Examples of non ACS-causes of elevated troponin levels:
\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\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:"8798",leadTitle:null,fullTitle:"Cells of the Immune System",title:"Cells of the Immune System",subtitle:null,reviewType:"peer-reviewed",abstract:"The cells of the immune system are lymphocytes (T-cells, B-cells and NK (natural killer) cells), neutrophils, eosinophils, and monocytes/macrophages. This book is an overview of some types of these cells and their role in recognizing and/or reacting against foreign material. The immune system is characterized by collaboration between cells and proteins. The development of all cells of the immune system begins in the bone marrow with a hematopoietic stem cell. Two chapters deal with neutrophils, three chapters with T-cells, four chapters with eosinophils, and other chapters review the immunomodulation of macrophages, the role of transcription factor KLF4 in regulating plasticity of myeloid-derived suppressor cells, immune reconstitution after allogeneic hematopoietic stem cell transplantation, and role of sorption detoxification in the therapy of acute radiation sickness.",isbn:"978-1-78985-584-5",printIsbn:"978-1-78985-583-8",pdfIsbn:"978-1-83880-430-5",doi:"10.5772/intechopen.80249",price:119,priceEur:129,priceUsd:155,slug:"cells-of-the-immune-system",numberOfPages:246,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"4e8acf20a4e80bc7c97cb34d1672e53d",bookSignature:"Ota Fuchs and Seyyed Shamsadin Athari",publishedDate:"May 13th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/8798.jpg",numberOfDownloads:10572,numberOfWosCitations:4,numberOfCrossrefCitations:7,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:17,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:28,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 6th 2019",dateEndSecondStepPublish:"May 21st 2019",dateEndThirdStepPublish:"July 20th 2019",dateEndFourthStepPublish:"October 8th 2019",dateEndFifthStepPublish:"December 7th 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"36468",title:"Dr.",name:"Ota",middleName:null,surname:"Fuchs",slug:"ota-fuchs",fullName:"Ota Fuchs",profilePictureURL:"https://mts.intechopen.com/storage/users/36468/images/system/36468.jpeg",biography:"Ota Fuchs graduated from the Chemical Technological University, Prague, Czech Republic, in 1971. He obtained his Ph.D. in Biochemistry from the Faculty of Natural Sciences, Charles University, Prague, in 1981. He is employed as a Senior Scientist at the Institute of Hematology and Blood Transfusion, Prague. He undertook as visiting scientist short-term affiliations at the Beatson Institute for Cancer Research, Glasgow, UK; Institute of Experimental Medicine of the Russian Academy of Medical Sciences in St Peterburg, Russia; and Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Canada. Dr. Fuchs was the principal investigator of five projects of the Internal Grant Agency of the Ministry of Health of the Czech Republic and one grant project of the Grant Agency of Czech Republic.",institutionString:"Institute of Hematology and Blood Transfusion",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"4",institution:{name:"Institute of Haematology and Blood Transfusion",institutionURL:null,country:{name:"Czech Republic"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"139889",title:"Dr.",name:"Seyyed Shamsadin",middleName:null,surname:"Athari",slug:"seyyed-shamsadin-athari",fullName:"Seyyed Shamsadin Athari",profilePictureURL:"https://mts.intechopen.com/storage/users/139889/images/system/139889.jpeg",biography:"Dr. Seyyed Shamsadin Athari, MPH, Ph.D., is an Assistant Professor of Immunology, Department of Immunology, School of medicine, Zanjan University of Medical Sciences, Iran. He completed postdocs in allergy and asthma toxicology and, asthma management and controlling a network fellowship. He has published more than 30 books and 110 papers in international journals in immunology, allergy, and asthma. He is also on the editorial board of more than seventy journals. He has several scientific inventions to his credit and has recorded gene sequences in a gene bank. Dr. Athari has been invited as a top speaker at more than forty international congresses and symposiums. He is a recipient of several top researcher and young scientist awards.",institutionString:"Zanjan University of Medical Sciences",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"Zanjan University of Medical Sciences",institutionURL:null,country:{name:"Iran"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1034",title:"Classical Immunology",slug:"classical-immunology"}],chapters:[{id:"71229",title:"Introductory Chapter: Development of Neutrophils and Their Role in Hematopoietic Microenvironment Regulation",doi:"10.5772/intechopen.91269",slug:"introductory-chapter-development-of-neutrophils-and-their-role-in-hematopoietic-microenvironment-reg",totalDownloads:809,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:null,signatures:"Ota Fuchs",downloadPdfUrl:"/chapter/pdf-download/71229",previewPdfUrl:"/chapter/pdf-preview/71229",authors:[{id:"36468",title:"Dr.",name:"Ota",surname:"Fuchs",slug:"ota-fuchs",fullName:"Ota Fuchs"}],corrections:null},{id:"67756",title:"Neutrophil Function Impairment Is a Host Susceptibility Factor to Bacterial Infection in Diabetes",doi:"10.5772/intechopen.86600",slug:"neutrophil-function-impairment-is-a-host-susceptibility-factor-to-bacterial-infection-in-diabetes",totalDownloads:1052,totalCrossrefCites:5,totalDimensionsCites:11,hasAltmetrics:0,abstract:"Diabetes mellitus is a highly prevalent noncommunicable disease globally. One of the main complications of diabetes is the increased susceptibility to bacterial infection. Neutrophils play a crucial role in inflammatory response against bacterial infections, once they are the first cells recruited to the sites of injury. In diabetes, there is a failure in the neutrophil functions, including migration, ROS production, phagocytosis, and bacterial killing, which are associated with the high incidence of bacterial infections. Herein, we point out pieces of evidence revealing the primary molecular mechanisms involved with impairment of neutrophil functions in diabetes, with relationship with high susceptibility to bacterial infections.",signatures:"Daniella Insuela, Diego Coutinho, Marco Martins, Maximiliano Ferrero and Vinicius Carvalho",downloadPdfUrl:"/chapter/pdf-download/67756",previewPdfUrl:"/chapter/pdf-preview/67756",authors:[{id:"296748",title:"Dr.",name:"Vinicius",surname:"Carvalho",slug:"vinicius-carvalho",fullName:"Vinicius Carvalho"},{id:"303254",title:"Dr.",name:"Daniella",surname:"Insuela",slug:"daniella-insuela",fullName:"Daniella Insuela"},{id:"303255",title:"Dr.",name:"Diego",surname:"Coutinho",slug:"diego-coutinho",fullName:"Diego Coutinho"},{id:"303256",title:"Dr.",name:"Maximiliano",surname:"Ferrero",slug:"maximiliano-ferrero",fullName:"Maximiliano Ferrero"},{id:"303257",title:"Dr.",name:"Marco Aurelio",surname:"Martins",slug:"marco-aurelio-martins",fullName:"Marco Aurelio Martins"}],corrections:null},{id:"69166",title:"Immune-Mediated Inflammation: Human T CD4 Helper Lymphocyte Diversity and Plasticity in Health and Disease",doi:"10.5772/intechopen.89230",slug:"immune-mediated-inflammation-human-t-cd4-helper-lymphocyte-diversity-and-plasticity-in-health-and-di",totalDownloads:785,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The CD4+ T helper (Th) cells have a critical role in organizing the adaptive immune response. The emerging cells of the differentiation after the immune synapse produce helper T cell subpopulations that activate, suppress, or regulate the immune response upon interaction with varying immune cells. There are two main Th cell functional categories: the “effector cells” and the “regulatory T cells.” Classic T helper lymphocytes can also be distinguished by their lineage according to the developmental microenvironment, the expression of cell adhesion-homing receptors, the profile of cytokines they are exposed to, and the involved transcription factors. Traditionally, the CD4+ and CD8+ phenotypes have been considered as helper and cytotoxic/suppressor T lymphocytes, respectively. Currently, the distinction is little rigorous. The immune response is exceedingly complex beyond the classic Th1 and Th2 effector cells’ involvement, and other populations of helper T lymphocytes like the Th17, Tfh, Th22, and Th9 lymphocytes have been phenotypically characterized. These lymphocytes also participate in the pathogenesis of several immune-mediated inflammatory disorders. Here, we revisit and discuss the essential aspects of the state of the art regarding phenotypic diversity and plasticity of TCD4 cells in the T lymphocyte repertoire frame and their potential implication in human inflammatory diseases.",signatures:"Rodolfo Alberto Kölliker Frers, Matilde Otero-Losada, María Inés Herrera, Sabrina Porta, Vanesa Cosentino, Eduardo Kerzberg, Lucas Udovin and Francisco Capani",downloadPdfUrl:"/chapter/pdf-download/69166",previewPdfUrl:"/chapter/pdf-preview/69166",authors:[{id:"120703",title:"Dr.",name:"Francisco",surname:"Capani",slug:"francisco-capani",fullName:"Francisco Capani"},{id:"193560",title:null,name:"Matilde",surname:"Otero-Losada",slug:"matilde-otero-losada",fullName:"Matilde Otero-Losada"},{id:"205589",title:"Dr.",name:"Rodolfo Alberto",surname:"Kölliker Frers",slug:"rodolfo-alberto-kolliker-frers",fullName:"Rodolfo Alberto Kölliker Frers"},{id:"306018",title:"BSc.",name:"Sabrina",surname:"Porta",slug:"sabrina-porta",fullName:"Sabrina