General indications for echocardiographic examination in the intensive care unit.
\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"9325",leadTitle:null,fullTitle:"Mathematical Theorems - Boundary Value Problems and Approximations",title:"Mathematical Theorems",subtitle:"Boundary Value Problems and Approximations",reviewType:"peer-reviewed",abstract:"The main content of this book is related to construction of analytical solutions of differential equations and systems of mathematical physics, to development of analytical methods for solving boundary value problems for such equations and the study of properties of their solutions. A wide class of equations (elliptic, parabolic, and hyperbolic) is considered here, on the basis of which complex wave processes in biological and physical media can be simulated.The method of generalized functions presented in the book for solving boundary value problems of mathematical physics is universal for constructing solutions of boundary value problems for systems of linear differential equations with constant coefficients of any type. In the last sections of the book, the issues of calculating functions based on Padé approximations, binomial expansions, and fractal representations are considered. The book is intended for specialists in the field of mathematical and theoretical physics, mechanics and biophysics, students of mechanics, mathematics, physics and biology departments of higher educational institutions.",isbn:"978-1-83880-072-7",printIsbn:"978-1-83880-071-0",pdfIsbn:"978-1-83880-341-4",doi:"10.5772/intechopen.83329",price:119,priceEur:129,priceUsd:155,slug:"mathematical-theorems-boundary-value-problems-and-approximations",numberOfPages:148,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"38c88a4ec0ff6c0184a6694c21ddedc5",bookSignature:"Lyudmila Alexeyeva",publishedDate:"December 9th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/9325.jpg",numberOfDownloads:3468,numberOfWosCitations:3,numberOfCrossrefCitations:4,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:10,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:17,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 7th 2019",dateEndSecondStepPublish:"March 24th 2020",dateEndThirdStepPublish:"May 23rd 2020",dateEndFourthStepPublish:"August 11th 2020",dateEndFifthStepPublish:"October 10th 2020",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"232525",title:"Prof.",name:"Lyudmila",middleName:"Alexeyevna",surname:"Alexeyeva",slug:"lyudmila-alexeyeva",fullName:"Lyudmila Alexeyeva",profilePictureURL:"https://mts.intechopen.com/storage/users/232525/images/system/232525.jpg",biography:"Lyudmila Alexeyeva (born in 1947, Kaliningrad, Russia), Doctor of physical and mathematical sciences, professor, academician of International Eurasian Academy of Sciences, graduated with honors from the Mechanics and Mathematics Faculty of M.V. Lomonosov Moscow State University (Russia). \nThen she worked at the Institute of Mathematics and Mechanics of Academy of Sciences (Kazakhstan, Alma-Ata) in the laboratory of theory of seismic resistance of underground structures (1973-1991). From 1992 to the present day, she has run the Wave Dynamics Laboratory of Institute of Mathematics and Mathematical Modeling. From 2011 to 2018, she worked as the Head of Department of Mathematical Physics and Modeling in this institute. Concurrently, she worked as a Professor at al-Farabi Kazakh National University at Mechanics and Mathematics Faculty.\nShe has authored 5 monographs and over 300 scientific publications. Five doctoral and 14 candidate dissertations were defended under her supervision. For her active scientific work, she was awarded the State Scholarship for outstanding contribution to development of science and technology (four times), and a medal for labor valor.",institutionString:"Institute of Mathematics and Mathematical Modeling",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Institute of Mathematics and Mathematical Modeling",institutionURL:null,country:{name:"Kazakhstan"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"163",title:"Applied Mathematics",slug:"applied-mathematics"}],chapters:[{id:"71181",title:"Exact Traveling Wave Solutions of One-Dimensional Parabolic-Parabolic Models of Chemotaxis",doi:"10.5772/intechopen.91214",slug:"exact-traveling-wave-solutions-of-one-dimensional-parabolic-parabolic-models-of-chemotaxis",totalDownloads:578,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"In this chapter we consider several different parabolic-parabolic systems of chemotaxis which depend on time and one space coordinate. For these systems we obtain the exact analytical solutions in terms of traveling wave variables. Not all of these solutions are acceptable for biological interpretation, but there are solutions that require detailed analysis. We find this interesting, since chemotaxis is present in the continuous mathematical models of cancer growth and invasion (Anderson, Chaplain, Lolas, et al.) which are described by the systems of reaction–diffusion-taxis partial differential equations, and the obtaining of exact solutions to these systems seems to be a very interesting task, and a more detailed analysis is possible in a future study.",signatures:"Maria Vladimirovna Shubina",downloadPdfUrl:"/chapter/pdf-download/71181",previewPdfUrl:"/chapter/pdf-preview/71181",authors:[null],corrections:null},{id:"71864",title:"Generalized and Fundamental Solutions of Motion Equations of Two-Component Biot’s Medium",doi:"10.5772/intechopen.92064",slug:"generalized-and-fundamental-solutions-of-motion-equations-of-two-component-biot-s-medium",totalDownloads:472,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Here processes of wave propagation in a two-component Biot’s medium are considered, which are generated by arbitrary forces actions. By using Fourier transformation of generalized functions, a fundamental solution, Green tensor, of motion equations of this medium has been constructed in a non-stationary case and in the case of stationary harmonic oscillation. These tensors describe the processes of wave propagation (in spaces of dimensions 1, 2, 3) under an action of power sources concentrated at coordinates origin, which are described by a singular delta-function. Based on them, generalized solutions of these equations are constructed under the action of various sources of periodic and non-stationary perturbations, which are described by both regular and singular generalized functions. For regular acting forces, integral representations of solutions are given that can be used to calculate the stress-strain state of a porous water-saturated medium.",signatures:"Lyudmila Alexeyeva and Yergali Kurmanov",downloadPdfUrl:"/chapter/pdf-download/71864",previewPdfUrl:"/chapter/pdf-preview/71864",authors:[null],corrections:null},{id:"71708",title:"Boundary Integral Equations of no Stationary Boundary Value Problems for the Klein-Gordon Equation",doi:"10.5772/intechopen.91693",slug:"boundary-integral-equations-of-no-stationary-boundary-value-problems-for-the-klein-gordon-equation",totalDownloads:463,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The non-stationary boundary value problems for Klein-Gordon equation with Dirichlet or Neumann conditions on the boundary of the domain of definition are considered; a uniqueness of boundary value problems is proved. Based on the generalized functions method, boundary integral equations method is developed to solve the posed problems in strengths of shock waves. Dynamic analogs of Green’s formulas for solutions in the space of generalized functions are obtained and their regular integral representations are constructed in 2D and 3D over space cases. The singular boundary integral equations are obtained which resolve these tasks.",signatures:"Bayegizova Aigulim and Dadayeva Assiyat",downloadPdfUrl:"/chapter/pdf-download/71708",previewPdfUrl:"/chapter/pdf-preview/71708",authors:[null],corrections:null},{id:"72313",title:"Singular Boundary Integral Equations of Boundary Value Problems for Hyperbolic Equations of Mathematical Physics",doi:"10.5772/intechopen.92449",slug:"singular-boundary-integral-equations-of-boundary-value-problems-for-hyperbolic-equations-of-mathemat",totalDownloads:577,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The method of boundary integral equations is developed for solving the nonstationary boundary value problems (BVP) for strictly hyperbolic systems of second-order equations, which are characteristic for description of anisotropic media dynamics. The generalized functions method is used for the construction of their solutions in spaces of generalized vector functions of different dimensions. The Green tensors of these systems and new fundamental tensors, based on it, are obtained to construct the dynamic analogues of Gauss, Kirchhoff, and Green formulas. The generalized solution of BVP has been constructed, including shock waves. Using the properties of integrals kernels, the singular boundary integral equations are constructed which resolve BVP. The uniqueness of BVP solution has been proved.",signatures:"Lyudmila A. Alexeyeva and Gulmira K. Zakiryanova",downloadPdfUrl:"/chapter/pdf-download/72313",previewPdfUrl:"/chapter/pdf-preview/72313",authors:[null],corrections:null},{id:"73135",title:"Padé Approximation to Solve the Problems of Aerodynamics and Heat Transfer in the Boundary Layer",doi:"10.5772/intechopen.93084",slug:"pad-approximation-to-solve-the-problems-of-aerodynamics-and-heat-transfer-in-the-boundary-layer",totalDownloads:394,totalCrossrefCites:2,totalDimensionsCites:4,hasAltmetrics:0,abstract:"In this chapter, we describe the applications of asymptotic methods to the problems of mathematical physics and mechanics, primarily, to the solution of nonlinear singular perturbed problems. We also discuss the applications of Padé approximations for the transformation of asymptotic expansions to rational or quasi-fractional functions. The applications of the method of matching of internal and external asymptotics in the problem of boundary layer of viscous gas by means of Padé approximation are considered.",signatures:"Igor Andrianov and Anatoly Shatrov",downloadPdfUrl:"/chapter/pdf-download/73135",previewPdfUrl:"/chapter/pdf-preview/73135",authors:[null],corrections:null},{id:"71383",title:"Alternative Representation for Binomials and Multinomies and Coefficient Calculation",doi:"10.5772/intechopen.91422",slug:"alternative-representation-for-binomials-and-multinomies-and-coefficient-calculation",totalDownloads:476,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Polynomials play an important role in many fields of mathematics as well as in other areas such as physics and engineering. Binomials and multinomies represent a special kind of polynomials, regarded as a wide frame of study by some mathematical branches such as discrete mathematics. Under this subject a novel method was recently developed that addresses the task of performing the calculation of binomial and multinomial coefficients, by means of the setting of an arrangement of sequences of summations. The document unfolded hereby aims to be an extension of that work. Through this document, firstly it will be deemed an equation resultant from that work, targeted at binomial calculations, and will be extended to the multinomial instance. Afterwards a theoretical case of study will be presented, to expose the application of this framework. And lastly an algorithm will be raised to set it up on a computer algebra system (CAS), and some practical examples will be bestowed.",signatures:"José Alfredo Sánchez de León",downloadPdfUrl:"/chapter/pdf-download/71383",previewPdfUrl:"/chapter/pdf-preview/71383",authors:[null],corrections:null},{id:"72426",title:"How Are Fractal Interpolation Functions Related to Several Contractions?",doi:"10.5772/intechopen.92662",slug:"how-are-fractal-interpolation-functions-related-to-several-contractions-",totalDownloads:508,totalCrossrefCites:2,totalDimensionsCites:5,hasAltmetrics:0,abstract:"This chapter provides an overview of several types of fractal interpolation functions that are often studied by many researchers and includes some of the latest research made by the authors. Furthermore, it focuses on the connections between fractal interpolation functions resulting from Banach contractions as well as those resulting from Rakotch contractions. Our aim is to give theoretical and practical significance for the generation of fractal (graph of) functions in two and three dimensions for interpolation purposes that are not necessarily associated with Banach contractions.",signatures:"SongIl Ri and Vasileios Drakopoulos",downloadPdfUrl:"/chapter/pdf-download/72426",previewPdfUrl:"/chapter/pdf-preview/72426",authors:[null],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"7653",title:"Wavelet Transform and Complexity",subtitle:null,isOpenForSubmission:!1,hash:"74bd7559ad44e50940d35974905e98ee",slug:"wavelet-transform-and-complexity",bookSignature:"Dumitru Baleanu",coverURL:"https://cdn.intechopen.com/books/images_new/7653.jpg",editedByType:"Edited by",editors:[{id:"105623",title:"Dr.",name:"Dumitru",surname:"Baleanu",slug:"dumitru-baleanu",fullName:"Dumitru Baleanu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7428",title:"Advances on Tensor Analysis and their Applications",subtitle:null,isOpenForSubmission:!1,hash:"2339ac5eb978557d01451489e961b102",slug:"advances-on-tensor-analysis-and-their-applications",bookSignature:"Francisco Bulnes",coverURL:"https://cdn.intechopen.com/books/images_new/7428.jpg",editedByType:"Edited by",editors:[{id:"92918",title:"Dr.",name:"Francisco",surname:"Bulnes",slug:"francisco-bulnes",fullName:"Francisco Bulnes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6444",title:"New Insights into Bayesian Inference",subtitle:null,isOpenForSubmission:!1,hash:"8a6c48ec7bdf923a126816fdbbb24274",slug:"new-insights-into-bayesian-inference",bookSignature:"Mohammad Saber Fallah Nezhad",coverURL:"https://cdn.intechopen.com/books/images_new/6444.jpg",editedByType:"Edited by",editors:[{id:"150393",title:"Dr.",name:"Mohammad Saber Fallah",surname:"Nezhad",slug:"mohammad-saber-fallah-nezhad",fullName:"Mohammad Saber Fallah Nezhad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8181",title:"Applied Mathematics",subtitle:null,isOpenForSubmission:!1,hash:"85b873324d4e1af230fea39738ba9be5",slug:"applied-mathematics",bookSignature:"Bruno Carpentieri",coverURL:"https://cdn.intechopen.com/books/images_new/8181.jpg",editedByType:"Edited by",editors:[{id:"92921",title:"Dr.",name:"Bruno",surname:"Carpentieri",slug:"bruno-carpentieri",fullName:"Bruno Carpentieri"}],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:"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. 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Development Tendencies and Empirical Approach",slug:"entrepreneurship-development-tendencies-and-empirical-approach",publishedDate:"January 24th 2018",bookSignature:"Ladislav Mura",coverURL:"https://cdn.intechopen.com/books/images_new/6165.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"85474",title:"Associate Prof.",name:"Ladislav",middleName:null,surname:"Mura",slug:"ladislav-mura",fullName:"Ladislav Mura"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"181601",title:"Prof.",name:"Er'El",middleName:null,surname:"Granot",fullName:"Er'El Granot",slug:"er'el-granot",email:"erelgranot@gmail.com",position:null,institution:{name:"Ariel University",institutionURL:null,country:{name:"Israel"}}}]},book:{id:"6165",title:"Entrepreneurship",subtitle:"Development Tendencies and Empirical Approach",fullTitle:"Entrepreneurship - Development Tendencies and Empirical Approach",slug:"entrepreneurship-development-tendencies-and-empirical-approach",publishedDate:"January 24th 2018",bookSignature:"Ladislav Mura",coverURL:"https://cdn.intechopen.com/books/images_new/6165.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"85474",title:"Associate Prof.",name:"Ladislav",middleName:null,surname:"Mura",slug:"ladislav-mura",fullName:"Ladislav Mura"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"12301",leadTitle:null,title:"Ion Exchange - Newest Research and Advances",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tThe goal of this book is to give the reader an overview of a field related to various applications in chemistry, chemical engineering, and nanotechnology. This book aims to provide information about the design of ion exchangers, their application in environmental technologies, and in biotechnology and pharmaceutical applications. This book will be written by authors in the field of experimental methods and critical reviews from multi-disciplines such as chemistry, membranes, and materials science. Among others, some of the topics covered will be Structure of ion exchangers, Synthesis of ion exchangers, Synthesis of inorganic ion exchangers, Properties of ion exchangers, Ion exchange voltammetry, Ion exchange as a separations method, Ion exchange in analytical chemistry, Ion exchange and extraction, Ion exchange membranes, Preparation of organic-inorganic hybrid ion exchangers, Application in environmental technologies, Application in biotechnology and pharmaceutical applications.
