.5 ± 0.5d | ** |
Valeric | 1.2 ± 0.3b | 1.5 ± 0.2d | *** |
Hexanoic | 5.2 ± 1.5b | 4.9 ± 2.6b | ** |
1-Butanol | 1.6 ± 0.02 | 1.5 ± 0.43 | ns |
1-Pentanol | 7.5 ± 0.4b | 11.6 ± 2.4c | *** |
1-Hexanol | 20.8 ± 1.5 | 20.5 ± 2.6 | ns |
2-Heptanol | 0.7 ± 0.1a | 1.1 ± 0.4a | *** |
2,3-Butanediol | 40.2 ± 4.3 | 34.3 ± 5.2 | ns |
Hexanal | 26.1 ± 0.8b | 28.9 ± 5.89 | *** |
Benzaldehyde | 1.2 ± 0.1bc | 1.4 ± 0.9c | *** |
Ethyl 2-methyl butanoate | 0.1 ± 0.01ab | 0.1 ± 0.03a | *** |
1.2 ± 0.03c | 0.8 ± 0.4c | ** | |
μ-Butyrolactone | 2.2 ± 0.6c | 3.6 ± 1.2c | ** |
2-Heptanone | 5.2 ± 0.4b | 4.8 ± 1.2c | *** |
Acetoin | 5.4 ± 0.8ab | 4.2 ± 1.4ab | *** |
2-Undecanone | 4.2 ± 0.2ab | 3.1 ± 0.6ab | *** |
Limonene | 0.3 ± 0.4a | 0.25 ± 0.6b | ** |
1-Methyl- | 158.4 ± 22.1a μg/kg | 147.1 ± 15.8b | ** |
2-Methyl pyrazine | 121.3 ± 34.0ab | 138.2 ± 36.5c | *** |
2,6-Dimethyl pyrazine | 263.4 ± 42bc | 273.1 ± 40.8d | ** |
2,3-Dimethyl pyrazine | 6.3 ± 0.1ab | 7.5 ± 0.9c | ** |
2-Ethyl-5-methyl pyrazine | 24.9 ± 1.5a | 23.4 ± 1.6c | *** |
2-Ethyl-6-methyl pyrazine | 35.3 ± 4.2b | 37.5 ± 3.2c | *** |
Trimethyl pyrazine | 26.4 ± 1.2bc | 49.8 ± 3.2d | *** |
2-Ethyl-3,5-dimethyl pyrazine | 26.9 ± 0.5c | 33.2 ± 0.9d | *** |
2-Pentyl furan | 23.1 ± 0.5ab | 22.5 ± 5.8b | * |
Furfurol | 72.3 ± 1.0a | 85.4 ± 4.4b | *** |
2-Furanmethanol | 12.6 ± 0.7b | 14.5 ± 2c | *** |
Quantified volatile compounds (μg/kg of oil ± SD) isolated in argan oil of two taxa.
q, quantifier ion. Different letters in the same row at mean concentration values indicate significant differences (
The results show some volatile compounds, including compounds of lipid peroxidation, Strecker degradation, and Maillard reaction, responsible for the formation of pyrazines and autoxidation of fatty acids. This study could help to adjust the argan oil aroma and perhaps meet new types of consumers. For the phytochemical part, we have undertaken a study on the volatile composition of argan oil. Extraction of the volatile compounds was carried out by solid-phase microextraction (SPME), and their identification and quantification were performed by gas chromatography-mass spectrometry (GC-MS). Finally, we were interested in the elucidation and quantification of polyphenols. These secondary metabolites are of great importance because of their antioxidant properties. In total, 11 phenolic compounds were identified and quantified in the argan tree. This could be achieved through the coupling of liquid chromatography and electrospray negative ion mass spectrometry (LC-ESI-MS). Among the polyphenols cited are procyanidins B1 and B2, (+)-catechin, (−)-epigallocatechin gallate, (−)-epicatechin, isoquercitrin, hyperoside, rutin, phloridzin, myricetin, and quercitrin. The unroasted kernels and the shell are characterized by a diverse phenolic composition. The pulp is quantitatively rich in total polyphenols (69.53 mg gallic acid equivalent/g). It showed a free radical scavenging activity, measured by DPPH. Important relative to other parts of the fruit (0.12 ± 0.004 μM Trolox equivalents/mg) and antioxidant activity (ABTS•+) (0.287 ± 0.05 μM equivalent/mg Trolox). Interestingly, the results obtained confirm that argan fruit polyphenols deserve to be exploited as much as nutritional and pharmaceutical supplements because of their antioxidant properties, which can surely contribute to the safeguarding of the argan tree. The aim of this work was to identify and quantify the phenolic compounds of argan fruit and by-products of argan oil extraction. Total phenolic content and antioxidant activity by DPPH and ABTS were evaluated. The LC-MS examination resulted in the detection of 10 compounds of which 8 were unambiguously identified. The identified compounds are classified into three groups: flavanols, flavonols, and dihydrochalcones. The results showed that six compounds were detected in the pulp: isoquercitrin and hyperoside are predominant (25.8 and 18.5 mg/100 g, respectively); they are followed by rutin (7.2 mg/100 g) and quercitrin (0.32 mg/100 g). Epicatechin and procyanidin B2 were also detected but could not be quantified. The phenolic compounds of the fruit shell of the argan tree have not been the subject of any prior work. The major phenolic compound isolated from the shell is (−)-epicatechin (0.45 mg/100 g), followed by isoquercitrin (0.32 mg/100 g). Rutin and phloridzin have the same level (0.18 mg/100 g), hyperoside and procyanidins B1 and B2 both 0.08 mg/100 g, myricetin 0.04 mg/100 g, and finally the quercitrin that was detected could not be quantified. As for kernels and meal, a major compound was detected; however this compound could not be identified by Tandem mass spectrometry (Mw = 423.5, Rt: 8.5 min).
The average oil density of Mostaganem taxa seems low compared to Tindouf oil. For the refractive index, a small difference is noted between the two taxa of
"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges".