Porta"},{id:"306019",title:"MSc.",name:"Vanesa",surname:"Cosentino",slug:"vanesa-cosentino",fullName:"Vanesa Cosentino"},{id:"306020",title:"Dr.",name:"Eduardo",surname:"Kersberg",slug:"eduardo-kersberg",fullName:"Eduardo Kersberg"},{id:"306021",title:"Dr.",name:"Lucas",surname:"Udovin",slug:"lucas-udovin",fullName:"Lucas Udovin"},{id:"306022",title:"Dr.",name:"María Inés",surname:"Herrera",slug:"maria-ines-herrera",fullName:"María Inés Herrera"}],corrections:null},{id:"70362",title:"Resident Memory T Cells",doi:"10.5772/intechopen.90334",slug:"resident-memory-t-cells",totalDownloads:970,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Until recently, T cells were thought to remain in circulation until recruitment of the inflammation and only a small number of T cells remained in the peripheral tissues without inflammation. However, studies have found that a group of T cells settled in the tissues and remained there for a long time. Those cells are named as tissue-resident memory T cells (TRM). TRM cells are transcriptionally, phenotypically, and functionally distinct from other T cells, which recirculate between blood, secondary lymphoid organs, and non-lymphoid tissues. They undergo a distinct proliferation that discriminates them from circulating T cells and their main cell surface markers are CD69, CD103, and CD49a. Upon exposure to the same or similar diseases, TRM cells provide a first line of adaptive cellular defense against infection in peripheral non-lymphoid tissues, such as skin, lungs, digestive, and urogenital tracts. This approach forms the basis of a novel vaccination strategy called “prime and pull”, which ensures long-term local immunity. On the other hand, abnormal activated and malignant TRM may contribute to numerous human inflammatory diseases such as psoriasis and vitiligo. Here in this chapter, we aimed to emphasize TRM cell location, migration, phenotypic structure, maintenance, and diseases associated with TRM cells.",signatures:"Hasan Akbaba",downloadPdfUrl:"/chapter/pdf-download/70362",previewPdfUrl:"/chapter/pdf-preview/70362",authors:[{id:"260489",title:"Dr.",name:"Hasan",surname:"Akbaba",slug:"hasan-akbaba",fullName:"Hasan Akbaba"}],corrections:null},{id:"67340",title:"Modulating the T Lymphocyte Immune Response via Secretome Produced miRNA: From Tolerance Induction to the Enhancement of the Anticancer Response",doi:"10.5772/intechopen.86598",slug:"modulating-the-t-lymphocyte-immune-response-via-secretome-produced-mirna-from-tolerance-induction-to",totalDownloads:866,totalCrossrefCites:0,totalDimensionsCites:3,hasAltmetrics:0,abstract:"T cells are key mediators of graft tolerance/rejection, development of autoimmunity, and the anticancer response. Consequently, differentially modifying the T cell response is a major therapeutic target. Most immunomodulatory approaches have focused on cytotoxic agents, cytokine modulation, monoclonal antibodies, mitogen activation, adoptive cell therapies (including CAR-T cells). However, these approaches do not persistently reorient the systemic immune response thus necessitating continual therapy. Previous murine studies from our laboratory demonstrated that the adoptive transfer of polymer-grafted (PEGylated) allogeneic leukocytes resulted in the induction of a persistent and systemic tolerogenic state. Further analyses demonstrated that miRNA isolated from the secretome of polymer-modified or control allogeneic responses effectively induced either a tolerogenic (TA1 miRNA) or proinflammatory (IA1 miRNA) response both in vitro and in vivo that was both systemic and persistent. In a murine Type 1 diabetes autoimmune model, the tolerogenic TA1 therapeutic effectively attenuated the disease process via the systemic upregulation of regulatory T cells while simultaneously downregulating T effector cells. In contrast, the proinflammatory IA1 therapeutic enhanced the anticancer efficacy of naïve PBMC by increasing inflammatory T cells and decreasing regulatory T cells. The successful development of this secretome miRNA approach may prove useful treating both autoimmune diseases and cancer.",signatures:"Mark D. Scott, Duncheng Wang, Wendy M. Toyofuku and Xining Yang",downloadPdfUrl:"/chapter/pdf-download/67340",previewPdfUrl:"/chapter/pdf-preview/67340",authors:[{id:"202243",title:"Dr.",name:"Mark",surname:"Scott",slug:"mark-scott",fullName:"Mark Scott"},{id:"205640",title:"BSc.",name:"Wendy",surname:"Toyofuku",slug:"wendy-toyofuku",fullName:"Wendy Toyofuku"},{id:"205641",title:"BSc.",name:"Xining",surname:"Yang",slug:"xining-yang",fullName:"Xining Yang"},{id:"296981",title:"Dr.",name:"Duncheng",surname:"Wang",slug:"duncheng-wang",fullName:"Duncheng Wang"}],corrections:null},{id:"67337",title:"Mucosal Macrophage Polarization Role in the Immune Modulation",doi:"10.5772/intechopen.86609",slug:"mucosal-macrophage-polarization-role-in-the-immune-modulation",totalDownloads:837,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Immunotherapy has advantages including few side effects and low probability of abuse by patients. Recently, functional materials with immunomodulatory functions, which act through reduction of free radicals, have been developed for cancer and anti-inflammatory therapy. However, the therapeutic application of natural functional materials involves a complex mechanism along with various organic factors. These substances, including polysaccharides and triterpenoids, have immunomodulatory effects. However, to our knowledge, the mechanism underlying the action of such substances in the physiological immunity of animals remains unclear. Immune cells, particularly macrophages, are crucial in the modulation of immune response. Macrophages polarise into two types, namely, M1 and M2, from the M0 form, based on the physiological microenvironment factors. M1 macrophages have functions in pathogen elimination through phagocytosis, oxidative damage, and complement system activation. M2 macrophages are involved in tissue recovery and tumour tissues containing ample M2 macrophages that release growth factors, which promote angiogenesis. In this study, we focus on the immunomodulation of the macrophage to further understand the effects of the physiological microenvironment factors on macrophage polarisation.",signatures:"Tsung-Meng Wu, Shiu-Nan Chen and Yu-Sheng Wu",downloadPdfUrl:"/chapter/pdf-download/67337",previewPdfUrl:"/chapter/pdf-preview/67337",authors:[{id:"116110",title:"Dr.",name:"Shiu-Nan",surname:"Chen",slug:"shiu-nan-chen",fullName:"Shiu-Nan Chen"},{id:"274564",title:"Prof.",name:"Yu-Sheng",surname:"Wu",slug:"yu-sheng-wu",fullName:"Yu-Sheng Wu"},{id:"276936",title:"Prof.",name:"Tsung-Meng",surname:"Wu",slug:"tsung-meng-wu",fullName:"Tsung-Meng Wu"}],corrections:null},{id:"69417",title:"KLF4-Mediated Plasticity of Myeloid-Derived Suppressor Cells (MDSCs)",doi:"10.5772/intechopen.89151",slug:"klf4-mediated-plasticity-of-myeloid-derived-suppressor-cells-mdscs-",totalDownloads:710,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Robustness of tissues refers to their capability to maintain normal functions despite perturbation such as injuries. Recent studies suggest a key role of the immune system in injury repair. In this process, several immune cell lineages exhibit considerable plasticity as they migrate toward the site of damage and contribute to repair. For example, myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immature cells and possess phenotypic plasticity in cancer, a pathological status that is considered as “wounds that do not heal.” They are characterized by their potent ability to suppress immune responses. In cutaneous wound healing, MDSCs not only execute their immunosuppressive function to inhibit inflammation but also stimulate cell proliferation once they adopt a fate of a totally different cell type. At a molecular level, we found that Krüppel-like factor 4 (KLF4), a transcription factor with multiple roles in homeostasis and disease development plays a critical role in regulating MDSCs. In this review, KLF4-mediated plasticity of MDSCs and the underlying mechanisms are discussed.",signatures:"Daping Fan, Samir Raychoudhury and Walden Ai",downloadPdfUrl:"/chapter/pdf-download/69417",previewPdfUrl:"/chapter/pdf-preview/69417",authors:[{id:"306954",title:"Dr.",name:"Walden",surname:"Ai",slug:"walden-ai",fullName:"Walden Ai"},{id:"309713",title:"Dr.",name:"Daping",surname:"Fan",slug:"daping-fan",fullName:"Daping Fan"},{id:"312803",title:"Dr.",name:"Samir",surname:"Raychoudhury",slug:"samir-raychoudhury",fullName:"Samir Raychoudhury"}],corrections:null},{id:"71836",title:"Eosinophilic Phenotype: The Lesson from Research Models to Severe Asthma",doi:"10.5772/intechopen.92123",slug:"eosinophilic-phenotype-the-lesson-from-research-models-to-severe-asthma",totalDownloads:655,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Eosinophilic airway inflammation is a hallmark in the pathophysiological and clinical definition of asthma. In the last decades, asthma evolved in the recognition of different phenotypes identified by natural history, clinical and physiological characteristics, and the underlying immune mechanisms. Among these phenotypes, many have been associated with eosinophilic-driven inflammation. This is the case of either early-onset allergic Th2 asthma or late-onset persistent eosinophilic asthma. Both animal models and analysis from human samples have contributed to elucidate the role of eosinophils in the asthmatic inflammatory response and the synergic role of Th2 cytokines. In severe asthma, high numbers of eosinophils can persist despite treatment with inhaled and oral corticosteroids leading to the definition of severe refractory eosinophilic asthma. The