\r\n\r\n\tIn this book, the authors will focus on recent studies, applications, and new technological developments on the fundamental properties of ion exchangers.
",isbn:"978-1-83768-391-8",printIsbn:"978-1-83768-390-1",pdfIsbn:"978-1-83768-392-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"8dd8a87a8e42422ab2f346d7d33f2f18",bookSignature:"Dr. Selcan Karakuş",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/12301.jpg",keywords:"Selectivity, Diffusion, Isotherm, Electrodialyzer, Computer Simulation, Activity Coefficients, Thermodynamic, Kinetic Model, Semiempirical Models, Ion Exchange Resins, Ion Exchange Composites, Biosorbents",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 10th 2022",dateEndSecondStepPublish:"July 8th 2022",dateEndThirdStepPublish:"September 6th 2022",dateEndFourthStepPublish:"November 25th 2022",dateEndFifthStepPublish:"January 24th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"a month",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Multidisciplinary Nanoscience Technology Research Group Leader from Istanbul University (Cerrahpasa) and holder of three registered patents on advanced metal/ metal oxide-based nanostructures. Assoc. Prof. Selcan Karakuş has research experience in nanoparticles, nanocomposites, nanoemulsions, metal oxide nanostructures, and sensors.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"206110",title:"Dr.",name:"Selcan",middleName:null,surname:"Karakuş",slug:"selcan-karakus",fullName:"Selcan Karakuş",profilePictureURL:"https://mts.intechopen.com/storage/users/206110/images/system/206110.jpeg",biography:"Assoc. Prof. Selcan Karakuş is currently working at the Department of Chemistry, Istanbul University - Cerrahpasa, Turkey. She obtained her Master of Science degree in Physical Chemistry from Istanbul University (IU) in 2006. She obtained her Doctor of Philosophy degree in Physical Chemistry from IU in 2011. She has worked as a visiting researcher at the University of Massachusetts, Department of Polymer Science and Engineering. She has research experience in nanoparticles, nanocomposites, nanoemulsions, metal oxide nanostructures, and sensors. She has worked on different projects funded by Istanbul University - Cerrahpasa and has published several research articles and book chapters in her area of interest.",institutionString:"Istanbul University Cerrahpaşa",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"4",institution:{name:"Istanbul University Cerrahpaşa",institutionURL:null,country:{name:"Turkey"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"8",title:"Chemistry",slug:"chemistry"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"429341",firstName:"Paula",lastName:"Gavran",middleName:null,title:"Ms.",imageUrl:"//cdnintech.com/web/frontend/www/assets/author.svg",email:"paula@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"6519",title:"Science and Technology Behind Nanoemulsions",subtitle:null,isOpenForSubmission:!1,hash:"f4dd10764e9841064827609a62952748",slug:"science-and-technology-behind-nanoemulsions",bookSignature:"Selcan Karakuş",coverURL:"https://cdn.intechopen.com/books/images_new/6519.jpg",editedByType:"Edited by",editors:[{id:"206110",title:"Dr.",name:"Selcan",surname:"Karakuş",slug:"selcan-karakus",fullName:"Selcan Karakuş"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9199",title:"Sonochemical Reactions",subtitle:null,isOpenForSubmission:!1,hash:"72f3010437d022fd2a932421ff4a9200",slug:"sonochemical-reactions",bookSignature:"Selcan Karakuş",coverURL:"https://cdn.intechopen.com/books/images_new/9199.jpg",editedByType:"Edited by",editors:[{id:"206110",title:"Dr.",name:"Selcan",surname:"Karakuş",slug:"selcan-karakus",fullName:"Selcan Karakuş"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6694",title:"New Trends in Ion Exchange Studies",subtitle:null,isOpenForSubmission:!1,hash:"3de8c8b090fd8faa7c11ec5b387c486a",slug:"new-trends-in-ion-exchange-studies",bookSignature:"Selcan Karakuş",coverURL:"https://cdn.intechopen.com/books/images_new/6694.jpg",editedByType:"Edited by",editors:[{id:"206110",title:"Dr.",name:"Selcan",surname:"Karakuş",slug:"selcan-karakus",fullName:"Selcan Karakuş"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7604",title:"Colloid Science in Pharmaceutical Nanotechnology",subtitle:null,isOpenForSubmission:!1,hash:"f3940914be015381c3928eae31c2457e",slug:"colloid-science-in-pharmaceutical-nanotechnology",bookSignature:"Selcan Karakuş",coverURL:"https://cdn.intechopen.com/books/images_new/7604.jpg",editedByType:"Edited by",editors:[{id:"206110",title:"Dr.",name:"Selcan",surname:"Karakuş",slug:"selcan-karakus",fullName:"Selcan Karakuş"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"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:"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:"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:"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"}},{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"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"52583",title:"Role of Echocardiography in the Critically Ill Patients",doi:"10.5772/65068",slug:"role-of-echocardiography-in-the-critically-ill-patients",body:'\nEchocardiography (echo) is one of the most powerful diagnostic and monitoring tools available to the modern emergency/critical care practitioner. The provision of echo is fundamental to the management of patients with acute cardiovascular disease. Since its inception in 1950s, echocardiography has evolved significantly. Its role has expanded beyond cardiology into operating theaters, intensive care units, and emergency departments [1]. It is an easy, inexpensive, noninvasive, and portable technique, which can be rapidly performed at bedside. It is devoid of complications and, for the most part, universally available. This review focuses on growing importance of echocardiography for critically ill patients in the intensive care and high dependency unit settings including indications, modalities, measurements, and therapeutic impact.
\nEchocardiography has been included in international guidelines regarding the management of cardiac arrest and in the universal definition of acute myocardial infarction (AMI). In the acutely ill and critical care settings, echocardiography can be used to measure/monitor cardiac output (CO) and to determine abnormalities of cardiac physiology and coronary perfusion, as well as providing more standard anatomical information related to diagnosis.
\nThis chapter is not intended to be a comprehensive review of echocardiographic techniques. Instead, it focuses on the indications, therapeutic impact, and some of the most common scenarios (Table 1) where dilemmas can be answered using echocardiography in critically ill patients.
Hypovolemia/hypotension | \n
Hemodynamic instability | \n
Ventricular dysfunction | \n
Evaluation of cardiac thrombus or embolus | \n
Pulmonary embolism infective endocarditis | \n
Acute valvular regurgitations | \n
Pericardial effusions/cardiac tamponade | \n
Complications after cardiac procedures/cardiothoracic surgery | \n
Acute aortic syndromes | \n
General indications for echocardiographic examination in the intensive care unit.
The challenges of imaging in the acute settings are well studied and may influence echocardiographic findings and interpretation in critically ill patients. These include a number of factors such as filling status, metabolic status, patient habitus and positioning, positive pressure ventilation, intubation/mechanical ventilation, different ventilation modalities, weaning inotropic status, lung injury, the presence of lines/dressings and/or drains, and extracorporeal support. The echocardiographic data should be interpreted in the case scenario of the acutely/critically ill patient, particularly when time-specific factors further challenge the echocardiographer (i.e., cardiac arrest).
\nTransthoracic echocardiography (TTE) is a widely available, inexpensive tool, which is generally the initial imaging modality in the assessment of acute cardiac conditions (Table 2). It is used in the majority of clinical scenarios associated with cardiac emergencies. Findings can be overlooked if the study is restricted to standard imaging only. The study should be comprehensive and undertaken with a fully equipped echocardiographic machine. The easiest and least invasive way to image cardiac structures is echocardiography using the transthoracic approach [2]. This noninvasive imaging modality is of great value in the critical care settings because of its portability, widespread availability, and rapid diagnostic capability.
\nIndication | \nAUS | \n
---|---|
Assessment of volume status in critically ill patient | \nU | \n
Hypotension/hemodynamic instability of uncertain or suspected cardiac etiology | \nA | \n
Suspected complication of MI | \nA | \n
Acute chest pain with suspected MI, inconclusive ECG during pain | \nA | \n
Respiratory failure/hypoxemia of uncertain etiology | \nA | \n
Respiratory failure/hypoxemia when noncardiac etiology is already established | \nU | \n
To guide therapy of known acute PE | \nA | \n
To establish diagnosis of suspected PE | \nI | \n
Reevaluation of known PE change RV function and PAP after therapy | \nA | \n
Routine surveillance of prior PE, with normal RV function and PAP | \nI | \n
No chest pain but laboratory and/or other features indicative of MI | \nA | \n
Severe deceleration injury/chest trauma with suspected or possible pericardial effusion, valvular, or cardiac injury | \nA | \n
Routine evaluation in mild chest trauma without ECG or biomarker changes | \nI | \n
Indications for echocardiography in acute care settings, evaluated using appropriate use scores (AUS).