\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.
",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\\n\\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\\n\\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nOAI-PMH
\\n\\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\\n\\nLicense
\\n\\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\\n\\nPeer Review Policies
\\n\\nAll scientific works are Peer Reviewed prior to publishing. Read more
\\n\\nOA Publishing Fees
\\n\\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\\n\\nDigital Archiving Policy
\\n\\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n\\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\\n\\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\\n\\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\\n\\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
\\n\\n\\n"}]'},components:[{type:"htmlEditorComponent",content:'
The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\n\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\n\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\n\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
\n\n\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{},profiles:[{id:"396",title:"Dr.",name:"Vedran",middleName:null,surname:"Kordic",slug:"vedran-kordic",fullName:"Vedran Kordic",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/396/images/7281_n.png",biography:"After obtaining his Master's degree in Mechanical Engineering he continued his education at the Vienna University of Technology where he obtained his PhD degree in 2004. He worked as a researcher at the Automation and Control Institute, Faculty of Electrical Engineering, Vienna University of Technology until 2008. His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. His research interests include the application of agent technology for achieving agile control in the manufacturing environment.",institutionString:null,institution:null},{id:"605",title:"Prof",name:"Dil",middleName:null,surname:"Hussain",slug:"dil-hussain",fullName:"Dil Hussain",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/605/images/system/605.jpg",biography:"Dr. Dil Muhammad Akbar Hussain is a professor of Electronics Engineering & Computer Science at the Department of Energy Technology, Aalborg University Denmark. Professor Akbar has a Master degree in Digital Electronics from Govt. College University, Lahore Pakistan and a P-hD degree in Control Engineering from the School of Engineering and Applied Sciences, University of Sussex United Kingdom. Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. He has contributed in stochastic estimation of control area especially, in the Multiple Target Tracking and Interactive Multiple Model (IMM) research, Ball & Beam Control Problem, Robotics, Levitation Control. He has contributed in developing Algorithms for Fingerprint Matching, Computer Vision and Face Recognition. He has been supervising Pattern Recognition, Formal Languages and Distributed Processing projects for several years. He has reviewed many books on Management, Computer Science. Currently, he is an active and permanent reviewer for many international conferences and symposia and the program committee member for many international conferences.\nIn teaching he has taught the core computer science subjects like, Digital Design, Real Time Embedded System Programming, Operating Systems, Software Engineering, Data Structures, Databases, Compiler Construction. In the Engineering side, Digital Signal Processing, Computer Architecture, Electronics Devices, Digital Filtering and Engineering Management.\nApart from his Academic Interest and activities he loves sport especially, Cricket, Football, Snooker and Squash. He plays cricket for Esbjerg city in the second division team as an opener wicket keeper batsman. He is a very good player of squash but has not played squash since his arrival in Denmark.",institutionString:null,institution:null},{id:"611",title:"Prof.",name:"T",middleName:null,surname:"Nagarajan",slug:"t-nagarajan",fullName:"T Nagarajan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universiti Teknologi Petronas",country:{name:"Malaysia"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:6585},{group:"region",caption:"Middle and South America",value:2,count:5888},{group:"region",caption:"Africa",value:3,count:2382},{group:"region",caption:"Asia",value:4,count:12514},{group:"region",caption:"Australia and Oceania",value:5,count:1006},{group:"region",caption:"Europe",value:6,count:17531}],offset:12,limit:12,total:132506},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{topicId:"21"},books:[{type:"book",id:"11434",title:"Indigenous Populations - Perspectives From Scholars and Practitioners in Contemporary Times",subtitle:null,isOpenForSubmission:!0,hash:"c0d1c1c93a36fd9d726445966316a373",slug:null,bookSignature:"Dr. Sylvanus Gbendazhi Barnabas",coverURL:"https://cdn.intechopen.com/books/images_new/11434.jpg",editedByType:null,editors:[{id:"293764",title:"Dr.",name:"Sylvanus",surname:"Barnabas",slug:"sylvanus-barnabas",fullName:"Sylvanus Barnabas"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11436",title:"Beauty",subtitle:null,isOpenForSubmission:!0,hash:"0e15ba86bab1a64f950318f3ab2584ed",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/11436.