combined role of IL-4-, IL-13- and IL-5-associated pathways has focused the view over the T2-type endotypes, wherein a specific biological pathway explains the observable properties of different phenotypes and the identifiable biomarkers can predict response to monoclonal antibodies directed against a selected immune target. In the era of precision medicine and personalized therapy, both the identification of Th2 molecules and eosinophils as targets and biomarkers have become the best clue for treating and monitoring severe asthma.",signatures:"Guida Giuseppe and Antonelli Andrea",downloadPdfUrl:"/chapter/pdf-download/71836",previewPdfUrl:"/chapter/pdf-preview/71836",authors:[{id:"50973",title:"Dr.",name:"Giuseppe",surname:"Guida",slug:"giuseppe-guida",fullName:"Giuseppe Guida"},{id:"319970",title:"Dr.",name:"Andrea",surname:"Antonelli",slug:"andrea-antonelli",fullName:"Andrea Antonelli"}],corrections:null},{id:"69136",title:"Eosinophilic Disorders: Extrinsic and Intrinsic Immune Response, New Diagnostic Perspectives, and Therapeutic Alternatives",doi:"10.5772/intechopen.89229",slug:"eosinophilic-disorders-extrinsic-and-intrinsic-immune-response-new-diagnostic-perspectives-and-thera",totalDownloads:909,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Eosinophils are immune response cells located in the peripheral blood, bone marrow, and lymph nodes, among others; an increase in the number of eosinophils in the peripheral blood above 5000/mm3 is associated with conditions ranging from infections (bacterial and parasitic) and allergy (asthma, rhinitis, or drugs), even neoplasms. Various study groups have classified them according to their etiology, thus facilitating their diagnosis and treatment. The WHO divides them as primary and secondary and also considers the number of eosinophils/mm3 and the involvement of white organs, while others have divided them into intrinsic and extrinsic. The former include mutations in the pluripotential hematopoietic cells, which lead to chronic myeloid leukemias with clonal expansion of eosinophils and extrinsic ones where the changes are related to a TH2 response activated by different cytosines such as IL-5. Current treatments are specifically aimed at modifying the clonal expansion of eosinophils with corticosteroids, hydroxyurea, interferon (peg) alpha, imatinib, among others, and bone marrow transplantation, while in extrinsic alterations corticosteroids and IL inhibitors are used −5 (mepolizumab).",signatures:"Maria-de-Lourdes Irigoyen-Coria, Vilma-Carolina Bekker-Mendez, Maria-Isabel Leyva-Carmona, Cecilia Rosel-Pech, Samuel Moreno-Olivares and David Solis-Hernandez",downloadPdfUrl:"/chapter/pdf-download/69136",previewPdfUrl:"/chapter/pdf-preview/69136",authors:[{id:"74720",title:"Dr.",name:"Vilma-Carolina",surname:"Bekker-Mendez",slug:"vilma-carolina-bekker-mendez",fullName:"Vilma-Carolina Bekker-Mendez"},{id:"306444",title:"B.Sc.",name:"Maria-de-Lourdes",surname:"Irigoyen-Coria",slug:"maria-de-lourdes-irigoyen-coria",fullName:"Maria-de-Lourdes Irigoyen-Coria"},{id:"306967",title:"Dr.",name:"Maria-Isabel",surname:"Leyva-Carmona",slug:"maria-isabel-leyva-carmona",fullName:"Maria-Isabel Leyva-Carmona"},{id:"306968",title:"B.Sc.",name:"David",surname:"Solís-Hernandez",slug:"david-solis-hernandez",fullName:"David Solís-Hernandez"},{id:"306977",title:"MSc.",name:"Cecilia",surname:"Rosel-Pech",slug:"cecilia-rosel-pech",fullName:"Cecilia Rosel-Pech"},{id:"309508",title:"Dr.",name:"Samuel",surname:"Moreno-Olivares",slug:"samuel-moreno-olivares",fullName:"Samuel Moreno-Olivares"}],corrections:null},{id:"68409",title:"Eosinophilic Cholangitis",doi:"10.5772/intechopen.86004",slug:"eosinophilic-cholangitis",totalDownloads:540,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"A variety of benign etiologies of biliary stricture may initially be mistaken for hilar cholangiocarcinoma. Consequently, many patients undergo surgery for a benign disease that could have been treated medically. Eosinophilic cholangitis (EC) is an uncommon, benign, self-limiting disease that should be considered when approaching a case of obstructive jaundice since it causes biliary stricture formation. Transmural eosinophilic infiltration of the biliary tree is characteristic of EC. It may initially be indistinguishable from hilar cholangiocarcinoma. We worked on a case of a patient who was referred to our hospital for jaundice and abdominal mass investigation with the provisional diagnosis of cholangiocarcinoma. During the workup, the index of suspicion for malignancy remained high as the typical laboratory and radiological findings for benign causes of biliary stricture were not present. Hence, the patient underwent left hepatectomy with caudate lobe resection and received a retrograde diagnosis of EC. The case demonstrates that EC could present in the elderly with cardinal signs of cancer and absence of the typical findings of EC which was not previously reported. Furthermore, this disorder has been reported to respond well to steroid therapy, hence, diagnostic criteria for EC would provide another treatment option for elderly and/or those who are not fit for surgery.",signatures:"Gilles Jadd Hoilat, Judie Noemie Hoilat, Mohamad Fekredeen Ayas, Sana Riaz and Divey Manocha",downloadPdfUrl:"/chapter/pdf-download/68409",previewPdfUrl:"/chapter/pdf-preview/68409",authors:[{id:"294042",title:"Dr.",name:"Gilles Jadd",surname:"Hoilat",slug:"gilles-jadd-hoilat",fullName:"Gilles Jadd Hoilat"},{id:"298929",title:"Dr.",name:"Judie Noemie",surname:"Hoilat",slug:"judie-noemie-hoilat",fullName:"Judie Noemie Hoilat"},{id:"298930",title:"Dr.",name:"Mohamad Fekredeen",surname:"Ayas",slug:"mohamad-fekredeen-ayas",fullName:"Mohamad Fekredeen Ayas"},{id:"310025",title:"Dr.",name:"Sana",surname:"Riaz",slug:"sana-riaz",fullName:"Sana Riaz"},{id:"312685",title:"Dr.",name:"Divey",surname:"Manocha",slug:"divey-manocha",fullName:"Divey Manocha"}],corrections:null},{id:"68968",title:"Eosinophilic Granulomatosis with Polyangiitis: The Beginning of a New Era",doi:"10.5772/intechopen.89054",slug:"eosinophilic-granulomatosis-with-polyangiitis-the-beginning-of-a-new-era",totalDownloads:549,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare type of anti-neutrophil cytoplasm antibody-associated vasculitis (AAV) with unique features, such as involvement of eosinophils in the pathogenesis, which requires different therapies from those used for other AAV. Conventional treatment includes glucocorticoids (GC) and immunosuppressants. GC are the cornerstone of the initial treatment of EGPA, but relapses are frequent. Cyclophosphamide is typically used in combination with GC for patients with life- and/or organ-threatening disease manifestations. Azathioprine and methotrexate are recommended to maintain remission after induction with cyclophosphamide or as a GC-sparing agent. Nowadays, a better comprehension of the physiopathology of EGPA has opened new therapeutic targets, such as interleukin-5, which has a key role in the refractory disease, relapses, and GC dependence, especially for asthma manifestations. Mepolizumab is the first anti-IL5 antibody approved to treat EGPA. Another anti-IL5 monoclonal antibody, reslizumab, and an anti-IL5 receptor monoclonal antibody, benralizumab, are now being investigated for EGPA.",signatures:"Carlos Melero Moreno, Marta Corral Blanco and Rocío Magdalena Díaz Campos",downloadPdfUrl:"/chapter/pdf-download/68968",previewPdfUrl:"/chapter/pdf-preview/68968",authors:[{id:"178740",title:"Dr.",name:"Carlos",surname:"Melero Moreno",slug:"carlos-melero-moreno",fullName:"Carlos Melero Moreno"},{id:"306316",title:"Dr.",name:"Rocío Magdalena",surname:"Díaz Campos",slug:"rocio-magdalena-diaz-campos",fullName:"Rocío Magdalena Díaz Campos"},{id:"306317",title:"Dr.",name:"Marta",surname:"Corral Blanco",slug:"marta-corral-blanco",fullName:"Marta Corral Blanco"}],corrections:null},{id:"69097",title:"Assessment of Immune Reconstitution Following Hematopoietic Stem Cell Transplantation",doi:"10.5772/intechopen.89198",slug:"assessment-of-immune-reconstitution-following-hematopoietic-stem-cell-transplantation",totalDownloads:1026,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential curative treatment for both congenital and hematological malignancies. Immune reconstitution after allogeneic hematopoietic stem cell transplantation is implicated in successful transplant outcomes such as overall survival and relapse-free survival. The reconstitution of immune cell subsets after HSCT occurs in different phases at different time points encompassing pre-engraftment, engraftment, and post-engraftment. The recovery of innate cellular immunity with the appearance of monocytes, dendritic cells, and natural killer cells in peripheral blood correlates with initiation of cellular engraftment. The cellular adaptive immunity is characterized by both thymic-independent expansion of T cells infused with graft and thymus-dependent expansion of naïve T cells derived from donor stem cells. The humoral immunity consists of B-cell reconstitution, which consists primarily of transitional and naïve subsets with the recovery of memory B cells that occur much later. 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In both situations, the main factors which determine the survival are the degree of bone marrow suppression and gastrointestinal tract damage due to the presence of a large pool of fast-dividing cells. Leuko- and neutropenia are main limiting factors which may contribute to chemotherapy failure. Hematopoietic cytokines the part of conventional therapy in this field, but their effects require boosting. That is why the use of means and methods of adsorption therapy is considered promising. Sorption therapy creates a basis for sorption detoxification, a doctrine of curative measures directed to the removal of toxic endogenous or exogenous compounds from body fluids. The most widely used types are the purification of blood or its components (hemosorption), oral administration of sorption materials (enterosorption) and application-sorption therapy of wounds and burns. 