A nondiagnostic TTE usually requires a transesophageal echocardiography (TEE). TEE allows better imaging of the posterior structures and heart in general, due to the position of the probe and better acoustic transmission. Certain situations that warrant TEE include acute aortic syndromes, unexplained hypotension, trauma, morbid obesity, prosthetic valve dysfunction, valvular regurgitations/vegetation, and mechanical ventilation with high-level positive end-expiratory pressure and source of cardiac emboli. TEE should be done cautiously in patients with coagulopathy, potential trauma to airway or esophagus, and in patients who are unable to protect their own airways or severely hypoxic without mechanical ventilation. During the study, the airway and hemodynamics should be monitored. In the ICU, transthoracic echocardiography (TTE) may, in certain cases, fail to provide adequate image quality because of different factors that can potentially hinder the quality of the ultrasound signal, be it air, bone, calcium, a foreign body, or any other type of interposed structure.
\nOther imaging modalities include contrast echocardiography, 3D-echo, lung ultrasound examination, focused cardiac ultrasound, and pocket imaging devices.
\nPatients may present with a spectrum of conditions ranging from cardiogenic shock, acute pulmonary edema, isolated RV dysfunction, or heart failure (HF) complicating an ACS. Since HF is not a diagnosis
Assessment of the left ventricular (LV) systolic function is an integral part of the medical management of hemodynamically unstable critically ill patients. Assessment of the global LV function can be quickly obtained by “eyeballing” from the parasternal long- and short-axis, apical two- and four-chamber, and subcostal views and real-time visualization of the kinetics and size of the cardiac cavities, a combination of ejection fraction/fractional shortening, Doppler patterns of ventricular filling and tissue. Doppler imaging supplements to the information from the echocardiogram. Assessment of the chamber size and LV wall thickness is also done. Findings may include increase in the left ventricular end-systolic and diastolic volume, increase in end-systolic and diastolic diameter and abnormal wall motion. Two other modes of imaging that are relatively easy to obtain for the assessment of the LV function are the atrioventricular plane displacement (AVPD) and systolic tissue Doppler velocities (sTD) [3].
\nTTE was shown to be an excellent diagnostic tool for assessment of the LV function in the ICU, even when positive end expiratory pressure was present [4]. However, if the TTE provides suboptimal imaging for evaluation of ventricular function, TEE can be obtained for better assessment. It is important to remember that significant LV dysfunction is common in critically ill patients and the “normal” values quoted from noncritical care studies may not be valid.
\nBedside echocardiography is an important tool for identification of the cause of hemodynamic instability (which may be of cardiogenic, hypovolemic, or distributive origin) and for the further management (i.e., administration of fluid, vasoactive, or inotropic agent infusion). Classically, septic shock has been considered to be a hyperdynamic state characterized by normal or high cardiac output (CO). But echocardiographic studies indicate that ventricular performance is often diminished in those patients. LVEF might not be a reliable index of LV systolic function in patients with early septic shock.
\nDefined as a transient, stress-induced dysfunction of the LV apex, it predominantly affects female patients (90%). Takotsubo cardiomyopathy mimics an ACS, echo findings show a reversible LV dysfunction with regional wall motion abnormalities, but these patients have no angiographic evidence of ACS. Akinesia has also been demonstrated in the LV mid-cavity, LV base, and RV, with or without sparing of the other LV segments (Figure 1). Echo is a useful tool for the follow-up as the LV function must completely recover over time to confirm the diagnosis.
Takotsubo’s cardiomyopathy.
LV measurements also provide data on myocardial injury, cardiomyopathies, and fluid status. The left atrial size is evaluated as an enlarged Left atrium (LA) may indicate significant valvular disease, intra-atrial shunting and atrial fibrillation, all of which may in turn cause hemodynamic instability. Finally, the aortic and mitral valves are assessed to complete the examination of left ventricular function. Two-dimensional speckle tracking echocardiography (STE) offers potentially useful information in acute HF patients with underlying cardiomyopathies.
\nIn the ICU, when EF is normal or supernormal and ventricular filling pressure (pulmonary artery occlusion pressure) is elevated, diastolic dysfunction should be suspected. The filling patterns related to the diastolic function can be influenced by different factors such as heart rate, ischemia, left atrial pressure, ventricular hypertrophy, and valvular pathologies. In patients with an abnormal relaxation pattern (E/A < 1), and peak E velocity <50 cm/s, LV filling pressures are usually normal [5]. With restrictive filling (E/A ≥ 2, mitral E deceleration time <150 ms), mean LA pressure is often increased. Patients with heart failure with preserved LV ejection fraction (HFpEF) present with signs and/or symptoms of HF and several echocardiographic findings.
\nIn both acute systolic and diastolic HF, interstitial edema may be diagnosed at the bedside by the demonstration of an abnormally high number of bilateral sonographic B-lines (also called ultrasound lung comets). Two-dimensional speckle tracking echocardiography offers diagnostic data in acute heart failure associated with cardiomyopathies, specifically when ejection fraction appears preserved [5].
\nEcho is a very useful tool in the management of critically ill patients with cardiac arrest. The use of echo in an advanced cardiac life support (ACLS) is supported by international evidence-based recommendations. Peri-resuscitation echocardiography does not impact upon high-quality cardiopulmonary resuscitation (CPR) when appropriately applied and requires special training in advanced cardiac life support (ACLS) compliant manner. Images should be obtained only during the pulse/rhythm check. It can provide data to diagnose or exclude certain potential reversible causes of cardiac arrest (including severe LV/RV dysfunction, myocardial infarction, hypovolemia, pulmonary embolism (PE), tension pneumothorax, or tamponade). Echo is particularly useful in situations of pulseless electrical activity (electromechanical dissociation—EMD) to differentiate between pseudo-EMD and true EMD. Though there is extensive data, we need further recommendations regarding how to use echo during a code situation and specific guidelines for termination of resuscitation.
\nRight ventricular (RV) function can be altered by massive pulmonary embolism and acute respiratory distress syndrome (ARDS), the two main causes of acute cor pulmonale, in the critical care settings [6]. Other causes of acute RV dysfunction include RV infarction associated with inferior myocardial infarction, myocardial contusion, fat or air embolism, acute sickle-cell crisis, and sepsis. In unstable critically ill patients, specifically those with massive PE and acute respiratory distress syndrome, a diagnosis of RV dysfunction may guide therapy (e.g., use of thrombolytics, vasopressors, volume resuscitation, and catheter-directed interventional therapy). RV size and function are frequently evaluated by visual comparison with the left ventricle. RV kinetics of the cavity and septum, and diastolic dimensions are also measured, using either TTE or TEE. Measuring the ratio between the RV and LV end diastolic areas from apical four-chamber view is one of the best ways to evaluate RV dilation [7]. The diastolic ventricular ratio of 0.6–1.0 is consistent with moderate RV dilation and a ratio of 1 is consistent with severe RV dilation. Tricuspid regurgitation, right atrial dilation, and inferior vena caval dilation are commonly associated with RV diastolic enlargement.
\nThough pulmonary angiography remains the gold standard for diagnosis of pulmonary embolism (PE), other available imaging modalities include ventilation-perfusion scanning, spiral computed tomography (CT), and magnetic resonance imaging (MRI) angiography. TTE can help to establish a prompt diagnosis to identify patients with high-risk features, especially if the patient is hemodynamically unstable. Overall, the sensitivity of TTE for the diagnosis of pulmonary embolism is about 50–60% while the specificity is around 80–90%. In some situations, that is, in critically ill patients, TEE may improve the sensitivity.
\nThe main indirect findings for pulmonary embolism (Table 3) are the consequences of acutely increased pulmonary artery/right heart pressures [5]. In pulmonary embolism, RV hypokinesia is not necessarily global but can be limited to the mid-RV free wall while the contraction of the RV apex may be normal or hyperdynamic (McConnell sign) (Figure 2).
\nThrombus into right chambers | \n
RV systolic dysfunction/global RV hypokinesia | \n
Dilatation RA, RV (end-diastolic RV/LV diameter.0.6 or area.1.0) | \n
Mild to severe TR | \n
Pulmonary arterial dilatation | \n
Abnormal septal motion toward LV | \n
McConnell sign—mid-RV wall hypokinesia with apical sparing | \n
Pulmonary hypertension around 40–50 mm Hg (60 mm Hg in the case of pre-existing pulmonary hypertension) | \n
Lack of respiratory variation of the inferior vena cava | \n
Echocardiographic finding in pulmonary embolism.
As other clinical conditions can produce acute cor pulmonale in the ICU, better visualization of the pulmonary arteries is needed to achieve high accuracy for the diagnosis of PE. This goal can be achieved by using TEE. TEE helps to achieve a better visualization of the pulmonary arteries and detecting emboli that are lodged in the main and right pulmonary arteries. The diagnosis is made when an embolus is visualized. When the index of suspicion for PE is high and TEE is negative, then pulmonary angiography or helical computed tomography should be considered as the next step. The demonstration of acute cor pulmonale with echocardiography has important prognostic and therapeutic implications. The presence of cor pulmonale with massive PE is associated with increased mortality, whereas the absence of RV dysfunction is associated with a better prognosis.
\nThrombus in the right ventricle.
Measurement of CO is an important data in the assessment of critically ill patients with unstable hemodynamics. Cardiac output and stroke volume can be established by combining Doppler data derived from blood flow velocity through a conduit and the cross-sectional area of the conduit. The most common and most reliable technique is using the left ventricular outflow tract and aortic valve. Another method using an esophageal probe inserted in sedated patients, to measure blood flow velocity waveforms in the descending aorta combined with a nomogram, is particularly useful in adult patients to provide continuous monitoring of cardiac function.
\nAccurate measurement of volume status and LV preload is important for management of critically ill patients. Besides, invasive pressure measurements to assess LV filling may not correlate well with LV volume. Echo can be very useful in adequately evaluating preload. Measurements from two-dimensional and Doppler echo include LV end-diastolic volume (EDV), LV end-diastolic area (EDA), transmitral diastolic filling pattern, and mitral and pulmonary venous flow.
\n“Eyeballing” LV end-diastolic (LVED) and end-systolic (LVES) areas provide a quick assessment of intracardiac volume status. Findings in hypovolemic patients include hyperdynamic LV with a reduced end-diastolic volume and “kissing” papillary muscles in systole, suggesting an increased ejection fraction with an empty ventricle at end-systole. Septic patients tend to have a reduced afterload, which is usually demonstrated by a normal LVED area, but a reduced LVES area. Patients with chronic cardiac failure have a dilated LV and may be hypovolemic even with a higher LVED area.
\nRight atrial pressure measurement is also helpful in the evaluation of the circulating volume status and often measured by the diameter and change in caliber with inspiration of the inferior vena cava. A dilated vena cava (diameter of 20 mm) without a normal inspiratory decrease in caliber (50% with gentle sniffing) usually indicates elevated right atrial pressure. Available data suggest inferior vena cava diameter variation with inspiration can be used a guide to fluid therapy [8]. A small vena cava in mechanically ventilated patient excludes the presence of elevated right atrial pressure, as these patients usually have dilation of the inferior vena cava [9].
\nPulmonary hypertension is usually diagnosed when systolic pulmonary pressure is ~35 mm Hg, diastolic pulmonary pressure is ~15 mm Hg, and mean pulmonary pressure is ~25 mm Hg. Critically ill patients commonly have pulmonary arterial hypertension, possibly from various cardiac, pulmonary, and systemic processes. Several echocardiographic methods have been validated for noninvasive estimation of pulmonary artery pressure [10], which are useful in critically ill patients. A large number of ICU patients have some degree of tricuspid and pulmonary regurgitation, which are needed to measure pulmonary arterial pressure. The tricuspid and pulmonary regurgitation velocities determine systolic and diastolic pulmonary artery pressures.