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11440",title:"Aggression and Violent Behaviour",subtitle:null,isOpenForSubmission:!0,hash:"7f1d671b6a9e4df140f63d940ee2a1e1",slug:null,bookSignature:"Dr. Catherine Athanasiadou-Lewis",coverURL:"https://cdn.intechopen.com/books/images_new/11440.jpg",editedByType:null,editors:[{id:"287692",title:"Dr.",name:"Catherine",surname:"Lewis",slug:"catherine-lewis",fullName:"Catherine Lewis"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11441",title:"Psychometrics - New Insights",subtitle:null,isOpenForSubmission:!0,hash:"c0fb1dfb98e0ae76496610595407145e",slug:null,bookSignature:" Sandro Misciagna",coverURL:"https://cdn.intechopen.com/books/images_new/11441.jpg",editedByType:null,editors:[{id:"103586",title:null,name:"Sandro",surname:"Misciagna",slug:"sandro-misciagna",fullName:"Sandro Misciagna"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11443",title:"Empathy - Advanced Research and Applications",subtitle:null,isOpenForSubmission:!0,hash:"4c1042dfe15aa9cea6019524c4cbff38",slug:null,bookSignature:"Ph.D. Sara Ventura",coverURL:"https://cdn.intechopen.com/books/images_new/11443.jpg",editedByType:null,editors:[{id:"227763",title:"Ph.D.",name:"Sara",surname:"Ventura",slug:"sara-ventura",fullName:"Sara Ventura"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11444",title:"Happiness - Biopsychosocial and Anthropological Perspectives",subtitle:null,isOpenForSubmission:!0,hash:"fa84e7fc3611e5428e070239dcf5a93f",slug:null,bookSignature:"Dr. Floriana Irtelli and Prof. Fabio Gabrielli",coverURL:"https://cdn.intechopen.com/books/images_new/11444.jpg",editedByType:null,editors:[{id:"174641",title:"Dr.",name:"Floriana",surname:"Irtelli",slug:"floriana-irtelli",fullName:"Floriana Irtelli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11478",title:"Recent Advances in the Study of Dyslexia",subtitle:null,isOpenForSubmission:!0,hash:"26764a18c6b776698823e0e1c3022d2f",slug:null,bookSignature:"Prof. Jonathan Glazzard",coverURL:"https://cdn.intechopen.com/books/images_new/11478.jpg",editedByType:null,editors:[{id:"294281",title:"Prof.",name:"Jonathan",surname:"Glazzard",slug:"jonathan-glazzard",fullName:"Jonathan Glazzard"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11777",title:"LGBT Communities",subtitle:null,isOpenForSubmission:!0,hash:"e08bb222c250dcebf093b7ab595a14a7",slug:null,bookSignature:"Dr. Deborah Woodman",coverURL:"https://cdn.intechopen.com/books/images_new/11777.jpg",editedByType:null,editors:[{id:"463750",title:"Dr.",name:"Deborah",surname:"Woodman",slug:"deborah-woodman",fullName:"Deborah Woodman"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11781",title:"Family Therapy - Recent Advances in Clinical and Crisis Settings",subtitle:null,isOpenForSubmission:!0,hash:"8c5b7d5e4233594de70d2f830209b757",slug:null,bookSignature:"Dr. Oluwatoyin Olatundun Ilesanmi",coverURL:"https://cdn.intechopen.com/books/images_new/11781.jpg",editedByType:null,editors:[{id:"440049",title:"Dr.",name:"Oluwatoyin Olatundun",surname:"Ilesanmi",slug:"oluwatoyin-olatundun-ilesanmi",fullName:"Oluwatoyin Olatundun Ilesanmi"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11782",title:"Personality Traits - The Role in Psychopathology",subtitle:null,isOpenForSubmission:!0,hash:"d3a491e5194cad4c59b900dd57a11842",slug:null,bookSignature:" Vladimir V. Kalinin",coverURL:"https://cdn.intechopen.com/books/images_new/11782.jpg",editedByType:null,editors:[{id:"31572",title:null,name:"Vladimir V.",surname:"Kalinin",slug:"vladimir-v.-kalinin",fullName:"Vladimir V. Kalinin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11783",title:"Motivation and Success",subtitle:null,isOpenForSubmission:!0,hash:"f660b7cd35b9af94bdfc3564df138161",slug:null,bookSignature:"Dr. Simon George Taukeni",coverURL:"https://cdn.intechopen.com/books/images_new/11783.jpg",editedByType:null,editors:[{id:"202046",title:"Dr.",name:"Simon George",surname:"Taukeni",slug:"simon-george-taukeni",fullName:"Simon George Taukeni"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"12109",title:"Occupational Stress",subtitle:null,isOpenForSubmission:!0,hash:"2dc8ab0bc980393022adbacd9a23d219",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/12109.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:41},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:11},{group:"topic",caption:"Business, Management and Economics",value:7,count:6},{group:"topic",caption:"Chemistry",value:8,count:21},{group:"topic",caption:"Computer and Information Science",value:9,count:20},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:15},{group:"topic",caption:"Engineering",value:11,count:58},{group:"topic",caption:"Environmental Sciences",value:12,count:8},{group:"topic",caption:"Immunology and Microbiology",value:13,count:10},{group:"topic",caption:"Materials Science",value:14,count:27},{group:"topic",caption:"Mathematics",value:15,count:9},{group:"topic",caption:"Medicine",value:16,count:121},{group:"topic",caption:"Nanotechnology and Nanomaterials",value:17,count:9},{group:"topic",caption:"Neuroscience",value:18,count:3},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:7},{group:"topic",caption:"Physics",value:20,count:11},{group:"topic",caption:"Psychology",value:21,count:10},{group:"topic",caption:"Robotics",value:22,count:4},{group:"topic",caption:"Social Sciences",value:23,count:8},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:4}],offset:12,limit:12,total:18},popularBooks:{featuredBooks:[{type:"book",id:"10584",title:"Engineered Wood Products for Construction",subtitle:null,isOpenForSubmission:!1,hash:"421757c56a3735986055250821275a51",slug:"engineered-wood-products-for-construction",bookSignature:"Meng Gong",coverURL:"https://cdn.intechopen.com/books/images_new/10584.jpg",editors:[{id:"274242",title:"Dr.",name:"Meng",middleName:null,surname:"Gong",slug:"meng-gong",fullName:"Meng Gong"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10222",title:"Demyelination Disorders",subtitle:null,isOpenForSubmission:!1,hash:"b6c26ceccacdde70c41c587361bd5558",slug:"demyelination-disorders",bookSignature:"Stavros J. Baloyannis, Fabian H. Rossi and Welwin Liu",coverURL:"https://cdn.intechopen.com/books/images_new/10222.jpg",editors:[{id:"156098",title:"Emeritus Prof.",name:"Stavros J.",middleName:"J.",surname:"Baloyannis",slug:"stavros-j.