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\r\n\tThis book “Bacterial Biofilms” will aim to describe both negative and positive impacts of bacterial biofilms in the medical and environmental arena. This book is dispensed into different chapters that describe the role of bacteria in human day-to-day life. The content of this book will be written in a simple scientific language that would accommodate and enlighten audiences from different scientific backgrounds not limited to scientists, higher degree and undergraduate research students in the field of environmental microbiology, infectious diseases, immunologist, pharmacist, medical practitioner, and school students. Bacteria that prefer to exist in colonized forms i.e., in biofilm state have been responsible for detrimental effects on humans, animals, birds, and plant's health in terms of biofilm-associated infections and morbidity, and mortality. The problem of biofilm-associated infection is drastic in lower- and middle-income countries in comparison to developed countries. One big aspect of biofilms is its resistance to antibiotics and antibacterial agents that constitutes collapse of the healthcare system and hindrance of global economic development. On the other hand, biofilms are essential and have been promising in terms of bioremediation of organic pollutants, water purification system, and great acquaintance in the extraction of mineral ores in the mining industry.
",isbn:"978-1-80355-796-0",printIsbn:"978-1-80355-795-3",pdfIsbn:"978-1-80355-797-7",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"e33c0f1032b2a0f72bdf921c0b8a3fea",bookSignature:"Dr. Theerthankar Das",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11092.jpg",keywords:"Infection, Antibiotic Resistance, Treatment, Microbial Remediation, Health and Economic Catastrophic, Bacterial Biofilms, Medical Impacts, Environmental Impacts, Healthcare, Water Purification System, Mining Industry, Minerals",numberOfDownloads:336,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 26th 2021",dateEndSecondStepPublish:"November 23rd 2021",dateEndThirdStepPublish:"January 22nd 2022",dateEndFourthStepPublish:"April 12th 2022",dateEndFifthStepPublish:"June 11th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"9 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"A pioneering researcher in bacterial biofilms, University of Sydney Research Fellow, published numerous scientific articles, book chapters, book editions in relates to bacterial biofilm and infection. Dr. Das won various research funding/grants from Sydney University, Industry, and the Australian Government valued at more than $4.5 million.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"179493",title:"Dr.",name:"Theerthankar",middleName:null,surname:"Das",slug:"theerthankar-das",fullName:"Theerthankar Das",profilePictureURL:"https://mts.intechopen.com/storage/users/179493/images/system/179493.png",biography:"Dr. Theerthankar Das (Department of Infectious Diseases and Immunology, School of Medical Sciences, University of Sydney, Australia) is an experienced microbiologist. He joined the University of Sydney after being awarded the prestigious University of Sydney Fellowship in 2015. His primary research focuses on the development of novel strategies to disrupt bacterial biofilms. In recent years, he has won various research funding/grants from Sydney University, Industry, and the Australian Government valued at more than $4.5 million. To date, Dr. Das has authored/co-authored thirty publications, and six book chapters in eminent journals and books and have edited a book and guest editor for Scientific Journal. He is also a reviewer for many high-impact scientific journals. 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Worldwide, biomarkers have been primarily studied specifically in the setting of diseases. Even so, it is imperative to understand the concept that a biomarker in the human milieu can be present as a result of normal physiological functioning and need not be the result of a pathological process always. Analysis of various biomarkers, both quantitatively and qualitatively have resulted in better understanding of physiological as well as pathological processes of the human body. An ideal biomarker should aid in early diagnosis, help in risk stratification, be able to monitor response to treatment modalities and predict outcomes better than the clinical processes and investigations existing in medical practice at that point of time [2].
In medical practice, biomarkers can be of diagnostic or prognostic value. In the setting of practicing Emergency medicine, diagnostic biomarkers assume greater significance. In the Emergency department, where time is of the essence, diagnostic biomarkers help in quick clinical decision making as well as patient disposition. A biomarker that is able to make a clinical differentiation between two similar disease conditions is highly valuable for an emergency physician. This helps in rapid diagnosis, which leads to faster treatment initiation. Faster the treatment can be initiated, faster the patient movement. A faster TAT (turnaround time) for patients in the ED translates to lesser waiting times in the ED. An ideal biomarker in the Emergency department should have the following characteristics—High diagnostic accuracy which involves a high degree of sensitivity with reasonable specificity, should be reproducible across platforms and should be cost effective to the patient and the clinician.
Numerous biomarkers have been extensively studied for the purpose of clinical utility, but only a few handfuls have proved their mettle in clinical practice. The abundance of biomarker tests available, pose a not so friendly dilemma to the clinician of the present. Understandably, there is still a long way to traverse from the laboratory table to the patient bedside. Numerous trials and research activities are underway across the world in the field of biomarkers. Most of them are still in various phases of preclinical trials and are expected to be available by the patient’s bedside in a few years’ time.
In modern clinical practice, biomarkers are being used more and more for clinical decision making. The current gamut of biomarkers available in the clinical realm have changed the way we practice medicine. The increase in the use of biomarkers for clinical decision making has expedited the patient disposition to a great extent. Having said that, there is also the other side of the coin which is the increase in the health care cost. The over dependence of clinicians on biomarkers should be viewed with caution as this escalates the overall cost of treatment and the patients will have to bear that burden. The decision to make use of biomarkers in the clinical context should be individualised and targeted to prevent its overuse or abuse [3]. This will put a strain on the already scarce resources in the health care sector. It is always pertinent to remember that—A biomarker should always be evaluated in the clinical context and should never be used as a standalone tool for clinical decision making.
In Emergency medical practice, majority of the biomarker work has been focussed in the field of cardiology, renal failure and sepsis, as early detection and prompt interventions in the early phases of the diseases can significantly alter the natural course of the disease and improve the patient morbidity and mortality. Other areas of focus are hepatic diseases, traumatic brain injury, venous thromboembolism etc., where biomarkers are increasingly being tested for their clinical utility. Therefore, the chapter focuses in detail on these clinically significant biomarkers.
Acute coronary syndromes have been in the forefront of novel biomarker evaluation research due to its widespread prevalence as well as the need for detection in a time sensitive manner. Almost 20 million patients with symptoms of acute coronary syndromes present to emergency departments in North America and Europe annually [4, 5]. Numerous studies have been performed on various biomarkers, the conventional markers as well as high sensitive variants, and also with respect to different time frames. In the Emergency department, making a rapid diagnosis of acute myocardial infarction is of utmost importance, as
Historically, biomarkers like LDH (lactate dehydrogenase) and AST (aspartate aminotransferase) were tried in the detection of an acute coronary syndrome especially towards the end of 20th century. Their clinical significance slowly began to decline with the advent of better alternatives as well as lack of specificity. The next in line were the markers with better specificity and sensitivity, namely—the troponins and creatine kinase. As the 21st century is taking its foothold, the scientific community is focussing its attention on these biomarkers for detection of acute coronary events, a leading cause of death worldwide. The research was primarily focussed on Creatine Kinase – MB fraction, which used to be the gold standard of evaluation of ACS. But, that has given way to the newer biomarkers—Troponin I and Troponin T – both conventional and high sensitive, which are being studied extensively across the globe.