\nSignificant valvular abnormalities can be present in the critically ill patient without being clinically recognized. In the ICU, TTE can provide valuable information concerning valvular integrity and function [11] but may be suboptimal and TEE may be indicated. Adequate and accurate evaluation of the valvular structures may often be required in the critically ill patients. The most common indications for bedside echocardiography for evaluation of the valvular apparatus in this population are for suspected endocarditis, acute valvular stenosis or regurgitation, critical aortic stenosis, significant mitral stenosis, or prosthetic valve dysfunction including regurgitation and obstruction. Information regarding etiology, pathogenesis, and severity of the valvular lesions, valvular anatomy and function, chamber size, function, and wall thickness of the ventricles can be readily obtained by echo. Abnormalities such as vegetation, thrombus, fibrosis, calcification, immobile, or prolapsing leaflets or prosthetic valve dehiscence can be detected by echo [5].
\nSuspected tamponade is the most common indication for assessment of the pericardium in the critically ill patient. The pericardial space can be filled with a variety of substances including fluid, pus, blood, or air. Presence of fluid in this space is detected as an echo-free space. TTE easily detects pericardial effusion (Figure 3), usually in the parasternal long and short-axis and the apical views. But, given higher chances of suboptimal TTE in critically ill patients, TEE may be warranted, particularly in patients with poor acoustic windows or post cardiothoracic surgical patients.
Pericardial effusion.
Echocardiography is also useful in the management of pericardial effusion, as pericardiocentesis can be performed safely under echocardiographic guidance [12]. Echocardiography also can be used to accurately place the needle during the drainage, immediately monitor the results of the pericardiocentesis, and serially monitor to evaluate the reaccumulation of the effusion.
\nThe most common causes of cardiac tamponade in the ICU are listed in Table 4.
Complication of myocardial infarction (e.g., ventricular rupture) | \n
Blunt or penetrating chest trauma | \n
Proximal ascending aortic dissection | \n
Myocardial or coronary perforation secondary to catheter-based interventions (i.e., after | \n
intravenous pacemaker lead insertion, central catheter placement, or percutaneous coronary interventions) | \n
Uremic or infectious pericarditis | \n
Compressive hematoma after cardiac surgery | \n
Pericardial involvement by metastatic disease or other systemic processes | \n
Common causes of cardiac tamponade in intensive care unit.
There are several 2D-echo findings that suggest a hemodynamically significant pericardial fluid collection (Table 5). The rate of accumulation of the pericardial fluid, and collection and size of the collection determine the intrapericardial pressure. Although diastolic RV collapse (inward diastolic motion of the RV free wall) occurs later, it is a more specific sign and is best appreciated from the parasternal or subcostal long-axis views [13] (Figure 4).
Usually large pericardial effusion | \n
Swinging heart | \n
RA collapse (rarely LA) | \n
Diastolic collapse of the anterior RV-free wall (rarely LV) | \n
IVC dilatation (no collapse with inspiration) | \n
TV flow increases and MV flow decreases during inspiration (reverse in expiration) | \n
Systolic and diastolic flows are reduced in systemic veins in expiration and reverse flow with atrial contraction is increased | \n
Echo findings of hemodynamically significant pericardial effusion.
Cardiac tamponade.
If the patient\'s condition requires urgent pericardiocentesis, the procedure may be echocardiographically guided, as this has been shown to reduce complications. Echocardiography can additionally be used to verify whether the collection has been completely drained. TEE is rarely indicated in this setting.
\nIn patients who develop dynamic Left Ventricular Outflow Tract (LVOT) obstruction with resultant decrease in cardiac output, particularly the ones who fail to respond to inotropic support, echo is a valuable diagnostic tool. In these patients, right heart catheterization can often be misleading, resulting in inappropriate management.
\nThe commonest cause of cardiogenic shock is severe systolic dysfunction from acute myocardial infarction and echo remains an excellent initial diagnostic tool. Shock due to LV dysfunction remains the leading cause of mortality in AMI (50–70%) [14]. Other etiologies include mechanical complications of AMI, myocarditis, cardiomyopathy, valvular heart disease, RV dysfunction, myocardial contusion, and acute aortic dissection. TTE should be obtained first in this set of patients and TEE may be warranted when TTE is suboptimal. Common findings of cardiogenic shock complicating acute myocardial infarction are shown in Table 6.
Depressed EF, regional wall motion abnormalities, decrease in stroke volume, CO, elevated LV pressures, mitral regurgitation infarction | \n|
RV dilatation, dyssynergy, paradoxical septal motion, and McConnell sign, decrease of tricuspid annulus systolic excursion (TAPSE) | \n|
Obvious cardiac tamponade or only pericardial collection in subacute free wall rupture (30% of rupture) | \n|
Complete or partial rupture of the posterior papillary muscle with partial or complete flail of the mitral valve. Also from acute systolic anterior motion of the mitral valve secondary to dynamic LVOT obstruction | \n
Echo findings in cardiogenic shock complicating acute myocardial infarction.
In patients with hemodynamic instability after cardiothoracic operations, bedside echocardiography has been shown as a valuable tool in the critical care management [15]. TTE is often suboptimal and TEE is warranted as it obtains information that can help determine the etiology of hypotension in this set of patients. Most frequently encountered echocardiographic findings of LV dysfunction, cardiac tamponade, RV failure, hypovolemia, and valvular dysfunction have been described in earlier sections of this chapter.
\nEcho is useful in other situations such as evaluation of coronary arteries in suspected coronary disruption, RV dysfunction, and TAPSE (pre-, intra-, and postoperative TAPSE) evaluation, immediately after heart transplant (to rule out early rejection, early RV dysfunction, tamponade, or other causes of instability). Echo is an initial modality of imaging in patients who underwent catheterization/electrophysiology procedures presenting with potential acute complications include ventricular failure, cardiogenic shock, tamponade, displacement of implanted devices, and occlusion of coronary stents.
\nExtracorporeal support is increasingly used to support critically ill patients with severe cardiac and/or respiratory failure. Echocardiography for extracorporeal support is highly specialized. Thus echocardiography has a vital role in excluding any potentially treatable underlying cause for cardiorespiratory failure, essential to determine the requirement for the RV and/or LV support and level of support required, mandatory to exclude cardiovascular contraindications for initiation of the support. Echocardiography subsequently has a vital role in its successful implementation, including confirming/guiding correct cannula placement, ensuring the goals of support are met, detecting complications, and assessing tolerance to assistance. Finally, in patients requiring extracorporeal cardiac support, various echocardiographic parameters have been proposed to be used in conjunction with clinical and hemodynamic assessment in order to attempt to predict those patients who can be successfully weaned.
\nIn the critically ill patient population, heart rates of 100–120/min may be required to maintain adequate cardiac output.
\nAtrial arrhythmias, common in the acute settings, present challenging conditions for assessing cardiac function and hemodynamics, especially when irregular (as in atrial fibrillation). Use of echo in critically ill patients is done with caution. In atrial fibrillation, measurements are obtained from an average of about 10 consecutive heartbeats, to permit the use of echocardiographic parameters usually used in sinus rhythm, to predict elevated filling pressures. The “index beat” method using the measurement performed on the cardiac cycle following a pair of equal preceding cardiac cycles, is also being used in practice.
\nEchocardiography is one of the first investigations to be performed as soon as the arrhythmia is successfully terminated. Etiologies include ischemic and nonischemic causes that require echocardiographic evaluation.
\nTTE is a good initial investigation tool for evaluation of the proximal aorta (ascending aorta and arch). Because of the close anatomic relationship between the thoracic aorta and the esophagus, TEE allows optimal visualization of the entire thoracic aorta.
\nDiagnosis and management of aortic dissection is an emergency and these patients are often critically ill. Of the various available imaging modalities, echo, particularly TEE has been recommended for evaluation of suspected aortic dissection (Figure 5). TEE has the ability to assess the following, including extension of dissection into the proximal coronary arteries, the point of entry and exit between the true and false lumens, the presence of thrombus in the false lumen, the presence of pericardial or mediastinal hematoma or effusion, severity, and mechanism of associated aortic valve regurgitation, and ventricular function.
\nAscending aortic dissection on TEE.
TEE is useful in various phases of management including evaluation of aortic regurgitation as a contraindication prior to insertion, to confirm the position of the catheter, to ensure correct functioning of the balloon, and to rule out complications such as aortic dissection.
\nBlunt or penetrating chest trauma may cause severe injury to the heart and great vessels. A rapid, focused assessment with echocardiography can detect pericardial collection, myocardial contusion, mediastinal hematomas, aortic intramural hematomas, aortic dissection or transection, and pleural collections. Both TTE and TEE play an important role in the assessment of patients with chest trauma, and TEE may be indicated in patients with polytrauma and/or on mechanical ventilation or when a traumatic, acute aortic syndrome is suspected. It is important to distinguish aortic from cardiac injuries. Also, traumatic pseudoaneurysms must be differentiated from true aneurysms. Trauma may cause aortic rupture, dissection, or intramural hematoma. Partial disruption of the aortic wall may lead to pseudoaneurysm. Once pericardial tamponade is excluded, a standard echocardiogram is useful in other conditions, like cardiac contusion/dysfunction, myocardial rupture, septal and valvular injury. Acute MI from coronary artery dissection and arrhythmias in acute trauma patients warrant echocardiographic evaluation.
\nFebrile illness in critically ill patients warrants evaluation including infective endocarditis. See section on valvular lesions evaluations. Echocardiography is the test of choice for the noninvasive diagnosis of endocarditis. The echocardiographic findings may include new valvular regurgitation, an oscillating intracardiac mass on a valve or supporting structure or in the path of a regurgitant jet or an iatrogenic device, valve abscesses and new partial dehiscence or vegetation of a prosthetic valve. TEE has also been clearly shown to be superior to TTE for diagnosing complications of endocarditis, such as aortic root abscess, fistulas, and ruptured chordae tendineae of the mitral valve.
\nPleural effusion on echo.
Echocardiogram often finds the presence of pleural effusions (Figure 6) and can be used as a diagnostic tool while evaluating the cardiovascular system, especially in patients with acute dyspnea and decompensated heart failure.
\nIn critically ill patients with unexplained embolic stroke or refractory hypoxemia, the presence of a right-to-left shunt needs to be excluded. Common positions of right-to-left shunt are atrial septal defect or patent foramen ovale at the cardiac level, arteriovenous fistula at the pulmonary level and pulmonary arteriovenous fistulas. Bubble study, color Doppler studies, and contrast-enhanced studies are done to increase the detection rate of intracardiac shunt.
\nPatients presenting with acute unexplained embolic stroke and arterial occlusions, echocardiography should be obtained to investigate a potential embolic source of cardiac origin. In this situation, TEE is the preferred imaging of choice. Possible cardiac sources of emboli include thrombus in the left atrial or appendage, LV thrombus, valvular vegetation, right-sided clots (right atrium, right ventricle, vena cava) combined with a right-to-left intracardiac shunt (leading to a paradoxical embolus), thoracic atheromatosis, and cardiac tumors. TEE is a valuable tool in evaluating the left atrium and appendage for the presence of thrombus, for patients with atrial fibrillation or flutter in whom cardioversion is considered.
\nEchocardiography is now considered as an indispensable tool and primary imaging modality for diagnosis and management of hemodynamic monitoring in critically ill patients. However, echocardiography is subject to variations in interpretation, which can potentially lead to errors, as with any diagnostic and monitoring tool and caution need to be undertaken during interpretation. Nevertheless, it provides advantages including noninvasiveness and rapid and accurate real-time anatomical and functional assessment of the cardiovascular system under stressful situations and is very useful in assisting therapeutic procedures.
\nChronic myeloproliferative disorders are a group of clonal diseases of the stem cell. It is a group of several diseases with some common features. They derive from a multipotential hematopoietic stem cell. A clone of neoplastic cells in all these neoplams is characterized by a lower proliferative activity than that of acute myeloproliferative diseases. In each of these diseases, leukocytosis, thrombocythemia, and polyglobulia may appear at some stage, depending on the diagnosis [1, 2].