-baloyannis",fullName:"Stavros J. Baloyannis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9544",title:"Global Trade in the Emerging Business Environment",subtitle:null,isOpenForSubmission:!1,hash:"fb8cb09b9599246add78d508a98273d5",slug:"global-trade-in-the-emerging-business-environment",bookSignature:"Muhammad Mohiuddin, Jingbin Wang , Md. Samim Al Azad and Selim Ahmed",coverURL:"https://cdn.intechopen.com/books/images_new/9544.jpg",editors:[{id:"418514",title:"Dr.",name:"Muhammad",middleName:null,surname:"Mohiuddin",slug:"muhammad-mohiuddin",fullName:"Muhammad Mohiuddin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10979",title:"Parenting",subtitle:"Challenges of Child Rearing in a Changing Society",isOpenForSubmission:!1,hash:"6f345ebcf4fd61e73643c69063a12c7b",slug:"parenting-challenges-of-child-rearing-in-a-changing-society",bookSignature:"Sayyed Ali Samadi",coverURL:"https://cdn.intechopen.com/books/images_new/10979.jpg",editors:[{id:"52145",title:"Dr.",name:"Sayyed Ali",middleName:null,surname:"Samadi",slug:"sayyed-ali-samadi",fullName:"Sayyed Ali Samadi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9808",title:"Contemporary Topics in Patient Safety",subtitle:"Volume 1",isOpenForSubmission:!1,hash:"fb6371607c2c6c02c6a2af8892765aba",slug:"contemporary-topics-in-patient-safety-volume-1",bookSignature:"Stanislaw P. Stawicki and Michael S. Firstenberg",coverURL:"https://cdn.intechopen.com/books/images_new/9808.jpg",editors:[{id:"181694",title:"Dr.",name:"Stanislaw P.",middleName:null,surname:"Stawicki",slug:"stanislaw-p.-stawicki",fullName:"Stanislaw P. Stawicki"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10681",title:"Biodegradation Technology of Organic and Inorganic Pollutants",subtitle:null,isOpenForSubmission:!1,hash:"9a6e10e02788092872fd249436898e97",slug:"biodegradation-technology-of-organic-and-inorganic-pollutants",bookSignature:"Kassio Ferreira Mendes, Rodrigo Nogueira de Sousa and Kamila Cabral Mielke",coverURL:"https://cdn.intechopen.com/books/images_new/10681.jpg",editors:[{id:"197720",title:"Ph.D.",name:"Kassio",middleName:null,surname:"Ferreira Mendes",slug:"kassio-ferreira-mendes",fullName:"Kassio Ferreira Mendes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10764",title:"Antenna Systems",subtitle:null,isOpenForSubmission:!1,hash:"2fbf1c7a5d92723f08198fc9b526a8ad",slug:"antenna-systems",bookSignature:"Hussain Al-Rizzo and Said Abushamleh",coverURL:"https://cdn.intechopen.com/books/images_new/10764.jpg",editors:[{id:"153384",title:"Prof.",name:"Hussain",middleName:null,surname:"Al-Rizzo",slug:"hussain-al-rizzo",fullName:"Hussain Al-Rizzo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10668",title:"Sustainability of Concrete With Synthetic and Recycled Aggregates",subtitle:null,isOpenForSubmission:!1,hash:"55856c6a8bc3a5b21dae5a1af09a56b6",slug:"sustainability-of-concrete-with-synthetic-and-recycled-aggregates",bookSignature:"Hosam M. Saleh",coverURL:"https://cdn.intechopen.com/books/images_new/10668.jpg",editors:[{id:"144691",title:"Prof.",name:"Hosam",middleName:null,surname:"Saleh",slug:"hosam-saleh",fullName:"Hosam Saleh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10803",title:"Reactive Oxygen Species",subtitle:null,isOpenForSubmission:!1,hash:"176adcf090fdd1f93cb8ce3146e79ca1",slug:"reactive-oxygen-species",bookSignature:"Rizwan Ahmad",coverURL:"https://cdn.intechopen.com/books/images_new/10803.jpg",editors:[{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9032",title:"Corporate Social Responsibility",subtitle:null,isOpenForSubmission:!1,hash:"f609bf3251d7cc7bae0099a4374adfc3",slug:"corporate-social-responsibility",bookSignature:"Beatrice Orlando",coverURL:"https://cdn.intechopen.com/books/images_new/9032.jpg",editors:[{id:"232969",title:"Prof.",name:"Beatrice",middleName:null,surname:"Orlando",slug:"beatrice-orlando",fullName:"Beatrice Orlando"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10351",title:"Enhanced Liposuction",subtitle:"New Perspectives and Techniques",isOpenForSubmission:!1,hash:"f08ed6de16da357614586c5b58ed4dfa",slug:"enhanced-liposuction-new-perspectives-and-techniques",bookSignature:"Diane Irvine Duncan",coverURL:"https://cdn.intechopen.com/books/images_new/10351.jpg",editors:[{id:"279869",title:"Dr.",name:"Diane Irvine",middleName:null,surname:"Duncan",slug:"diane-irvine-duncan",fullName:"Diane Irvine Duncan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10779",title:"21st Century Nanostructured Materials",subtitle:"Physics, Chemistry, Classification, and Emerging Applications in Industry, Biomedicine, and Agriculture",isOpenForSubmission:!1,hash:"72c67f97f9bef68200df115b5fd79884",slug:"21st-century-nanostructured-materials-physics-chemistry-classification-and-emerging-applications-in-industry-biomedicine-and-agriculture",bookSignature:"Phuong V. Pham",coverURL:"https://cdn.intechopen.com/books/images_new/10779.jpg",editors:[{id:"236073",title:"Dr.",name:"Phuong",middleName:"Viet",surname:"Pham",slug:"phuong-pham",fullName:"Phuong Pham"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:4386},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"10584",title:"Engineered Wood Products for Construction",subtitle:null,isOpenForSubmission:!1,hash:"421757c56a3735986055250821275a51",slug:"engineered-wood-products-for-construction",bookSignature:"Meng Gong",coverURL:"https://cdn.intechopen.com/books/images_new/10584.jpg",publishedDate:"April 28th 2022",numberOfDownloads:3665,editors:[{id:"274242",title:"Dr.",name:"Meng",middleName:null,surname:"Gong",slug:"meng-gong",fullName:"Meng Gong"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10222",title:"Demyelination Disorders",subtitle:null,isOpenForSubmission:!1,hash:"b6c26ceccacdde70c41c587361bd5558",slug:"demyelination-disorders",bookSignature:"Stavros J. Baloyannis, Fabian H. Rossi and Welwin Liu",coverURL:"https://cdn.intechopen.com/books/images_new/10222.jpg",publishedDate:"May 4th 2022",numberOfDownloads:1713,editors:[{id:"156098",title:"Emeritus Prof.",name:"Stavros J.",middleName:"J.",surname:"Baloyannis",slug:"stavros-j.