Creatine Kinase is an intracellular enzyme with a dimeric molecule which has 3 isoforms—CK-MM (muscle), CK-BB (brain) and CK-MB (myocardium), based on the organ of origin. CK-MB is the isoenzyme fraction which is predominantly seen in cardiac muscle and hence the utility in detecting cardiac muscle damage. This marker is leaked into the systemic circulation from the cellular cytosol due to disruption of the cell membrane as a result of myocardial injury. This marker can be assayed by a clinician to help in the diagnosis of myocardial infarction. CK-MB isoenzyme can be detected in the bloodstream about 4–6 hours after the onset of chest pain. It peaks by 12–24 hrs and returns to baseline by 12–48 hours. This short time window of rise and fall of CK MB is especially useful in detecting reinfarction or infarct extension in a patient in whom the troponin values might be already elevated as a result of an infarct. It is also helpful in identifying complications in patients who have undergone revascularization procedures in the cardiac care unit. The reference values for CK-MB are as follows—males: ≤ 7.7 ng/mL and females: ≤ 4.3 ng/mL. CK MB assay should always be viewed with a pinch of salt since it is a subunit of the total CK in the system. Abnormal elevations of CK MB can be detected along with an increased level of total CK in cases of traumatic muscle injuries, rhabdomyolysis, myopathies etc. It is worthwhile to note that the normally CK-MB fraction accounts for only 3–5% of the total CK in the body and any increase beyond 30–50% of the total CK should prompt suspicion of abnormal beta subunit synthesis. But, over the past few years, the burden of diagnosis of acute myocardial injury has been shifted on to the shoulders of troponins [6].
Troponin is a complex protein molecule comprising of three regulatory proteins playing an integral role in the contraction of cardiac and skeletal muscle. These three subunits are namely—Troponin I (TnI), Troponin T (TnT) and Troponin C (TnC). Each subunit has a unique function. Troponin T binds to the troponin components of Tropomyosin, troponin I inhibits the interaction of myosin with actin and troponin C has the sites for binding of calcium ions to initiate muscle contraction.
Similar to creatine kinase, any cellular injury leads to leakage of the troponins into the systemic circulation thereby providing a window for diagnosis of acute myocardial infarction. Troponins have much higher specificity and sensitivity than creatine kinase. The utility of cardiac troponins especially – Troponin T and Troponin I has been validated in various studies across the world and hence has been incorporated into the diagnostic guidelines of acute myocardial infarction.
Normally troponins are not detectable in the bloodstream due to the minute quantities in open circulation, which is <0.01 ng/mL for Troponin T and ≤ 0.04 ng/mL for Troponin I. After a myocardial injury, elevated troponin levels in the bloodstream can be detected within a period of 4–6 hours, by conventional methods. The reason for this delay in detection has been attributed to the molecular weight and size (21–37 kDa). This can cause clinically significant delay in the diagnosis of myocardial infarction especially in the setting of nonspecific ECG changes. This has led to the advent of high sensitive assays which can detect troponins at much lower levels (at the levels of ng/L) and that too, much earlier than conventional methods. Troponins can be detected as early as 2 hours after the ischemic event by high sensitive troponin assays currently in clinical practice. This also has a caveat, that is, troponin levels can be detected in the circulation even without myocardial injury [4, 5]. Hence a troponin value above the 99th percentile is taken as a diagnostic cut-off for detection of myocardial ischemia. A 20% rise or fall from the baseline within a period of 3–6 hours can confirm the diagnosis of an acute myocardial infarction according to the National Academy of Clinical Biochemistry [6]. It has been recommended by the American college of Cardiology (ACC) that serial values of troponin be considered at 6–9 hr. intervals to rule out NSTEMI [7]. European Society of Cardiology has also reiterated the importance of doing serial assessments of troponins rather than making a clinical decision based on a single value [8]. In a recent large multicentre evaluation in patients with suspected ACS who presented within 8 hours of symptom onset, it was found that it was possible to diagnose ACS with 3-hour marker samples rather than the conventional method of doing serial markers at 6 hour intervals, without losing out on the diagnostic accuracy [9]. Along with clinical evidence of MI, an elevation of troponin level more than 5 times the upper limit compared to the baseline is needed to diagnose a PCI-related MI and more than 10 times the upper limit to diagnose a CABG-related MI [10]. Multiple studies have shown that there is correlation between the levels of troponins and development of adverse cardiac events [11, 12].
Elevated troponin levels may not always indicate myocardial injury [13, 14]. It can also be elevated in non-ischemic conditions as well. A rise/fall in troponin levels are needed to detect acute MI in patients in whom troponins will be elevated otherwise, like renal failure. Even though sensitivity is increased, specificity has come down which may indicate an underlying disease than an acute coronary event. Various causes of nonischemic elevation of troponins are detailed in the below table (Table 1). The troponin levels have to be interpreted only in the appropriate clinical setting, failing which the physician may be misled to an alternate diagnosis [15].
Cardiac | Non Cardiac |
---|---|
• Congestive cardiac failure | • Pulmonary Embolism |
• Myocarditis | • Renal failure |
• Pericarditis | • Sepsis |
• Infiltrative diseases | • Stroke |
• Blunt chest trauma |
Examples of non ACS-causes of elevated troponin levels:
Numerous other biomarkers have piqued the interest of the scientific community to identify acute coronary events more early as well as more precisely. Very few have actually stood on their own when compared to troponin studies. The most common drawback being the cost of the investigation as well as availability. Some of the examples are discussed below.
Myoglobin (Mb) peaks within minutes of cardiac ischemia. With the recent advancements for detection of hs-troponin levels, the utility of Mb has come down in the diagnostic algorithm [16]. A few examples of other novel biomarkers of myocardial ischemia/injury that have undergone clinical trials are given below in Table 2. They include cardiac intracellular proteins, markers of neurohormonal activation, markers for haemostatic activity, vascular inflammation markers etc. [17]. In this study, the assessment of H-FABP within the first 4 h of symptoms was found to be superior to cTnT for detection of MI. But the reduced specificity of H-FABP is presently limiting its usefulness in clinical practice. Soluble CD40 ligand and choline which are biomarkers signalling the instability of atherosclerotic plaque formation, have been studied, but did not show add any prognostic or diagnostic value to the existing ones in practice. But the other biomarkers they studied along with this, did not show any favourable clinical significance.
• Myoglobin (Mb) P |
• Heart Fatty Acid Binding Protein (H-FABP) |
• Glycogen Phosphorylase-BB (GP-BB) |
• NT-Pro-Brain Natriuretic Peptide (NT-ProBNP) |
• D-Dimer |
• High Sensitivity C-Reactive Protein (HsCRP) |
• Myeloperoxidase (MPO) |
• Matrix Metalloproteinase-9 (MMP-9) |
• Pregnancy Associated Plasma Protein-A (PAPP-A) |
• Soluble CD40 Ligand (SCD40L) |
Newer biomarkers for cardiac ischemia.
Cardiac failure is a complex process involving a multitude of pathophysiological processes. As a result of this, various biomarkers have been identified which correlate with specific aspects of heart failure. The marker which has made its mark in a clinically significant manner are the natriuretic peptides-B type natriuretic peptide (BNP) and NT pro BNP.
BNP is secreted from the ventricles as a result of neurohormonal activation due to volume overload and resultant stretching of the myocardial muscle fibres. In patients with left ventricular dysfunction/failure, high plasma levels of BNP and NT pro BNP are specific for elevated filling pressures in the cardiac chambers. This can be used in the clinical context for the diagnosis as well as prognostication of cardiac failure. ProBNP is a 108-amino acid polypeptide precursor which is stored in secretory granules in both ventricles and, to a lesser extent, in the atria. After proBNP is secreted, it is cleaved to the 76-peptide, biologically inert N-terminal fragment NT-proBNP and the 32-peptide, biologically active hormone BNP. BNP is rapidly cleared from the circulation; the plasma half-life being approximately 20 min. No receptor-mediated clearance of NT-proBNP is known to occur, because of which NT-proBNP has a prolonged half-life of 60–120 min. The reference values for NT-proBNP varies widely with age and gender, which can be tricky for the clinician while assessing patients, especially in the elderly population (Table 3).
Age | Males | Females |
---|---|---|
≤45 yrs | 10–51 pg/mL | 10–140 pg/mL |
45–70 yrs | 10–100 pg/mL | 10–206 pg/mL |
≥70 yrs | 10–138 pg/mL | 10–1263 pg/mL |
Reference values for NT-ProBNP:
In the multicentre Breathing Not Properly Study [18], using plasma BNP level of 100 pg/mL as cut off, gave a sensitivity of 90%, specificity of 76% and a diagnostic accuracy of 81% which was superior to clinical assessment alone in a series of 1586 patients who presented to the ED with acute dyspnoea. A BNP level < 100 pg/ml or an NT-proBNP level < 300 pg/ml can essentially rule out Acute HF in most cases. When using N-terminal proBNP for the diagnosis of acute CHF, a value of 900 pg/mL has high specificity and sensitivity.