The research on interferon has been going on since the 1950s [3]. Then, the attention was paid to its influence on the immune system. It has been noted that it can exert an antiproliferative effect by stimulating cells of the immune system [4]. In 1987, a publication by Ludwig et al. was published, which reported the effectiveness of interferon alpha in the treatment of chronic myeloproliferative disorders [5].
More and more new studies have been showing the effectiveness of interferon alpha in reducing the number of platelets, reducing the need for phlebotomies in patients with polycythemia vera and also in reducing the number of leukocytes. Moreover, interferon reduced the symptoms of myeloproliferative disorders such as redness and itching of the skin. Additionally, it turned out to be effective in reducing the size of the spleen.
Further studies on the assessment of remission using molecular-level response assessments indicate that the interferon action in chronic myeloproliferation diseases targets cells from the mutant clone with no effect on normal bone marrow cells [6].
Over the years, interferon alpha-2a and interferon alpha-2b have been introduced into the treatment of chronic myeloproliferation, followed by their pegylated forms. The introduction of pegylated forms allowed for a reduction in the number of side effects and less frequent administration of the drug to patients. In recent years, monopegylated interferon alpha-2b has been used to further increase the interval between drug administrations while maintaining its antiproliferative efficacy.
The exact mechanism of action of interferon alpha in the treatment of chronic myeloproliferative disease is still not fully understood, but it has an impact on JAK2 (Janus Kinase) signal transducers and activates the STAT signal pathway (Janus Kinase/SignalTransducer and Activator of Transcription).
Interferon alpha binds to IFNAR1 and IFNAR2c, which are type I interferon receptors. Interferon alpha has an impact on JAK2(Janus Kinase) signal transducers and activates the STAT signal pathway. The disturbances in this signaling pathway are observed in chronic myeloproliferative disorders [7].
Interferon inhibits the JAK-STAT signaling pathway by directly inhibiting the action of thrombopoietin in this pathway [8].
So far, three driver mutations have been described in the course of chronic myeloproliferative diseases that affect the functioning of the JAK-STAT pathway.
JAK2 kinase and JAK1, JAK3, and TYK2 kinases belong to the family of non-receptor tyrosine kinases. They are involved in the intracellular signal transduction of the JAK-STAT pathway. It is a system of intracellular proteins used by growth factors and cytokines to express genes that regulate cell activation, proliferation, and differentiation. The mechanism of JAK activation is based on the autophosphorylation of tyrosine residues that occurs after ligand binds to the receptor. JAK2 kinase transmits signals from the hematopoietic cytokine receptors of the myeloid lineage (erythropoietin, granulocyte-colony stimulating factor thrombopoietin, and lymphoid lineage [9].
A somatic G/T point mutation in exon 14 of the JAK2 kinase gene converts valine to phenylalanine at position 617 (V617F) in the JAK2 pseudokinase domain, which allows constitutive, ligand-independent activation of the receptor to trigger a proliferative signal [10].
Mutation of the MPL gene, which encodes the receptor for thrombopoietin, increases the sensitivity of magekaryocytes to the action of thrombopoietin, which stimulates their proliferation [11].
Malfunction of calreticulin as a result of mutation of the CARL gene leads to the activation of the MPL-JAK/STAT signaling pathway, which is independent of the ligand, as calreticulin is responsible, for the proper formation of the MPL receptor. Consequently, there is a clonal proliferation of hematopoietic stem cells [12].
Below, we provide an overview of some clinical studies on the efficacy of interferon in chronic myeloproliferative disorders.
Polycythemia vera (PV) is characterized by an increase in the number of erythrocytes in the peripheral blood.
Polycythemia vera is caused by a clonal mutation in the multipotential hematopoietic stem cell of the bone marrow. The mutation leads to an uncontrolled proliferation of the mutated cell clone, independent of erythropoietin and other regulatory factors. As the mutation takes place at an early stage of hematopoiesis, an increase of the number of erythrocytes as well as of leukocytes and platelets is observed in the peripheral blood. The cause of proliferation in PV independent from external factors is a mutation in the Janus 2 (JAK2) tyrosine kinase gene. The V617F point mutation in the JAK2 gene is responsible for about 96% mutation, and in the remaining cases the mutation arises in exon 12. Both mutations lead to constitutive activation of the JAK-STAT signaling pathway [13].
As a result of the uncontrolled proliferation, blood viscosity increases, which generates symptoms such as headaches and dizziness, visual disturbances, or erythromelalgia. As the number of all hematopoietic cells, including the granulocytes ones, increases, the difficult to control symptoms of their hyperdegranulation may appear, among which gastric ulcer or skin itching is often observed. During the disease progression, the spleen and liver become enlarged.
The most common complication of the disease is episodes of thrombosis, especially arterial one. During the course of the disease, it can also evolve into myelofibrosis or acute myeloid leukemia.
The treatment of PV is aimed at preventing thromboembolic complications, relieving the general symptoms, the appearance of hepatosplenomegaly as well as preventing its progression.
Each patient should receive an antiplatelet drug chronically, and usually acetylsalicylic acid is the choice. Most often, the treatment is started with phlebotomy in order to rapidly lower the hematocrit level. If cytoreductive therapy is necessary, the drugs of first choice are hydroxycarbamide and interferon [2].
However, the research on the mechanism of the action of interferons is still ongoing. In vitro studies with CD34+ cells from peripheral blood of patients diagnosed with polycythemia vera showed that interferon inhibits clonal changed cells selectively. It was found that interferon alpha-2b and pegylated interferon alpha-2a reduce the percentage of cells with JAK2 V617F mutation by about 40%. Pegylated interferon alpha-2a works by activating mitogen-activated protein kinase P38. It affects CD34+ cells of patients with polycythemia vera by increasing the rate of their apoptosis [6].
A case of a patient with PV with a confirmed chromosomal translocation t(6;8) treated with interferon alpha-2b, which resulted in a reduction of the clone with translocation by 50% from the baseline value, was also described [14].
In 2019, the results of a phase II multicenter study were published, which aimed at assessing the effectiveness of recombinant pegylated interferon alpha-2a in cases of refractory to previously hydroxycarbamide therapy. The study included 65 patients with essential thrombocythemia (ET) and 50 patients with polycythemia vera. All patients had previously been treated with hydroxycarbamide and showed resistance to this drug or its intolerance.
The assessment of the response was performed after 12 months of treatment. Overall response rate to interferon was higher in patients diagnosed with ET than in patients with polycythemia vera. In essential thrombocythemia, the percentage of achieved complete remissions was 43 and 26% of partial remissions. The remission rate in ET patients was higher if calreticulin CALR gene mutation was present. Patients with polycythemia vera achieved complete remission in 22% of cases and partial remission in 38% of cases.
Treatment-related side effects that follow to discontinuation of treatment were reported in almost 14% of patients [15].
The duration of response to treatment with pegylated interferon alpha-2a and the assessment of its safety in long-term use in patients with chronic myeloproliferative disorders was the goal of a phase II of the single-center study. Forty-three adult patients with polycythemia vera and 40 patients with essential thrombocythemia were enrolled in the study. The complete hematological response was defined as a decrease in hemoglobin concentration below 15.0 g/l, without phlebotomies, a resolution of splenomegaly, and no thrombotic episodes in the case of PV, and for essential thrombocythemia—a decrease platelet count below 440,000/μl and two other conditions as above. The assessment of the hematological response was performed every 3–6 months. The median follow-up was 83 months.
The hematological response was obtained in 80% of cases for the entire group. In patients with polycythemia vera, 77% of patients achieved a complete response (CR) while 7% a partial response (PR). The duration of response averaged 65 months for CR and 35 months for PR. In the group of patients diagnosed with essential thrombocythemia, CR was achieved in 73% and PR in 3%. The durance of CR was 58 months and PR was 25 months.
The molecular response for the entire group was achieved in 63% of cases.
The overall analysis showed that the duration of hematological remission and its achievement with pegylated interferon alpha-2a treatment is not affected neither by baseline disease characteristics nor JAK2 allele burden and disease molecular status. There was also no effect on age, sex, or the presence of splenomegaly.
During the course of the study, 22% of patients discontinued the treatment, because of toxicity. Toxicity was the greatest at the beginning of treatment. The starting dose was 450 μg per week and was gradually tapered off.
Thus, on the basis of the above observations, the researchers established that pegylated interferon alpha-2a may give long-term hematological and molecular remissions [16].
The assessment of pegylated interferon alpha-2a in group of patients diagnosed with polycythemia vera only was performed. The evaluation was carried out on a group of 27 patients. Interferon decreased the JAK2 V617F allele burden in 89% of cases. In three patients who were JAK2 homozygous at baseline, after the interferon alpha-2a treatment wild-type of JAK2 reappeared. The reduction of the JAK2 allele burden was estimated from 49% to an average 27%, and additional in one patient the mutant JAK2 allele was not detectable after treatment. It can therefore be postulated that the action of pegylated interferon alpha-2a is directed to cells of the polycythemia vera clone [17].
In 2005, the results of treatment by pegylated interferon alpha-2b of 21 patients diagnosed with polycythemia vera and 21 patients diagnosed with essential thrombocythemia were published. In the case of polycythemia vera in 14 patients, PRV-1 gene mutation was initially detected. In 36% of cases, PRV-1 expression normalized after treatment with pegylated interferon alpha-2b. For the entire group of 42 patients, the remission assessment showed that complete remission was achieved in 69% cases after 6 months of treatment. However, only in 19 patients remission was still maintained 2 years after the start of the study. Pegylated interferon alpha-2b was equally effective in patients with PV and ET. The use and the type of prior therapy did not affect the achievement of remission [18].
Another study with enrolled only PV patients included 136 patients. They were divided into two arms. One group received interferon alpha-2b and the other group received hydroxycarbamide. Interferon dosage was administered in 3 million units three times a week for 2 years and then 5 million units two times a week. Hydroxycarbamide was administered at a dose between 15 and 20 mg/kg/day.
In the group of patients treated with interferon, a significantly lower percentage of patients developed erythromelalgia (9.4%) and distal parasthesia (14%) compared with the group treated with hydroxycarbamide, for whom these percentages were respectively: 29 and 37.5%. Interferon alpha-2b was found to be more effective in inducing a molecular response, which was achieved in 54.7% of cases, in comparison with hydroxycarbamide—19.4% of cases, despite the fact that the percentage of achieved general hematological responses did not differ between the groups and amounted about 70%. The 5-year progression free period in the interferon group was achieved in a higher percentage (66%) than in the hydroxycarbamide group (46.7%) [19].
The most recent form of interferon approved by the
Thanks to these changes to the structure of the molecule, it was possible to achieve a significant increase in its half-life. Ropeginterferon can be administered subcutaneously to patients every 14 days. The clinical trials conducted so far have assessed the ropeginterferon dose from 50 micrograms to a maximum dose of 500 microgams administered as standard every 2 weeks. The possible dose change in case of side effects includes not only the reduction of the drug dose itself, but also the extension of the interval between doses. The extension of the dosing interval up to 4 weeks was assessed.
Ropeginterforn was approved in 2019 by the EMA for the use in patients diagnosed with polycythemia vera without splenomegaly, as monotherapy.
Ropeginterferon, like the previous forms of interferons used in treatment, is contraindicated in patients with severe mental disorders, such as severe depression. It is also a contraindication in patients with noncompensatory standard treatment of disorders of the thyroid gland as well as severe forms of autoimmune diseases. The safety profile of ropeginterferon is similar to that of other forms of alpha interferons. The most common side effects are flu-like symptoms [20].
Ropeginterferon has been shown to exhibit in vitro activity against JAK2-mutant cells. The activity of ropeginterferon against JAK2-positive cells is similar to that of other forms of interferons used actually for standard therapy. Ropeginterferon has an inhibitory effect on erythroid progenitor cells with a mutant JAK2 gene. At the same time, it has almost no effect on progenitor cells without the mutated allele (JAK2-wile-type) and normal CD34+ cells. A gradual decrease of JAK2-positive cells was observed in patients with PV during ropeginterferon treatment. The examination was performed after 6 and 12 months of treatment. In comparison, the reduction in the percentage of JAK2 positive cells in patients treated with hydroxycarbamide was significantly lower.