-baloyannis",fullName:"Stavros J. Baloyannis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9544",title:"Global Trade in the Emerging Business Environment",subtitle:null,isOpenForSubmission:!1,hash:"fb8cb09b9599246add78d508a98273d5",slug:"global-trade-in-the-emerging-business-environment",bookSignature:"Muhammad Mohiuddin, Jingbin Wang , Md. Samim Al Azad and Selim Ahmed",coverURL:"https://cdn.intechopen.com/books/images_new/9544.jpg",publishedDate:"April 28th 2022",numberOfDownloads:2481,editors:[{id:"418514",title:"Dr.",name:"Muhammad",middleName:null,surname:"Mohiuddin",slug:"muhammad-mohiuddin",fullName:"Muhammad Mohiuddin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10979",title:"Parenting",subtitle:"Challenges of Child Rearing in a Changing Society",isOpenForSubmission:!1,hash:"6f345ebcf4fd61e73643c69063a12c7b",slug:"parenting-challenges-of-child-rearing-in-a-changing-society",bookSignature:"Sayyed Ali Samadi",coverURL:"https://cdn.intechopen.com/books/images_new/10979.jpg",publishedDate:"May 4th 2022",numberOfDownloads:1107,editors:[{id:"52145",title:"Dr.",name:"Sayyed Ali",middleName:null,surname:"Samadi",slug:"sayyed-ali-samadi",fullName:"Sayyed Ali Samadi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9808",title:"Contemporary Topics in Patient Safety",subtitle:"Volume 1",isOpenForSubmission:!1,hash:"fb6371607c2c6c02c6a2af8892765aba",slug:"contemporary-topics-in-patient-safety-volume-1",bookSignature:"Stanislaw P. Stawicki and Michael S. Firstenberg",coverURL:"https://cdn.intechopen.com/books/images_new/9808.jpg",publishedDate:"April 20th 2022",numberOfDownloads:3307,editors:[{id:"181694",title:"Dr.",name:"Stanislaw P.",middleName:null,surname:"Stawicki",slug:"stanislaw-p.-stawicki",fullName:"Stanislaw P. Stawicki"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10681",title:"Biodegradation Technology of Organic and Inorganic Pollutants",subtitle:null,isOpenForSubmission:!1,hash:"9a6e10e02788092872fd249436898e97",slug:"biodegradation-technology-of-organic-and-inorganic-pollutants",bookSignature:"Kassio Ferreira Mendes, Rodrigo Nogueira de Sousa and Kamila Cabral Mielke",coverURL:"https://cdn.intechopen.com/books/images_new/10681.jpg",publishedDate:"April 20th 2022",numberOfDownloads:3266,editors:[{id:"197720",title:"Ph.D.",name:"Kassio",middleName:null,surname:"Ferreira Mendes",slug:"kassio-ferreira-mendes",fullName:"Kassio Ferreira Mendes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10764",title:"Antenna Systems",subtitle:null,isOpenForSubmission:!1,hash:"2fbf1c7a5d92723f08198fc9b526a8ad",slug:"antenna-systems",bookSignature:"Hussain Al-Rizzo and Said Abushamleh",coverURL:"https://cdn.intechopen.com/books/images_new/10764.jpg",publishedDate:"April 28th 2022",numberOfDownloads:1868,editors:[{id:"153384",title:"Prof.",name:"Hussain",middleName:null,surname:"Al-Rizzo",slug:"hussain-al-rizzo",fullName:"Hussain Al-Rizzo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10668",title:"Sustainability of Concrete With Synthetic and Recycled Aggregates",subtitle:null,isOpenForSubmission:!1,hash:"55856c6a8bc3a5b21dae5a1af09a56b6",slug:"sustainability-of-concrete-with-synthetic-and-recycled-aggregates",bookSignature:"Hosam M. Saleh",coverURL:"https://cdn.intechopen.com/books/images_new/10668.jpg",publishedDate:"May 4th 2022",numberOfDownloads:856,editors:[{id:"144691",title:"Prof.",name:"Hosam",middleName:null,surname:"Saleh",slug:"hosam-saleh",fullName:"Hosam Saleh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10803",title:"Reactive Oxygen Species",subtitle:null,isOpenForSubmission:!1,hash:"176adcf090fdd1f93cb8ce3146e79ca1",slug:"reactive-oxygen-species",bookSignature:"Rizwan Ahmad",coverURL:"https://cdn.intechopen.com/books/images_new/10803.jpg",publishedDate:"April 28th 2022",numberOfDownloads:1704,editors:[{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9032",title:"Corporate Social Responsibility",subtitle:null,isOpenForSubmission:!1,hash:"f609bf3251d7cc7bae0099a4374adfc3",slug:"corporate-social-responsibility",bookSignature:"Beatrice Orlando",coverURL:"https://cdn.intechopen.com/books/images_new/9032.jpg",publishedDate:"March 16th 2022",numberOfDownloads:7489,editors:[{id:"232969",title:"Prof.",name:"Beatrice",middleName:null,surname:"Orlando",slug:"beatrice-orlando",fullName:"Beatrice Orlando"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"8737",title:"Rabies Virus at the Beginning of 21st Century",subtitle:null,isOpenForSubmission:!1,hash:"49cce3f548da548c718c865feb343509",slug:"rabies-virus-at-the-beginning-of-21st-century",bookSignature:"Sergey Tkachev",coverURL:"https://cdn.intechopen.com/books/images_new/8737.jpg",editedByType:"Edited by",publishedDate:"May 11th 2022",editors:[{id:"61139",title:"Dr.",name:"Sergey",middleName:null,surname:"Tkachev",slug:"sergey-tkachev",fullName:"Sergey Tkachev"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10861",title:"Furan