Apart from left ventricular failure, these biomarkers can be elevated in numerous other conditions which can cause myocardial stretch. Patients with right ventricular failure secondary to pulmonary embolism or pulmonary hypertension, valvular heart disease, arrhythmias such as atrial fibrillation, renal failure and advanced age may also have elevated levels of BNP or NT-proBNP [19]. In severe renal failure, the NT-pro BNP value of >1200 pg/mL is needed to make a diagnosis of cardiac failure. A common clinical scenario in which the patient is obese, the pro-BNP values can be falsely lower which can mask cardiac failure and lead to misdiagnosis.
The European Society of Cardiology Task Force has recommended that the algorithm for HF diagnosis should include an NP assay as the first step along with electrocardiography (ECG) and chest X-ray [20]. Biomarkers are not just useful in the diagnostic algorithm, but also in guiding treatment. In a meta-analysis [21] of 2686 patients in 12 randomised trials, the researchers found that the use of cardiac peptides to guide pharmacologic therapy significantly reduces mortality and HF related hospitalisation in patients with chronic HF.
As discussed in the previous section, Troponin I (TnI) also plays an important role in the pathophysiological profile of cardiac failure. Newer markers that have potential to be significance in the future for diagnosis and prognosis in heart failure include high-sensitivity C-reactive protein (hsCRP), uric acid and myeloperoxidase (MPO), soluble toll-like receptor-2 (ST2) and soluble fms-like tyrosine kinase receptor-1 (sFlt-1). Recently, a study in which the amount of exhaled acetone is measured has shown promise as a newer non-invasive modality for cardiac failure assessment [22]. A recent study attempted to evaluate the predictive utility of these biomarkers with a multimarker score which included BNP, troponin I and creatinine apart from the above markers. They concluded that a multimarker score significantly improves prediction of adverse events in ambulatory patients with chronic heart failure [23]. But, NACB’s practice guidelines on cardiac biomarker testing specifically recommends against routine use of biomarker testing only for risk stratification [24]. The newer entries into this field include galectin-3 [25], MR-proANP (midregion pro–atrial natriuretic peptide) [26], MR-proADM (mid regional pro-adrenomedullin), co-peptin, adiponectin, pentraxin-3, soluble ICAM-1(intercellular adhesion molecule-1), PAPP-A (pregnancy associated plasma protein A) etc.
In a case of suspected pulmonary embolism, laboratory evaluation by biomarker levels is primarily helpful in ruling out the diagnosis in low probability scenarios, rather than ruling in a confirmation of a diagnosis. D-dimer has been in clinical use extensively since the past few decades and the other markers which are increasingly used are troponins, BNP and Ischemia modified albumin (IMA).
D-dimer is a degradation product produced by plasmin during fibrinolysis. The reference value of D-dimer is ≤500 ng/mL Fibrinogen equivalent Units (FEU). It has very low specificity, but a high sensitivity. Due to the low specificity, a clinical diagnosis of pulmonary embolism requires a strong clinical suspicion. In order to help the clinician in this regard, various scoring systems to assess the probability of making a diagnosis of PE have been devised. Well’s criteria and its modified version are among the most commonly used. These scoring systems assist the clinician in assessing the probability of a diagnosis of PE along with the blood levels of the biomarker used. In patients with a low pretest probability of PE as assessed by well’s criteria and a negative d-dimer value, the diagnosis of pulmonary embolism can be essentially ruled out without any probability of adverse events happening later [27, 28].
Ischemia modified albumin (IMA) is a newer marker that has shown potential as a substitute for D-dimer as it has been found to be better than the latter in a few studies due to its better positive predictive value [29]. The reference value for IMA is ≤0.540 ABSU. In patients with pulmonary embolism, more so in those who develop RV dysfunction, other biomarkers like troponins and BNP are also found to be elevated. This occurs due to the increased pulmonary vascular resistance, pulmonary artery pressure and resultant RV afterload. The elevated troponin levels can pose a dilemma for a clinician who wants to rule out ACS as well in the clinical setting as the symptoms of both the conditions may overlap significantly. The elevated levels of BNP/NT pro-BNP in patients with pulmonary embolism have been found to be associated with increase in risk for complications and 30-day mortality [30].
Sepsis is a complex process that stems from a combination of features of a systemic inflammatory response to a known or presumed infection. It is associated with a very high mortality rate around 30% not to mention the significant economic impact on the healthcare system [31]. Sepsis can be viewed as a chain of events in the body as a response to an inciting agent through an inflammatory pathway. This provides clinicians the opportunity to diagnose sepsis early by either picking up the inciting agent or the inflammatory response to the agent. More than 170 biomarkers have been identified as useful for evaluating sepsis [32], which itself points to the fact that none of them can be used as a single marker for accurate diagnosis or prognosis. C-reactive protein, procalcitonin and serum lactate are among the prominent ones used extensively worldwide at present.
C-Reactive protein, one of the most commonly used markers for sepsis, is synthesised in the liver as an acute phase reactant. The normal levels in a healthy adult individual tends to be below 10 mg/L. Depending on the severity, any stress or stimulus can cause an elevation in the CRP levels, even manifold up to 500 mg/L. The levels peak around 36–48 hrs and the plasma half-life is approx. 19 hrs. Although very commonly used as an inflammatory marker, it lacks specificity as it is found to be elevated in numerous conditions like post-operative patients, burns, myocardial infarction and inflammatory/rheumatic diseases as well [33]. It can be elevated even in normal individuals especially in elderly as well as pregnancy. Moreover, even a viral infection can cause a mild increase in the serum levels of CRP, contrary to popular belief. The sensitivity and specificity of CRP as a marker for bacterial infections are 68–92% and 40–67%, respectively [34, 35]. CRP plasma levels have shown to correlate with the severity of infection [36] which makes it a useful marker to assess the response to pharmacological treatment.
It is a 116-amino acid polypeptide which is the prohormone of calcitonin. It has a short half-life (25–30 hours), and is encoded by the
Lactate is produced in the body even normally, which gets cleared off rapidly in healthy individuals. But, in cases of sepsis and resultant hypoperfusion, the levels of lactic acid increase when anaerobic metabolism increases in the body. Lactate clearance has been shown in a prominent light in the ‘Early goal directed therapy’ of septic patients. This indicates that, more than a diagnostic marker, lactate has prognostic significance in patients with sepsis. Recent studies have shown that patients with even a milder increase in serum levels in the range of 2–4 mmol/L were at an increased risk of morbidity and mortality [42]. In a study conducted in an urban academic centre which included 1278 patients with infections, those with lactate levels above 4 mmol/L had higher in-hospital mortality rates than patients with lactate levels less than 2.5 mmol/L (28.4% vs. 4.9%) [43]. The bottom line is, the better the lactate clearance, better the outcome of the patient [44].
Adrenomedullin (ADM) is a 52-amino acid ringed peptide produced from endothelial cells in cardiovascular, renal, pulmonary, cerebrovascular and endocrine tissues. It is a potent endogenous vasodilator in the human body. ADM is not easily measurable due to its very short half-life of 22 minutes in the circulation, its rapid degradation by proteases, and the formation of complexes with circulating complement factor H [45]. The prohormone of ADM - ProADM can be used as a surrogate marker for this purpose as it is more easily quantifiable, and the tools required for this are available commercially. The mid-regional fragment of proadrenomedullin (MR-proADM) is a marker of endothelial dysfunction/inflammation and therefore can be seen in elevated levels in numerous disease conditions. Pro-ADM has been found to be an independent predictor for adverse outcomes in patients with COPD [46]. It has also been studied in the context of burns, in which it was found to have utility in early recognition of onset of sepsis in burns victims [47]. It is still early days for MR-proADM in routine clinical practice as many studies [48] have failed to demonstrate any added utility with respect to other less expensive parameters presently available. For healthy individuals, the reference values for MR pro ADM is <0.5 nmol/L.
Cytokines like TNF, IL-1β and IL-6 are the predominant inflammatory mediators responsible for the initial inflammatory response and the levels correlate with the organ damage and mortality [49]. Similarly, High-mobility group box 1 protein (HMGB1) and Macrophage migration inhibitory factor (MIF) are also found to increase in patients with severe sepsis and septic shock and is correlated with the degree of organ failure [50, 51]. Lipopolysaccharide-binding protein (LBS) is an acute phase protein which increases in sepsis and makes it useful as a diagnostic tool as well as a marker for severity of the disease [52, 53]. Other biomarkers like serum amyloid A, eosinophil count, mannan and antimannan, and IFN-γ-inducible protein 10 also show potential to be of use in the future.