These results may suggest that ropeginterferon may cause elimination of the mutant clone, but further prospective clinical trials are needed to confirm this theory. The evaluation was performed on a group of patients enrolled in the PROUD-PV study who were treated in France [21].
In 2017, a multicenter study was opened in Italy. The study was of the second phase. In total, 127 patients with polycythemia vera were included in the study. All patients enrolled on the study had low-risk PV. The clinical trial consisted of two arms. Patients received phlebotomies and low-dose aspirin in one arm and ropeginterferon in the other arm. The aim of the study was to achieve a hematocrit of 45% or lower without any evidence of disease progression. Ropeginterferon was administered every 2 weeks at a constant dose of 100 μg.
The response to the treatment was assessed after 12 months. The reduction of hematocrit to the assumed level was achieved in significantly higher percentage of patients in the ropeginterferon group than of patients who received only phlebotomies and aspirin. In addition, none of the patients treated with ropeginterferon experienced disease progression during the course of the study, while among those treated with phlebotomies, 8% of patients progressed.
Grade 4 or 5 adverse events were not observed in patients treated with ropeginterferon, and the incidence of remaining adverse event (AE) was small and comparable in both arms. The most common side effects in the ropeginterferon group were flu-like symptoms and neutropenia; however, the third-grade neutropenia was the most common (8% of cases) [22].
One of the most important clinical studies on the use of ropeginterferon was the PROUD-PV study and its continuation: the CONTINUATION-PV study. These were three-phase, multicenter studies. The aim of the study was to compare the effectiveness of ropeginterferon in relation to hydroxycarbamide. The study included adult patients diagnosed with polycythemia vera treated with hydroxycarbamide for less than 3 years and no cytoreductive treatment at all. In total, 257 patients received this treatment. The patients were divided into two groups: those receiving ropeginterferon or the other being given hydroxycarbamide.
During the PROUD-study, drug doses were increased until the hematocrit was achieved below 45% without the use of phlebotomies, and the normalization of the number of leukocytes and platelets was reached.
The PROUD-PV study lasted 12 months. After this time, the patients continued the treatment under the CONTINUATION-PV study for further 36 months. After the final analysis performed in the 12th month at the end of PROUD study, it was found that the hematological response rates did not differ between the ropeginterferon and hydroxycarbamide treatment groups. These were consecutively 43% in the ropeginterferon arm and 46% in the control arm.
However, after analyzing the CONTINUATION- PV study, it turned out that after 36 months of treatment, the rates of hematological responses begin to prevail in the group of patients receiving ropeginterferon, 53% versus 38% in the control group. Thus, from the above data, it can be seen that the response rate to ropeginterferon increases with the duration of treatment [23].
Another analysis of patients participating in the PROUD and CONTINUATION studies was based on the assessment of treatment results after 24 months, dividing patients into two groups according to age (under and over 60 years).
The initial comparison of both groups of patients showed that older patients had a more aggressive course of the disease. Patients over 60 years of age had a higher percentage of cells with a mutant JAK2 allele. They experienced both general symptoms and some complications, such as thrombosis, more frequently. Both patients under 60 years of age and over 60 years of age in the ropeginterferon arm had a higher rate of molecular response, namely 77.1 and 58.7% compared with the HU remission: 33.3 and 36.1%, respectively. Significantly higher reductions in the JAK2 allele were observed in both groups of patients after ropeginterferon treatment: it was 54.8% for younger patients and 35.1% for elderly patients. For comparison, this difference in the group of patients treated with HU was 4.5 and 18.4%, respectively.
What is more, the age did not affect the frequency of ropeginterferon side effects. In addition, the incidence of adverse ropeginterferon disorders was similar to that observed in the hydroxycarbamide group [24].
Essential thrombocythemia is a clonal growth of multipotential stem cells in the bone marrow. The consequence of this is increased proliferation of megakaryocytes in the bone marrow and an increase in the number of platelets in the peripheral blood. The level of platelets above 450,000/μl is considered a diagnostic criterion.
Essential thrombocythemia may progress over time to a more aggressive form of myeloproliferation, i.e., myelofibrosis. The disease can also evolve into acute myeloid leukemia or myelodysplastic syndrome, both with very poor prognosis. Thromboembolic complications are serious, and they concern over 20% of patients. Thrombosis occurs in the artery and venous area. Moreover, in patients with a very high platelet count, above 1,000,000/μl, bleeding may occur as a result of secondary von Willebrand syndrome [1, 2].
The treatment of ET is primarily aimed to prevent thrombotic complications.
In low-risk patients, only acetylsalicylic acid is used. In cases of high-risk patients, hydroxycarbamide is the first-line drug for most patients. Anagrelide and interferon are commonly used as second-line drugs.
Due to the possible effects of hydroxycarbamide of cytogenetic changes in the bone marrow cells after long-lasting usage, some experts recommend the use of interferon in younger patients in the first line. Interferon is also used as the drug of choice in patients planning a pregnancy [25].
The efficacy of pegylated interferon alpha-2a was assessed on the basis of the group of 39 patients with essential thrombocythemia and 40 patients with polycythemia vera.
Of the overall group, 81% of patients were previously treated prior to the study entry. The patients received pegylated interferon alpha-2a in a dose of 90 μg once a week. The dose of 450 μg was associated with a high percentage of intolerance.
In patients with essential thrombocythemia, the complete remission was achieved in 76%, while the overall hematological response rate brought 81%. Moreover, the molecular remission was achieved in 38%, in 14% of cases, JAK2 transcript became not detectable.
Patients diagnosed with polycythemia vera achieved 70% complete hematological remission and 80% general hematological response to treatment. JAK2 transcript was undetectable in 6% of patients. Molecular remission was achieved in 54% of cases.
Pegylated interferon alpha-2a at the dose of 90 μg per week was very well tolerated. In total, 20% of patients experienced a grade of 3 or 4 of adverse reaction, which was neutropenia. In addition, an increase in liver function tests was observed. Grade 4 of AE was not observed among patients who started the treatment with 90 μg/week while grade 3 neutropenia was an adverse event in only 7% of cases [26].
The effect of interferon alpha-2b treatment in patients with ET and PV was investigated. The study was prospective. Some of the results concerning the group of patients with polycythemia vera are presented in the subsection on polycythemia vera. In total, 123 patients with diagnosed essential thrombocythemia participated in the study. All of them received interferon alpha-2b. The patients were divided into two groups depending on the presence of the JAK2 V617F mutation. The enrolled patients were between 18 and 65 years of age. The treatment they received was, sequentially, interferon alpha-2b in the dose of 3 million units three times a week for the first 2 years, after which time the dose was changed into a maintenance dose, which amounted to 5 million units two times a week.
The analysis showed that the patients with the JAK2 V617F mutation present in a higher percentage achieved an overall hematological response as well as a complete hematological response. The overall hematological response was achieved in 83% of patients with JAK2 mutation, and the complete hematological remission was achieved in 23 cases. In the group of ET patients without the JAK2 V617F mutation, overall hematological response was achieved in 61.4%, while the complete hematological remission was achieved in 12 patients. The 5-year progression-free survival was obtained in 75.9% in the JAKV617F group and only in 47.6% without the mutation.
A significant proportion of patients experienced mild side effects. Grade 3 and 4 of adverse events were severe, most of them being a fever. The isolated cases of elevated liver tests and nausea have also been reported [19].
Pegylated interferon alpha-2b in patients with essential thrombocythemia who were previously treated with hydroxycarbamide, anagrelide, and other forms of interferon alpha, however, due to the lack of efficacy or toxicity, the patients required a change of treatment, was assessed. Pegylated interferon alpha-2b turned out to be effective in these cases. It led to the complete hematological remission in 91% of patients after 2 months of therapy, and in 100% of patients after 4 months. However, merely 11 patients participated in the study. Also only two patients required treatment discontinuation due to the side effects such as depression and general fatigue grade 3 [27].
In case of pregnant patients, interferon is currently considered the only safe cytoreductive drug. Over the years, several analyses of the results of interferon treatment during pregnancy have been carried out.
The assessment of 34 pregnancies in 23 women diagnosed with ET was performed retrospectively. All the pregnancies included in the analysis were of high risk. This high risk was associated with a high platelet count above 1,500,000/μl, a history of thrombotic episode, severe microcirculation disorders, or a history of major hemorrhage.
It turned out that the use of interferon allowed the birth of an alive child in 73.5% of cases. There was no difference in efficacy between the basic and pegylated forms of interferon alpha. In pregnancies without interferon treatment, the percentage of live births was only 60%. Moreover, it was not found if the presence of the JAK2 V617F mutation had any influence on the course of pregnancy [28].
An analysis of the course of pregnancy in patients with ET was assessed in Italy. Data from 17 centers were taken into account. Data from 122 pregnancies were collected from 92 women. In patients diagnosed with essential thrombocythemia, the risk of the spontaneous loss of pregnancy is about 2.5 times higher than among the general population. In the contrary to the study quoted above, it was found that the presence of the JAK2 mutation increases the risk of pregnancy loss. The proportion of live births in patients exposed to interferon during pregnancy was 95%, compared with 71.6% in the group of patients not treated with interferon.
The multivariate analysis also showed that the use of acetylsalicylic acid during pregnancy had no effect on the live birth rate of patients with ET [29].
Whatever its form, interferon is the drug of first choice in pregnancy. Hydroxycarbamide and anagrelide should be withdrawn for about 6 months, and at least for 3 months, before the planned conception. Experts recommend the use of interferon in high-risk pregnancies [30]. A Japanese analysis of 10 consecutive pregnancies in ET patients showed 100% live births in patients who received interferon [31].
In myelofibrosis (MF), monoclonal megakaryocytes produce cytokines that stimulate the proliferation of normal, non-neoplastic fibroblasts and stimulate angiogenesis. The consequence of this is the gradual fibrosis of the bone marrow, impaired hematopoiesis in the bone marrow, and the formation of extramedullary location mainly in the sites of fetal hematopoiesis, i.e., in the spleen and the liver.
The production of various cytokines by neoplastic megakaryocytes leads to the proliferation of normal, noncancerous fibroblasts as well as to increased angiogenesis.
Progressive bone marrow fibrosis leads to worsening anemia and thrombocytopenia. On the other hand, the production of proinflammatory cytokines by megakaryoblasts leads to the general symptoms such as weight loss, fever, joint pain, night sweats, and consequently, progressive worsening of general condition.
The prognosis for myelofibrosis is poor. In about 20% of patients, myelofibrosis evolves into acute myeloid leukemia with poor prognosis.
Currently, the only effective method of treatment that gives a chance to prolong the life is allogeneic bone marrow transplantation. However, this method is only available to younger patients.
The goal of treatment of patients who have not been qualified for allotranspalntation is to reduce the symptoms and to improve the patient’s quality of life. In case of leukocytosis cytoreducing drugs, such as hydroxycarbamide, melphalan, or cladribine can be used. They cause a reduction in the number of leukocytes and may, to some extent, inhibit splenomegaly. Interferon alpha has been used successfully for the treatment of myelofibrosis for many years. The results of its effectiveness will be presented below [2].
Currently, the JAK2 inhibitor ruxolitinib is approved for the treatment of myelofibrosis with enlarged spleen in intermediate and high-risk patients. Ruxolitinib reduces the size of the spleen, reduces general symptoms, and improves the quality of life; however, it does not prolong the overall survival of patients [32].
In 2015, the results of a retrospective study were published to compare the histological parameters of the bone marrow before and after interferon treatment. Twelve patients diagnosed with primary myelofibrosis as well as post-PV MF and post-ET MF were enrolled in the study. Patients were treated with pegylated recombinant interferon alpha-2a or recombinant interferon alpha-2b in standard doses. The time of treatment was from 1 to 10 years. Some patients had previously been treated with hydroxycarbamide or anagrelide. In all cases, karyotype was normal. The prognostic factor of Dynamic International Prognostic Scoring System (DIPSS) was assessed at the beginning as well as during the treatment.