Derivatives",subtitle:"Recent Advances and Applications",isOpenForSubmission:!1,hash:"fdfc39cecd82f91b0effac994f75c877",slug:"furan-derivatives-recent-advances-and-applications",bookSignature:"Anish Khan, Mohammed Muzibur Rahman, M. Ramesh, Salman Ahmad Khan and Abdullah Mohammed Ahmed Asiri",coverURL:"https://cdn.intechopen.com/books/images_new/10861.jpg",editedByType:"Edited by",publishedDate:"May 11th 2022",editors:[{id:"293058",title:"Dr.",name:"Anish",middleName:null,surname:"Khan",slug:"anish-khan",fullName:"Anish Khan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10356",title:"Natural Medicinal Plants",subtitle:null,isOpenForSubmission:!1,hash:"943e56ccaaf19ff696d25aa638ae37d6",slug:"natural-medicinal-plants",bookSignature:"Hany A. El-Shemy",coverURL:"https://cdn.intechopen.com/books/images_new/10356.jpg",editedByType:"Edited by",publishedDate:"May 11th 2022",editors:[{id:"54719",title:"Prof.",name:"Hany",middleName:null,surname:"El-Shemy",slug:"hany-el-shemy",fullName:"Hany El-Shemy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10870",title:"Ultrasound Imaging",subtitle:"Current Topics",isOpenForSubmission:!1,hash:"2f0bc3733ab226d67fa73759ef0e12ad",slug:"ultrasound-imaging-current-topics",bookSignature:"Felix Okechukwu Erondu",coverURL:"https://cdn.intechopen.com/books/images_new/10870.jpg",editedByType:"Edited by",publishedDate:"May 11th 2022",editors:[{id:"68312",title:"Prof.",name:"Felix",middleName:null,surname:"Okechukwu Erondu",slug:"felix-okechukwu-erondu",fullName:"Felix Okechukwu Erondu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11392",title:"Leadership in a Changing World",subtitle:"A Multidimensional Perspective",isOpenForSubmission:!1,hash:"86a6d33cf601587e591064ce92effc02",slug:"leadership-in-a-changing-world-a-multidimensional-perspective",bookSignature:"Muhammad Mohiuddin, Bilal Khalid, Md. Samim Al Azad and Slimane Ed-dafali",coverURL:"https://cdn.intechopen.com/books/images_new/11392.jpg",editedByType:"Edited by",publishedDate:"May 11th 2022",editors:[{id:"418514",title:"Dr.",name:"Muhammad",middleName:null,surname:"Mohiuddin",slug:"muhammad-mohiuddin",fullName:"Muhammad Mohiuddin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10400",title:"The Application of Ant Colony Optimization",subtitle:null,isOpenForSubmission:!1,hash:"f4fdfd07ee1ab99fb7c740d6d0c144c6",slug:"the-application-of-ant-colony-optimization",bookSignature:"Ali Soofastaei",coverURL:"https://cdn.intechopen.com/books/images_new/10400.jpg",editedByType:"Edited by",publishedDate:"May 11th 2022",editors:[{id:"257455",title:"Dr.",name:"Ali",middleName:null,surname:"Soofastaei",slug:"ali-soofastaei",fullName:"Ali Soofastaei"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10915",title:"Leadership",subtitle:"New Insights",isOpenForSubmission:!1,hash:"0d72e79892f2a020cee66a52d09de5a4",slug:"leadership-new-insights",bookSignature:"Mário Franco",coverURL:"https://cdn.intechopen.com/books/images_new/10915.jpg",editedByType:"Edited by",publishedDate:"May 11th 2022",editors:[{id:"105529",title:"Dr.",name:"Mário",middleName:null,surname:"Franco",slug:"mario-franco",fullName:"Mário Franco"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10683",title:"Technological Innovations and Advances in Hydropower Engineering",subtitle:null,isOpenForSubmission:!1,hash:"7ce7ad8768bd2cad155470fe1fd883f4",slug:"technological-innovations-and-advances-in-hydropower-engineering",bookSignature:"Yizi Shang, Ling Shang and Xiaofei Li",coverURL:"https://cdn.intechopen.com/books/images_new/10683.jpg",editedByType:"Edited by",publishedDate:"May 11th 2022",editors:[{id:"349630",title:"Dr.",name:"Yizi",middleName:null,surname:"Shang",slug:"yizi-shang",fullName:"Yizi Shang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7102",title:"Pneumonia",subtitle:null,isOpenForSubmission:!1,hash:"9fd70142814192dcec58a176749f1b60",slug:"pneumonia",bookSignature:"Nima Rezaei",coverURL:"https://cdn.intechopen.com/books/images_new/7102.jpg",editedByType:"Edited by",publishedDate:"May 11th 2022",editors:[{id:"116250",title:"Dr.",name:"Nima",middleName:null,surname:"Rezaei",slug:"nima-rezaei",fullName:"Nima Rezaei"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9670",title:"Current Trends in Wheat Research",subtitle:null,isOpenForSubmission:!1,hash:"89d795987f1747a76eee532700d2093d",slug:"current-trends-in-wheat-research",bookSignature:"Mahmood-ur-Rahman Ansari",coverURL:"https://cdn.intechopen.com/books/images_new/9670.jpg",editedByType:"Edited by",publishedDate:"May 11th 2022",editors:[{id:"185476",title:"Dr.",name:"Mahmood-ur-Rahman",middleName:null,surname:"Ansari",slug:"mahmood-ur-rahman-ansari",fullName:"Mahmood-ur-Rahman Ansari"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"265",title:"Education",slug:"social-sciences-education",parent:{id:"23",title:"Social Sciences",slug:"social-sciences"},numberOfBooks:30,numberOfSeries:0,numberOfAuthorsAndEditors:520,numberOfWosCitations:196,numberOfCrossrefCitations:344,numberOfDimensionsCitations:542,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicId:"265",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"10495",title:"Insights Into Global Engineering Education After the Birth of Industry 5.0",subtitle:null,isOpenForSubmission:!1,hash:"e83ddb1aa8017926d0635bbe8a90feca",slug:"insights-into-global-engineering-education-after-the-birth-of-industry-5-0",bookSignature:"Montaha Bouezzeddine",coverURL:"https://cdn.intechopen.com/books/images_new/10495.jpg",editedByType:"Edited by",editors:[{id:"313464",title:"Dr.Ing.",name:"Montaha",middleName:null,surname:"Bouezzeddine",slug:"montaha-bouezzeddine",fullName:"Montaha