In patients who are hospitalised with burns, sepsis is considered as one of the most important causes for mortality. Biomarkers which can help pick up the onset of sepsis in burn patients in the early phase itself will be useful in the proactive management of complications. Procalcitonin, Tumour necrosis factor-alpha (TNF-alpha), MR Pro-ADM, Interleukins 6, 8 & 10, Presepsin are among the major ones studied in this context in addition to assessment of single-nucleotide polymorphisms (SNPs) and leukocyte transcriptomes [54].
PCT has been extensively studied in the context of sepsis, but literature regarding studies in burns are much lesser in comparison to other critical conditions. Serum levels of PCT were found to be elevated in patients who developed infections after burns in one of the initial studies done in 1993 which had 9 burns patients included among the 79 general patients enrolled in the study [55]. In a recent meta-analysis of around 12 studies in burns patients led the investigators to believe that PCT has a strong ability to differentiate between patients with sepsis and without sepsis [56]. The study proposed that a PCT value >1.47 ng/mL can prompt the clinicians to initiate early antibiotic therapy to counter the development of sepsis and improve patient outcomes.
It is a proinflammatory cytokine and has been researched worldwide in various disease conditions among the host of numerous inflammatory mediators. It is produced ubiquitously in the body in response to various stimuli which can be infectious or ischemic in nature. They include endotoxins, complement system activation, hypoxia, ischemia as well as reperfusion [57]. TNF-alpha has been found to be elevated in burns and the values are seen to be higher in patients found to be in sepsis [58]. It has also been shown to have a prognostic value in burns victims. In burns patients who were treated with GM-CSF, the values of TNF alpha were shown to come down gradually as the treatment progressed [59], hence proving its role as a prognostic indicator. Reference value: ≤ 2.8 pg/mL.
The interleukins (ILs) are a large class of cytokines that promote cell-to-cell interactions and the stimulation of humoral or cell-mediated immune responses. They were initially thought to be produced only by the leukocytes, but have been found to be produced from numerous sources since then. The IL family consists of a huge number of members of which IL-6, IL-8 and IL-10 have been shown to be associated with evaluation of sepsis in burns patients. IL-6 has been found to be elevated in burns patients with sepsis [60]. It not only helps in the early diagnosis, but also has prognostic significance regarding the mortality as the levels have been found to be correlating with the size of the burns [61]. Recently, a meta-analysis of studies done on critically ill patients regarding markers of sepsis found IL-6 to have a high specificity, hence making it a suitable marker to confirm an infectious process [62]. Similarly, studies have found that IL-8 levels in burns patients correlate with the development of sepsis and multi-organ failure resulting in mortality [63]. The authors of the study opined that it can be used as a biomarker for monitoring the morbidity and mortality of burn patients developing sepsis. IL-10, similar to its counterparts, have been shown to have a correlation to development of sepsis in burn patients. Normally, the serum levels increase after the injury and decline later. But a failure to decline over time and being persistently elevated should point towards the development of an infective process and may increase the chances of mortality [64], hence making it a prognostic indicator in burn patients.
Some of the other notable markers pertaining to burns patients are -
Conventionally, renal function tests which include serum levels of creatinine, urea and assessment of glomerular filtration rate are the methods used to quantify renal diseases. But, these conventional methods have a huge drawback. There is an unacceptable high time lag between the onset of tissue injury and derangement of these biochemical values. This hinders any active reno-protective interventions that may be initiated promptly. Moreover, the serum levels of these markers vary widely even in healthy individuals as it depends on various physical factors like age, gender, muscle mass etc. This has led the medical community to look for alternatives. Human neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), interleukin-18 (IL-18), cystatin C, clusterin, fatty acid binding protein, and osteopontin are the prominent ones that have been studied and NGAL has been the most prominent one of the lot.
Other markers that are being studied for their utility in kidney injury are Interleukin-18, Kidney injury molecule 1 (KIM-1), Cystatin – C, Sodium/Hydrogen Exchanger Isoform 3(NHE3) and Liver-type fatty acid binding protein (L-FABP). Kidney injury molecule 1 (KIM-1) and Interleukin-18 are found to be elevated in case of ischemic Acute Tubular Necrosis [72, 73]. Cystatin-C has been found to be better at estimating the GFR than the conventional method using creatinine [74]. Sodium/Hydrogen Exchanger Isoform 3(NHE3), which is found in the urine following tubular injury, has been found to be better than fractional excretion of sodium in differentiating between pre renal and intrinsic renal causes for renal failure [75]. Liver-type fatty acid binding protein (L-FABP) has also shown promise in animal studies for early detection of AKI and is being adapted as a possible biomarker for AKI [76].
Traumatic brain injury is a major cause of morbidity and mortality across the world [77]. The reasons are several, but the lion’s share of the incidents can be attributed to the high speed motor vehicle collisions. In addition to that, there are other contributing factors like falls as well as injuries due to contact sports. The acute injuries can be devastating and even fatal, but a huge number of those patients also develop chronic neurological sequelae which can be debilitating [78]. Given the complexity of the situation, the understanding of the mechanisms and pathophysiology of these chronic conditions are much less understood compared to their acute counterparts [79].
Traumatic Brain Injury (TBI) can be classified into acute or chronic based on the acuity of the event. Acute traumatic events as a result of MVA (motor vehicle accidents), falls or sporting events mostly result in immediate clinical symptoms or signs that are often diagnosed with the help of neuroimaging immediately by the clinician. A concussion as a result of contact sports or accidents can result in clinical features which can range from mild dizziness to complete unconsciousness. But, it will exhibit no discernible defects in neuroimaging of the patient [80]. Therefore it becomes a clinical diagnosis rather than a radiological diagnosis. Many patients, especially sportspersons who are part of contact sports like boxing have exhibited persistent symptoms for hours to days to months after the insult [81]. The shearing forces in an acceleration/deceleration injury causes axonal damage which is often responsible for the clinical manifestations. The acute event leads to a primary insult to the central nervous system which can manifest as cerebral oedema or even intracranial haemorrhage. This in turn leads to increase in the intracranial pressure which in turn causes cerebral hypoperfusion and resultant tissue hypoxia [82].
Traumatic head injury is not an area which usually requires a biomarker evaluation from the Neurosurgeon’s point of view for the purpose of acute care. Clinical decision making is often dependent on neuroimaging, which is a CT scan usually. But, recently, the role of biomarkers has become important in the decision making process of getting a neuroimaging. This is done with a view of reducing the radiation exposure to patients with mild head injury. These biomarkers are not usually present in the circulation and their presence generally indicates a breach of Blood–brain barrier. Some of the important biomarkers described in the recent literature are Glial fibrillary acidic protein (GFAP), calcium binding protein S100B, and tau protein [83]. The most important one in the horizon is S100 calcium binding protein B (S100B), which is a glial-specific protein which is primarily expressed by a subtype of mature astrocytes. It is elevated in neuronal damage which makes it a potential marker for CNS insults. In a study done on 512 adult patients with mild head injury (GCS 14–15, loss of consciousness and/or amnesia and no additional risk factors), the researchers used protein S100B levels as a clinical tool to determine whether the patient needed a CT scan [84]. They found that adult patients with mild head injury, without additional risk factors and with S100B levels of <0.10 mcg/L within 3 hours of injury, can safely be discharged from the hospital without neuroimaging. A recent study done in Sweden tries to shed light on the utility of biomarkers like total tau, protein S100B and neuron-specific enolase in assessing concussion injuries in sports persons [85].
Once the primary insult is over, the brain can suffer from secondary injury as a result of sequelae from the initial insult. This can occur after days, weeks, months or years after the initial event. This results from biochemical cascades that are triggered by the primary event. These secondary events are mediated by free radicals and reactive oxygen species that are generated as a result of tissue hypoxia, reperfusion injury and neuroinflammation [86]. The change in membrane permeability which results from the initial injury causes increase in the calcium uptake or activation of NMDA and AMPA receptors by glutamate can cause mitochondrial dysfunction [87]. Thus the inflammatory response leads to further cellular disruption and the vicious cycle continues to damage the nervous homeostasis. These inflammatory insults in the nervous system give rise to various inflammatory markers which can be detected in the system. These biomarkers have been extensively studied and their usefulness in the clinical environment hotly debated. Even though many of these markers many of them show enough promise within the confines of the laboratory, they are yet to come to the bedside to be used by the clinician in daily practice.
Many animal studies have demonstrated an increase in biochemical markers even after a single day after the insult and these can persist even after a month [88]. Acrolein, a post-traumatic neurotoxin can be quantified in brain tissue and can be elevated depending on the insult. A sustained upregulation has been demonstrated after brain injury, which suggests that it is a potential marker for neuronal injury and inflammation [89].
Proton Magnetic Resonance Spectroscopy (1H-MRS) is a technique which is able to measure the neurochemicals in the nervous system. This helps in detecting the neurotransmitters and metabolites, thereby quantifying the markers in various clinical conditions. Using this method, animal studies have found that endogenous antioxidants glutathione and ascorbic acid may be decreased up to 2 weeks following the insult [90]. F2-isoprostane, a lipid peroxidation by-product, has been found to be elevated on chronic brain injury or Chronic Traumatic Encephalopathy (CTE) which manifests years after the insult(s).