Bone marrow cellularity decreased in cases with increased bone marrow cellularity before the treatment. After the interferon treatment, a reduction in the degree of bone marrow fibrosis was found. The parameters, such as the density of naked nuclei and the density of megakaryocytes in the bone marrow, also improved.
It proves that if the JAK2 V617F mutation had been present, DIPSS was decreased after interferon treatment. This relationship was not observed in patients without the JAK2 V617F mutation. The improvement in peripheral blood morphological parameters and the overall clinical improvement correlated with the improvement in the assessed histological parameters of the bone marrow.
Before the initiation of interferon, seven patients had splenomegaly. During the treatment with interferon, the complete resolution of splenomegaly was achieved in 17% of patients (two cases), and its size decreased in 25% (three cases). A good clinical response was achieved in 83% during interferon therapy. There was no significant difference in response between the two types of interferon used [33].
A prospective study was also conducted in patients with low and intermediate-1 risk group myelofibrosis. Seventeen patients were enrolled. Patients received interferon alpha-2b (0.5–3 milion units/three times a week) or pegylated interferon alpha-2a (45–90 μg/week). The duration of therapy was on average 3.3 years.
Most of the patients responded to the treatment. Partial remission was found in seven patients and complete remission in two patients. Moreover, in four cases, the disease was stabilized and in one case the clinical improvement was achieved. Three patients did not respond to treatment at all and progressed to myelofibrosis. Additionally, the assessment in reducing spleen size was performed. At baseline, 15 patients have splenomegaly, nine of them achieved the compete regression of spleen size [34].
However, the efficacy of interferon in the treatment of myelofibrosis appears to be limited only to a less advanced form, when the bone marrow still has an adequate percentage of normal hemopoiesis and the marrow stroma is not significantly fibrotic. In more advanced stages, interferon was not shown to have any significant effect on the regression of the fibrosis process [35].
In 2020, the results of the COMBI study were published. That was a two-phase, multicenter, single-arm study that investigated the efficacy and safety of the combination of ruxolitinib and pegylated interferon alpha. Thirty-two patients with PV and 18 patients with primary and secondary myelofibrosis participated in the study. The patients were at age 18 and older. Remission was achieved in 44% of myelofibrosis cases, including 28% (5 patients) of complete remission. In patients with PV, the results were slightly worse: 31% of remissions, including 9% of complete remissions. Patients received pegylated interferon alpha-2a (45 μg/week) or pegylated interferon alpha-2b (35 μg/week) in low doses and ruxolitinib in doses of 5–20 mg twice a day.
For the entire group of patients (with PV and MF), the initial JAK2 allele burden was 47% at baseline, and after 2 years of treatment with interferon and ruxolitinib, it decreased to 12%.
The treatment toxicity was low. The highest incidence of side effects occurred at initiation of therapy. It was mostly anemia and thrombocytopenia.
The observations from the COMBI study show that, for the combination of interferon in lower doses with ruxolitinib, it may be effective and well tolerated even in the group of patients who had intolerance to interferon used as the only drug in higher doses. The combined treatment improved the bone marrow in terms of fibrosis and its cellularity. It also allowed to improve the value of peripheral blood counts [36].
It is currently known that some of the additional mutations are associated with a worse prognosis in patients with myelorpoliferation, including patients with myelofibrosis. Some of these mutations have been identified as high-risk molecular mutations. These are ASXL1, EZH2, IDH1/2, or SRSF2. Earlier studies have shown their association with a more aggressive course of the disease, worse prognosis, and shorter survival of patients, as well as a poorer response to treatment. Due to their importance, they have been included in the diagnostic criteria of myelofibrosis [37].
It is also known that the presence of driver mutations, i.e., JAK2, CALR, and MPL or triple negativity, may affect the course of myeloproliferation, including the incidence of thromboembolic complications.
The assessment of the influence of driver mutations and a panel of selected additional mutations on the effectiveness of interferon treatment in patients with myelofibrosis was performed on a group of 30 patients. Only the patients with low- and intermediate-1-risk were enrolled in the study. The treatment with pegylated interferon alpha-2a or interferon alpha-2b resulted in a complete remission in two patients and partial remission in nine patients. The disease progressed in three cases. One patient relapsed and four died. The remaining patients achieved a clinical improvement or disease stabilization. In the studied group, it was not found if the effectiveness of interferon treatment was influenced by the lack of driver mutations. Among the group of four patients with additional mutations, two died and one had disease progression. It was a mutation of ASXL1 and SRSF2. The treatment with interferon in patients without additional molecular mutations in the early stages of the disease may prevent further progression of the disease [38].
The side effects of interferon in the group of patients with myelofibrosis are similar to those occurring after the treatment of other chronic myeloproliferative diseases. The most frequently described are hematological toxicity- anemia and thrombocytopenia, less often is the appearance of leukopenia. Hematological toxicity usually resolves with dose reduction or extension of the dose interval. The most frequently nonhematological toxicity was fatigue, muscle pain, weakness, and depression symptoms. All symptoms are usually mild and do not exceed grade 2 [38].
However, the use of interferon in the treatment of myelofibrosis has not been recommended as a standard therapy. Interferon is still being evaluated in clinical trials, or it is used in selected patients as a nonstandard therapy in this diagnosis.
Mastocytosis is characterized by an excessive proliferation of abnormal mast cells and their accumulation in various organs.
The basis for the development of mastocytosis is ligand-independent activation of the KIT receptor, resulting from mutations in the KIT proto-oncogene. The KIT receptor is a trans membrane receptor with tyrosine kinase’s activity. Its activation stimulates the proliferation of mast cells. That excessive numbers of mast cells infiltrate tissues and organs and release mediators such as histamine, interleukine-6, tryptase, heparin, and others, which are responsible for the appearance of symptoms typical of mastocytosis. In addition, the infiltration of tissues for mast cells itself causes damage to the affected organs.
The prognosis of mastocytosis depends on the type of the disease. In the case of cutaneous mastocytosis (CM), in the majority of cases prognosis is good and the disease does not shorten the patient’s life, but in aggressive systemic mastocytosis (ASM), the average follow-up is about 40 months. Mast cell leukemia has a poor prognosis with a median follow-up of approximately 1 year.
Systemic mastocytosis usually requires the implementation of cytoreductive therapy. The first line of therapy is interferon alone or its combination with corticosteroids. In aggressive systemic mastocytosis, the first line in addition to interferon 2-CdA can be used. An effective drug turned out to be midostaurin in the case of the present KIT mutation. In patients without the KIT D816V mutation, treatment with imatinib may be effective. In the case of mast cell leukemia, multidrug chemotherapy is most often required, as in acute leukemias, followed by bone marrow transplantation [39].
Systemic mastocytosis requiring treatment is a rare disease, this is why the studies available in the literature evaluating various therapies concern mostly small groups of patients.
In 2002, the French authors presented their experiences on the use of interferon in patients with systemic mastocytosis. They included 20 patients. The patients received interferon alpha-2b in gradually increased doses.
The patients were assessed after 6 months. In cases in which bone marrow was infiltrated for mast cells at baseline, it still remained infiltrated after 6 months of treatment.
However, the responses were obtained in terms of symptoms related to mast cell degranulation. Partial remission was achieved in 35% of patients and minor remission in 30%. It concerns mainly skin lesions and vascular congestion. Moreover, the assessment of the histamine level in the plasma revealed a decrease of it in patients who previously presented symptoms related to the degranulation of mast cells, such as gastrointestinal disorders and flushing.
A high percentage of side effects were found during treatment. They concerned 35% of patients. Depression and cytopenia were most frequent ones [40].
Another analysis was a report of five patients with systemic mastocytosis treated with interferon and prednisolone. All patients received interferon alpha-2b in a dose of 3 million units three times a week and four patients additionally received prednisolone. Four patients responded to interferon treatment at varying degrees. One patient, who at baseline had bone marrow involvement by mast cells in above 10%, progressed to mast cell leukemia. In two patients, the symptoms C resolved completely and in one of them they partially disappeared. In one case, stabilizing disease was achieved [41].
In 2009, a retrospective analysis of patients treated with cytoreductive therapy due to mastocytosis was published. The authors collected data from 108 patients treated at the Mayo Clinic. This analysis allowed for the comparison of the efficacy of four drugs used in systemic mastocytosis. There were interferon alpha alone or in the combination with prednisone—among 40 patients, hydroxycarbamide—among 26 ones, imatinib—among 22 persons, and 2-chlorodeoxyadenosine (2-CdA)—among 22 patients.
After dividing the patients into three additional groups on the basis of the type of mastocytosis—indolent systemic mastocytosis, aggressive systemic mastocytosis, and systemic mastocytosis associated with another clonal hematological nonmast cell lineage disease (SM-AHNMD)—the effectiveness of each of type of therapy was assessed.
The highest response rates in indolent and aggressive mastocytosis were achieved with interferon treatment. They were 60% of the responses in both groups, and in the SM-AHNMD group of patients, the percentage was also one of the highest and amounted to 45%. The second most effective drug was 2-CdA. The response rates were 56% for indolent MS, 50% for aggressive MS, and 55% for SM-AHNMD. The patients treated with imatinib achieved response in 14, 50, and 9% by following groups, respectively. In contrast, patients with indolent and aggressive systemic mastocytosis did not respond to hydroxycarbamide treatment at all. The response rate in both groups was 0%. However, patients with MS associated with another clonal hematological nonmast cell lineage disease achieved 21% response to hydroxycarbamide. Additionally, it was found that only interferon relieved symptoms caused by the release of inflammatory mediators by mast cells.
The additional analysis showed no influence of the TET 2 mutation on the response to treatment [42].
In the literature, there are also single cases of mastocytosis presenting trials of nonstandard treatment. That is description of a patient with systemic mastocytosis with mast cell bone marrow involvement. Mutation of c-kit Asp816Val was present. Patient progressed despite treatment with dasatinib and 2-chlorodeoxyadenosine. The patient developed symptoms related to the degranulation of mast cells and increased ascites.
The patient was treated with pranlukast, which is an anti-leukotriene receptor antagonist due to an asthma episode. The rate of ascites growth decreased significantly after one administration. The patient required paracentesis every 10 days and not every 3 days, as before starting to take the drug. After 15 days of treatment with pranlukast, the patient received interferon alpha, which resulted in complete regression of ascites, resolution of pancytopenia, and complete disappearance of the c-kit mutation clone. The infiltration of mast cells in the bone marrow significantly decreased [43].
Interferon alpha was also effective in a patient with systemic mastocytosis associated with myelodysplastic syndrome with the c-kit D816V mutation, which was refractory to imatinib treatment [44].
Interferon alpha also proved to be effective in the treatment of osteoporotic lesions appearing in the course of mastocytosis.
The series of 10 cases with resolved mastocytosis and osteoporosis-related fractures was presented in 2011. The patients received interferon alpha in a dose of 1.5 million units three times a week as well as pamindronic acid. The patients were treated for an average of 60 months. For the first 2 years, pamindronate was given at a dose of 1 mg/kg every month, and then every 3 months.
During the course of the study, no patient had a new-bone fracture. The level of alkaline phosphatase decreased by 25% in relation to the value before treatment and tryptase by 34%. Bone density increased during treated with interferon and pamindronate. The increase was on average 12% in the spine bones and 1.9% in the hip bones. At the same time, there was no increase in the density of the hip bone and a minimal increase in the density of the spine in patients treated with pamindronate alone.
The results of this observation suggest that it is beneficial to add low doses of interferon alpha to pamindronate treatment in terms of bone density increase [45].
That experiences show that interferon used in systemic mastocytosis significantly improves the quality of life of patients by inhibiting the symptoms caused by degranulation of mast cells. They prevent bone fractures and, in some patients, they cause remission of bone marrow infiltration by mast cells.