Bouezzeddine"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9558",title:"Active Learning",subtitle:"Theory and Practice",isOpenForSubmission:!1,hash:"c55b272766d51c3d563abc25c026b939",slug:"active-learning-theory-and-practice",bookSignature:"Olena Lutsenko and Gregory Lutsenko",coverURL:"https://cdn.intechopen.com/books/images_new/9558.jpg",editedByType:"Edited by",editors:[{id:"225667",title:"Mrs.",name:"Olena",middleName:null,surname:"Lutsenko",slug:"olena-lutsenko",fullName:"Olena Lutsenko"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9535",title:"Education in Childhood",subtitle:null,isOpenForSubmission:!1,hash:"edc0b902fe67ee1b6fab1df4992cb55d",slug:"education-in-childhood",bookSignature:"Olga María Alegre de la Rosa, Luis Miguel Villar Angulo and Carla Giambrone",coverURL:"https://cdn.intechopen.com/books/images_new/9535.jpg",editedByType:"Edited by",editors:[{id:"338767",title:"Prof.",name:"Olga María",middleName:null,surname:"Alegre de la Rosa",slug:"olga-maria-alegre-de-la-rosa",fullName:"Olga María Alegre de la Rosa"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10807",title:"Teacher Education",subtitle:"New Perspectives",isOpenForSubmission:!1,hash:"3baeedd4e6dfcdbccca461891bd66a8d",slug:"teacher-education-new-perspectives",bookSignature:"Ulas Kayapinar",coverURL:"https://cdn.intechopen.com/books/images_new/10807.jpg",editedByType:"Edited by",editors:[{id:"232425",title:"Dr.",name:"Ulas",middleName:null,surname:"Kayapinar",slug:"ulas-kayapinar",fullName:"Ulas Kayapinar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10229",title:"Teacher Education in the 21st Century",subtitle:"Emerging Skills for a Changing World",isOpenForSubmission:!1,hash:"b01f9136149277b7e4cbc1e52bce78ec",slug:"teacher-education-in-the-21st-century-emerging-skills-for-a-changing-world",bookSignature:"Maria Jose Hernández-Serrano",coverURL:"https://cdn.intechopen.com/books/images_new/10229.jpg",editedByType:"Edited by",editors:[{id:"187893",title:"Dr.",name:"Maria Jose",middleName:null,surname:"Hernández-Serrano",slug:"maria-jose-hernandez-serrano",fullName:"Maria Jose Hernández-Serrano"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10191",title:"Health and Academic Achievement",subtitle:"New Findings",isOpenForSubmission:!1,hash:"7ee3f57e3911318305ac5c2eef39f8ab",slug:"health-and-academic-achievement-new-findings",bookSignature:"Blandina Bernal-Morales",coverURL:"https://cdn.intechopen.com/books/images_new/10191.jpg",editedByType:"Edited by",editors:[{id:"174721",title:"Dr.",name:"Blandina",middleName:null,surname:"Bernal-Morales",slug:"blandina-bernal-morales",fullName:"Blandina Bernal-Morales"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9560",title:"Creativity",subtitle:"A Force to Innovation",isOpenForSubmission:!1,hash:"58f740bc17807d5d88d647c525857b11",slug:"creativity-a-force-to-innovation",bookSignature:"Pooja Jain",coverURL:"https://cdn.intechopen.com/books/images_new/9560.jpg",editedByType:"Edited by",editors:[{id:"316765",title:"Dr.",name:"Pooja",middleName:null,surname:"Jain",slug:"pooja-jain",fullName:"Pooja Jain"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8697",title:"Virtual Reality and Its Application in Education",subtitle:null,isOpenForSubmission:!1,hash:"ee01b5e387ba0062c6b0d1e9227bda05",slug:"virtual-reality-and-its-application-in-education",bookSignature:"Dragan Cvetković",coverURL:"https://cdn.intechopen.com/books/images_new/8697.jpg",editedByType:"Edited by",editors:[{id:"101330",title:"Dr.",name:"Dragan",middleName:"Mladen",surname:"Cvetković",slug:"dragan-cvetkovic",fullName:"Dragan Cvetković"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8283",title:"Innovations in Higher Education",subtitle:"Cases on Transforming and Advancing Practice",isOpenForSubmission:!1,hash:"9c8b8a6fe8578fbf2398932ce8c1b717",slug:"innovations-in-higher-education-cases-on-transforming-and-advancing-practice",bookSignature:"Dominique Parrish and Joanne Joyce-McCoach",coverURL:"https://cdn.intechopen.com/books/images_new/8283.jpg",editedByType:"Edited by",editors:[{id:"197795",title:"Associate Prof.",name:"Dominique",middleName:null,surname:"Parrish",slug:"dominique-parrish",fullName:"Dominique Parrish"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7906",title:"The Essence of Academic Performance",subtitle:null,isOpenForSubmission:!1,hash:"69e39465b02c12b562c004ed8d591710",slug:"the-essence-of-academic-performance",bookSignature:"Bernard Nchindila and Trudy Corrigan",coverURL:"https://cdn.intechopen.com/books/images_new/7906.jpg",editedByType:"Edited by",editors:[{id:"196855",title:"Prof.",name:"Bernard",middleName:"Mwansa",surname:"Nchindila",slug:"bernard-nchindila",fullName:"Bernard Nchindila"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7819",title:"Education Systems Around the World",subtitle:null,isOpenForSubmission:!1,hash:"c3d5598e631502952f75b2181873f6ea",slug:"education-systems-around-the-world",bookSignature:"Gilson Porto Jr.",coverURL:"https://cdn.intechopen.com/books/images_new/7819.jpg",editedByType:"Edited by",editors:[{id:"279817",title:"Dr.",name:"Gilson",middleName:null,surname:"Porto",slug:"gilson-porto",fullName:"Gilson Porto"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7601",title:"Game Design and Intelligent Interaction",subtitle:null,isOpenForSubmission:!1,hash:"aef7c5d14fb716604538b9f7e1a3f2ef",slug:"game-design-and-intelligent-interaction",bookSignature:"Ioannis Deliyannis",coverURL:"https://cdn.intechopen.com/books/images_new/7601.jpg",editedByType:"Edited by",editors:[{id:"103622",title:"Dr.",name:"Ioannis",middleName:null,surname:"Deliyannis",slug:"ioannis-deliyannis",fullName:"Ioannis