Chronic neutrophilic leukemia (CNL) is a very rare disease. It is characterized by the clonal proliferation of mature neutrophils.
The diagnostic criteria proposed by the World Health Organization (WHO) comprise leukocyte counts above 25,000/μl (including more than 80% of rod and segmented
Physical examination often shows enlargement of the liver and spleen, moreover, patients complain on weight loss and weakness [1].
The prognosis varies. The average survival time for patients with CNL is less than 2 years.
Only few descriptions of chronic neutrophilic leukemia are available in the literature, and these are mostly single case reports.
Because it is an extremely rare disease, there are no established and generally accepted treatment standards. In most cases, patients are given hydroxycarbamide or interferon. Patients who are eligible for a bone marrow transplant may benefit from this treatment. Bone marrow allotransplantation remains the only method that gives a chance for a significant extension of life.
The German authors presented a series of 14 cases of chronic neutrophilic leukemia. The group of patients consisted of eight women and six men. The average age was 64.7 years. From the entire group of patients, longer survival was achieved only in three cases. One of these patients was treated with interferon alpha and achieved hematological remission, the other underwent bone marrow allotransplantation from a family donor, and the third one was treated with hydroxycarbamide and transfusions as needed. The follow-up period of the patient after allogeneic matched related donor transplantation (allo-MRD) was 73 months, and for the patient after interferon treatment it was 41 months.
The remaining patients died within 2 years of diagnosis. Six patients, the largest group, died due to intracranial bleeding, three patients died because of leukemia cell tissue infiltration, one patient because of the disease transformation into leukemia, and one patient because of pneumonia [46].
It can be seen from these experiences that treatment with interferon alpha can significantly extend the survival time of patients.
The case of a 40-year-old woman diagnosed with chronic neutrophilic leukemia is presented by Yassin and coauthors. Initially, the patient had almost 41,000 leukocytes in the peripheral blood. In a physical examination, splenomegaly and hepatomegaly were not present. Patient received pegylated interferon alpha-2a. The initially dose was 50 μg once a week for the first 2 weeks, then the dose was increased to 135 μg weekly for 6 weeks, and then the dose interval was extended to another 2 weeks. As a result of the treatment, the general condition of the patient improved and the parameters of peripheral blood counts were normalized [47].
Another case report presented in the literature describes a 41-year-old woman diagnosed with CNL accompanied by focal segmental glomerulosclerosis (FSGS). The patient had increasing leukocytosis for several months. On the admission to the hospital, leukocytosis was 94,000/μl. Moreover, the number of platelets in the morphology exceeded 1,000,000/μl. More than a year earlier, the patient had splenectomy due to splenomegaly and spleen infraction.
Additionally, JAK2 V617F mutation was found. Some authors suggest that the presence of JAK2 mutation may be associated with longer survival in CNL.
The patient received hydroxycarbamide for 3 months and reduction in the number of leukocytes was achieved. After this time, interferon alpha-2b was added to hydroxycarbamide. As a result, focal segmental glomerulosclerosis disappeared and the renal tests improved [48].
Another case of chronic neutrophilic leukemia with a JAK2 gene mutation concerns a 53-year-old man. The patient’s baseline leukocytosis was 33,500/μl, including the neutrophil count of 29,700/μl. The patient also had splenomegaly.
The treatment with interferon alpha-2b at a dose of 3 million units every other day was started. After a month of treatment, the number of leukocytes was reduced to less than 10,000/μl. Then the patient was treated chronically with interferon alpha-2b in doses of 3 million units every 2 weeks. As a result of the therapy, the number of leukocytes remains between 8 and 10,000/μl. The patient remains in general good condition [49].
A series of two CNL cases are also shown. The first patient was a 70-year-old woman with stable leukocytosis of about 35,000/μl and the remaining morphology parameters in normal range. The patient was only observed for 5 years until hepasplenomegaly progressed rapidly. Then, interferon alpha-2b was included. Due to the treatment, the rapid regression of hepatosplenomegaly was achieved.
The second case is a 68-year-old woman with baseline leukocytosis of almost 14,000/μl. In this case, the treatment with hydroxycarbamide was started immediately. However, no improvement was achieved. After 6 weeks of HU treatment, interferon alpha-2b 3 million units 3 times a week was implemented and leukocytosis decreased. Due to the interferon treatment, the disease stabilized for a long time. Because the patient experienced an adverse reaction, a severe flu-like syndrome, interferon was discontinued. After interferon withdrawal, the disease progressed gradually and the treatment attempts by busulfan and 6-mercaptopurine were unsuccessful. Therefore, interferon was readministered and the disease went into remission. Interferon treatment was continued at a reduced dose. The disease regression was achieved again.
Additionally, the patient showed an improvement in the function of granulocytes in terms of phagocytosis and an improvement in neutral killer (NK) cell function after treatment with interferon [50].
The above examples show that interferon alpha is effective in the treatment of chronic neutrophilic leukemia. The side effects are rare and can be managed with dose reductions. Moreover, in these cases, interferon is also effective in a reduced dose. Disease remission or regression can be achieved without typical of CNL complications, such as intracranial bleeding.
Interferon has been used in the past to treat chronic myeloid leukemia. The treatment with tyrosine kinase inhibitors is now a standard practice. However, in a small number of patients, they are ineffective or exhibit unmanageable toxicity. Therefore, the attempts are underway to use interferon in combination with TKI in lower doses, which is to ensure the enhancement of the antiproliferative effect while reducing the toxicity.
There are ongoing attempts to use ropeginterferon in patients diagnosed with chronic myeloid leukemia, in whom treatment with imatinib alone has not led to deep molecular response (DMR). The first phase study was conducted in a small group of patients with chronic myeloid leukemia. The patients in first chronic phase treated with imatinib who did not achieve DMR, but in complete hematologic remission and complete cytogenetic remission, were included in the study. Patients have been treated with imatinib for at least 18 months. Twelve patients were enrolled in the study, and they completed the study according to the protocol. These patients received additional ropeginterferon to imatinib and four achieved DMR. Low toxicity was observed during the treatment. Among the hematological toxicities, neutropenia was the most common. There was no nonhematological toxicity with a degree higher than 1/2 during the treatment. Moreover, it has been found that better effects and fewer side effects are obtained when ropeginterferon is administered for a longer time, but in lower doses. The comparison of the effectiveness of interferon in chronic myeloproliferative disorders based on selected articles is presented in Table 1 [51].
Source | Type of trial | Interferon | Diagnosis | No. | Prior treatment status | Response rate |
---|---|---|---|---|---|---|
Yacoubet al. [15] | Phase II, multicenter | Pegylated IFN alfa-2a | PV | 50 | Resistance to HU or HU intolerance | CR:22% PR:38% |
ET | 65 | CR:43% PR:26% | ||||
Masarova et al. [16] | Phase II, single-center | Pegylated IFN alfa-2a | PV | 43 | Untreated or previously treated with cytoreductive therapy | CR:77% PR:7% |
ET | 40 | CR:73% PR:3% | ||||
Samuelsson et al. [18] | Phase II | Pegylated IFN alfa-2b | PV | 21 | Untreated or previously treated with cytoreductive therapy | CR: 69% for the entire group |
ET | 21 | |||||
Huang BT et al. [19] | Open label, multicenter | IFN alfa-2b | PV | 136 | Untreated or previously treated with cytoreductive therapy | OHR:70% Molecular response:54.7% |
ET | 123 | OHR (JAK2+ patients):83% CHR:23 cases OHR (JAK2-patients): 61.4% CHR:12 cases | ||||
Gisslinger et al. [23] | phase III, multicenter | Ropeginterferon | PV | 257 | Previously treated | OHR:53% |
Quintás-Cardama et al. [26] | phase II | Pegylated IFN alfa-2a | PV | 40 | Untreated or previously treated with cytoreductive therapy | OHR:80% CR:70% Molecular remission:54% |
ET | 39 | OHR:81% CR:76% Molecular remission:38% | ||||
Sørensen et al. [36] | Phase III, multicenter, COMBI | Pegylated IFN alfa-2a with ruxolitinib or Pegylated IFN alfa-2b with ruxolitinib | PV | 32 | Untreated or previously treated with cytoreductive therapy | OHR:44% CR:28% |
MF | 18 | OHR:31% CR:9% | ||||
Casassus et al. [40] | Open label, multicenter | IFN alpha-2b | Mastocytosis | 20 | Untreated and previously treated | PR:35% Minor remission: 30% |
Comparison of the effectiveness of interferon in chronic myeloproliferative disorders.
PV: polycythemia vera; ET: essential thrombocythemia; MF: myelofibrosis; HU: hydroxycarbamide/hydroxyurea; CR: complete remission; PR: partial remission; and OHR: overall hematological response.
Interferon alpha appears to be an effective and safe drug in the most type of chronic myeloproliferative disorders. Nowadays, all forms of its using have similar effectiveness. Interferon alpha can be effective even in cases of resistance for first-line treatment. Trial research is currently underway to combine it with some new drugs, such as ruxolitinib, and to add it to the already well-established therapy, it is a promising option for patients with refractory disease.
From time to time, new forms of interferon, such as ropeginterferon, are introduced, which gives hope for better effectiveness, better safety profile, and greater comfort in its use for patients who have to be treated for many years. In the case of the use of interferons alpha in the treatment of chronic myeloproliferative diseases, there are still opportunities to extend its use and to study its combination with newly introduced drugs.
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He worked as a Executive Research & Development @ Cadila Pharmaceuticals Ltd, Ahmedabad. He received DBT-postdoc fellow @ Molecular Biophysics Unit, Indian Institute of Science, Bangalore under the supervision of Prof. P. Balaram, later he moved to NIH-postdoc researcher at Drexel University College of Medicine, Philadelphia, USA, after his return from postdoc joined NITK-Surthakal as a Adhoc faculty at department of chemistry. Since from August 2013 working as a Associate Professor, and in 2016 promoted to Profeesor in the School of Basic Sciences: Department of Chemistry and having 20 years of teaching and research experiences.",institutionString:null,institution:{name:"Rani Channamma University, Belagavi",country:{name:"India"}}},{id:"158492",title:"Prof.",name:"Yusuf",middleName:null,surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/158492/images/system/158492.jpeg",biography:"Prof. Dr. Yusuf Tutar conducts his research at the Hamidiye Faculty of Pharmacy, Department of Basic Pharmaceutical Sciences, Division of Biochemistry, University of Health Sciences, Turkey. He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. 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He received his post-doctoral training in oncology and cancer proteomics for two years at the Cancer Research Institute of Human Medical University in China. In 2001, he went to the University of Tennessee Health Science Center (UTHSC) in USA, where he was a post-doctoral researcher and focused on mass spectrometry and cancer proteomics. Then, he was appointed as an Assistant Professor of Neurology, UTHSC in 2005. He moved to the Cleveland Clinic in USA as a Project Scientist/Staff in 2006 where he focused on the studies of eye disease proteomics and biomarkers. He returned to UTHSC as an Assistant Professor of Neurology in the end of 2007, engaging in proteomics and biomarker studies of lung diseases and brain tumors, and initiating the studies of predictive, preventive, and personalized medicine (PPPM) in cancer. In 2010, he was promoted to Associate Professor of Neurology, UTHSC. Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. His current main research interest focuses on the studies of cancer proteomics and biomarkers, and the use of modern omics techniques and systems biology for PPPM in cancer, and on the development and use of 2DE-LC/MS for the large-scale study of human proteoforms.",institutionString:null,institution:{name:"Xiangya Hospital Central South University",country:{name:"China"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. 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He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. 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Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. 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He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. 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She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. 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He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/system/329795.png",biography:"Dr. Mohd Aftab Siddiqui is an assistant professor in the Faculty of Pharmacy, Integral University, Lucknow, India, where he obtained a Ph.D. in Pharmacology in 2020. He also obtained a BPharm and MPharm from the same university in 2013 and 2015, respectively. 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