Deliyannis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:30,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"59705",doi:"10.5772/intechopen.74943",title:"Augmented Reality Trends in Education between 2016 and 2017 Years",slug:"augmented-reality-trends-in-education-between-2016-and-2017-years",totalDownloads:2428,totalCrossrefCites:17,totalDimensionsCites:23,abstract:"The aim of this chapter is to review literature regarding using augmented reality (AR) in education articles published in between 2016 and 2017 years. The literature source was Web of Science and SSCI, SCI-EXPANDED, A&HCI, CPCI-S, CPCI-SSH, and ESCI indexes. Fifty-two articles were reviewed; however, 14 of them were not been included in the study. As a result, 38 articles were examined. Level of education, field of education, and material types of AR used in education and reported educational advantages of AR have been investigated. All articles are categorized according to target groups, which are early childhood education, primary education, secondary education, high school education, graduate education, and others. AR technology has been mostly carried out in primary and graduate education. “Science education” is the most explored field of education. Mobile applications and marker-based materials on paper have been mostly preferred. The major advantages indicated in the articles are “Learning/Academic Achievement,” “Motivation,” and “Attitude”.",book:{id:"6543",slug:"state-of-the-art-virtual-reality-and-augmented-reality-knowhow",title:"State of the Art Virtual Reality and Augmented Reality Knowhow",fullTitle:"State of the Art Virtual Reality and Augmented Reality Knowhow"},signatures:"Rabia M. Yilmaz",authors:[{id:"225838",title:"Dr.",name:"Rabia",middleName:null,surname:"Yilmaz",slug:"rabia-yilmaz",fullName:"Rabia Yilmaz"}]},{id:"59468",doi:"10.5772/intechopen.74344",title:"Virtual and Augmented Reality: New Frontiers for Clinical Psychology",slug:"virtual-and-augmented-reality-new-frontiers-for-clinical-psychology",totalDownloads:2315,totalCrossrefCites:13,totalDimensionsCites:21,abstract:"In the last decades, the applied approach for the use of virtual reality (VR) and augmented reality (AR) on clinical and health psychology has grown exponentially. These technologies have been used to treat several mental disorders, for example, phobias, stress-related disorders, depression, eating disorders, and chronic pain. The importance of VR/AR for the mental health field comes from three main concepts: (1) VR/AR as an imaginal technology, people can feel “as if they are” in a reality that does not exist in external world; (2) VR/AR as an embodied technology, the experience to feel user’s body inside the virtual environment; and (3) VR/AR as connectivity technology, the “end of geography’. In this chapter, we explore the opportunities provided by VR/AR as technologies to improve people’s quality of life and to discuss new frontiers for their application in mental health and psychological well-being promotion.",book:{id:"6543",slug:"state-of-the-art-virtual-reality-and-augmented-reality-knowhow",title:"State of the Art Virtual Reality and Augmented Reality Knowhow",fullTitle:"State of the Art Virtual Reality and Augmented Reality Knowhow"},signatures:"Sara Ventura, Rosa M. Baños and Cristina Botella",authors:[{id:"106036",title:"Dr.",name:"Rosa Maria",middleName:null,surname:"Baños",slug:"rosa-maria-banos",fullName:"Rosa Maria Baños"},{id:"227763",title:"Ph.D.",name:"Sara",middleName:null,surname:"Ventura",slug:"sara-ventura",fullName:"Sara Ventura"},{id:"229056",title:"Dr.",name:"Cristina",middleName:null,surname:"Botella",slug:"cristina-botella",fullName:"Cristina Botella"}]},{id:"63639",doi:"10.5772/intechopen.81086",title:"Cooperative Learning: The Foundation for Active Learning",slug:"cooperative-learning-the-foundation-for-active-learning",totalDownloads:3303,totalCrossrefCites:17,totalDimensionsCites:19,abstract:"The role of instructors is evolving from the presenter of information to the designer of active learning processes, environments, and experiences that maximize student engagement. The more active a lesson, the more students tend to engage intellectually and emotionally in the learning activities. Cooperative learning is the foundation on which many of the active learning procedures are based. Cooperative learning is the instructional use of small groups so that students work together to maximize their own and each other’s learning. Most of the active learning procedures, such as problem-based learning, team-learning, collaborative learning, and PALS, require that students work cooperatively in small groups to achieve joint learning goals. Cooperative learning is based on two theories: Structure-Process-Outcome theory and Social Interdependence theory. Four types of cooperative learning have been derived: formal cooperative learning, informal cooperative learning, cooperative base groups, and constructive controversy. There is considerable research confirming the effectiveness of cooperative learning. To be cooperative, however, five basic elements must be structured into the situation: positive interdependence, individual accountability, promotive interaction, social skills, and group processing.",book:{id:"6929",slug:"active-learning-beyond-the-future",title:"Active Learning",fullTitle:"Active Learning - Beyond the Future"},signatures:"David W. Johnson and Roger T. Johnson",authors:[{id:"259976",title:"Dr.",name:"David",middleName:null,surname:"Johnson",slug:"david-johnson",fullName:"David Johnson"},{id:"263004",title:"Dr.",name:"Roger",middleName:null,surname:"John