As detected by Proton Magnetic Resonance Spectroscopy (1H-MRS), there have been consistent results in detection of the following neurotransmitters in children with Autism Spectrum Disorder(ASD). There has been reduced levels of N-acetylaspartate (NAA), Creatine and phosphocreatine (Cr + PCr), Glutamine, Myo-Inositol and Choline containing compounds in the subcortical areas as well as cortical white matter and grey matter in varying degrees in children with ASD [91].
Neurodegenerative diseases can be extremely debilitating and distressing to not only the patient, but also the caregivers. Once diagnosed, the pathophysiological mechanisms can seldom be reversed and hence it becomes the source of social, financial and economic drain for not only families, but for the governmental health machinery itself. The social impact is huge, but the economic impact of these conditions cannot be ignored by any means.
Hence, it becomes imperative that the diagnosis can be made as early as possible thereby mitigating the scenario. An earlier diagnosis will help the clinician as well as the caregivers to come to a plan for further care of the patient. It is also essential to look at the therapeutic interventions which can arrest or at least slow down the progression of the disease. This is where the role of biomarkers come into picture. A biomarker can help in diagnosing a particular condition early. Even if the diagnosis cannot be confirmed, at least the possibility of the condition can be ascertained and hence be prepared against. This is where a biomarker helps in fighting the diseases which for all practical purposes, have no definitive curative measures available by the bedside.
Biomarkers in neurodegenerative conditions can be classified as fluid and radiological markers. Since radiology is an integral and essential part of assessment of the neurological system in modern medicine, many techniques have been developed which can detect the presence of markers within the brain tissue which can point towards the presence or likelihood of a particular disease condition. On the other hand, there are fluid biomarkers that can be detected in the fluid that flows all over the brain - the cerebrospinal fluid (CSF). Before we look into those markers, it needs to be kept in mind that quite a few markers have gone to the lab in the hunt for that perfect biomarker. But, none of them has been successful enough to be brought to the bedside for daily clinical practice. Among the many neurodegenerative conditions, Alzheimer’s disease has been the most extensively studied, because of its prevalence and impact on the society. But the biomarkers used in Alzheimer’s disease do overlap with many other conditions as well due to similarities in pathophysiology.
Biomarkers in neurodegenerative conditions can be detected in blood and cerebrospinal fluid (CSF) and are clubbed together to be called as fluid markers. The predominant ones are Amyloid β peptides/oligomers and Tau peptides. Neurofilament light chain (NfL), which is found in myelinated axons, is an important marker which indicates white matter damage and points towards neurodegeneration [92]. Serial NFL sampling in patients at risk of developing Alzheimer’s Disease, can be used to predict brain atrophy rates, cognitive impairment and disease progression [93]. These can be estimated by assays in blood as well as CSF. The major disadvantage these markers face is the low specificity and that hinders its utility in clinical practice. Another set of markers or radiological distinction characteristics can be detected in MRI and PET scans and are termed as radiological biomarkers. MRI utilises the various imaging modalities available to detect white matter lesions that are present in many of the neurodegenerative diseases. These include reduction in the volume, thickness, presence of microbleeds, myelin, iron, neuromelanin within the brain tissue in specific regions. PET targets various Tau lesions and Amyloid β aggregates in various regions within the neuronal system to detect the possibility of neurodegeneration. Apart from these, there are genetic biomarkers or specific genes that can predict the possibility of a neurodegenerative disease condition (Table 4).
Gene(s) | Disease syndrome associated |
---|---|
Familial - Early-onset Alzheimer’s disease | |
AD- Risk factors | |
Behavioural-variant frontotemporal dementia | |
Amyotrophic Lateral Sclerosis | |
Huntington’s disease | |
Parkinson’s disease | |
Prion Disease |
Genetic biomarkers for neurodegenerative diseases.
It is a proteinopathy which is characterised by accumulation of Tau neurofibrillary tangles and extracellular Amyloid β plaques. These can be assessed by radiological methods as well as by looking at the fluid biomarkers. It has a prolonged pre-clinical phase where there Tau lesions can be found in the subcortical regions even before profound clinical symptoms appear [94]. Similarly amyloid β aggregates are initially found in the neocortical regions and later subcortical and cerebellar regions [95]. Plasma levels of Aβ42 has been found to be decreased compared to controls in a study [96]. The National Institute on Ageing and Alzheimer’s Association Research Framework has defined AD by its underlying pathologic processes that can be documented by post-mortem examination or in vivo by biomarkers [97]. The biomarkers are classified into the 3 major groups- β amyloid deposition, pathologic tau, and neurodegeneration - AT(N). As and when newer biomarkers are discovered, they may be added into these categories. When it comes to therapeutics targeted based on these markers, there is still a long way to go to get these implemented in clinical practice. This may be due to the lack of direct correlation between the marker load with the clinical deterioration [98] as well as lack of specificity [99].
It is the most common presentation of synucleinopathy. The presentation can be similar to other similar conditions like Dementia with Lewy bodies. The typical feature can be aggregation of α-synuclein in the form of Lewy bodies which starts in the subcortical regions and later spread into the other regions [100]. Apart from the mutations in the genes, causality has been attributed to pesticide exposure as well as traumatic brain injury [101].
This encompasses a spectrum of disease conditions characterised by vacuolation, gliosis and neuronal loss in the cortical regions of the frontal and temporal lobes. Features of Tau protein accumulation, TDP-43 or fused in sarcoma can be seen in this condition [102]. Since they share a similar pathophysiology, Amyotrophic lateral sclerosis (ALS) and other similar motor neuron diseases are considered to be part of the same spectrum.
Huntington’s disease is characterised by progressive neuronal loss and astrogliosis in the striatum along with prominent degeneration of the other cortical regions [103]. Similar to other disease conditions, there is limited data available to look at the therapeutic use of markers in HD also. Plasma levels of IL-8, TNF-α [104], and NfL may become useful in the coming years in this regard. A decrease in the uptake of phosphodiesterase-10 PET tracer in the strial region may become an important marker with regard to therapeutics in HD [105]. Diagnosis of Prion diseases like sporadic Creutzfeldt-Jakob disease (sCJD) is done by EEG, MRI or CSF based biomarkers with the use of real-time quaking-induced conversion (RT-QuIC) which is preferred over 14-3-3 protein detection [106].
Since many of the neurodegenerative conditions present late in clinical practice, it is imperative that in order to tackle this menace, the scientific community will have to bring forth tools that can detect these early as well us much ahead of the phase of clinical presentation, even decades. It is in this regard, the biomarkers have a major role to play, whether they are radiological or fluid markers. Genetic markers are useful when we are dealing with hereditary conditions or familial variants of neurodegenerative conditions. Confirmation of the diagnosis is essential in determining the treatment and initiating it at the earliest for the best possible response.
Even though the field of biomarker evaluation is not very old, it is a fast changing world and newer techniques are being added to the mix quite often. A recent technique is the Multimer Detection System-Oligomeric Aβ, which looks at the tendency of plasma proteins to oligomerize [107]. Immune-infrared sensor assay to measure blood vessels for the propensity of the amyloid protein to form β-sheets has also been tried with some success as a potential biomarker [108]. Measurement of locus coeruleus, an early affected region, using special MRI techniques is also being explored as a potential target [109].
POCT refers to diagnostic evaluation at or near the site of patient care. A POC lab is not within the institutional central laboratory, but nearer to the patient care setting like ED or ICU. POC testing of biomarkers is increasingly becoming the norm at the moment. This has been touted as the next revolutionary step in faster healthcare delivery in the Emergency department. But, the challenge lies in transferring the resultant advantage to improvement in patient care and disposition. The benefit demonstrated on paper should be translated to better patient care by the bedside. If the results of the POC testing do not alter the course of management of the patient, it defeats the whole purpose of POCT.
Biomarkers are being increasingly used in the Emergency departments for faster patient disposition. Recently efforts are being undertaken to include an array of biomarkers in the triage scoring itself as a method of risk stratification of patients presenting to the ED [110]. In this study, the researchers included biomarkers from 3 distinct biological pathways for risk stratification of general medical patients presenting to the ED. The study included biomarkers of inflammation (pro-adrenomedullin [ProADM]), stress (copeptin) and infection (procalcitonin). They used a multi-marker approach to stratify patients and came to a conclusion that all the markers strongly predicted the risk of death, ICU admission and high initial triage priority, especially ProADM. It is a possibility that these methods may get introduced in clinical practice in the not so distant future.
Biomarkers are among the best tools in the hand of the clinicians at present. Each and every clinical condition has been tagged with a quantifiable biomarker which helps in faster clinical diagnosis as well as prognostication. Overall this would lead towards better healthcare delivery to the patient. But, the sheer vast numbers and volumes of various biomarkers in the research pipeline points towards a glaring fact. There is no single marker that can give a complete picture of the patient’s clinical condition. There is no ideal biomarker. A scoring system based on multiple markers would give a better picture than a single one. This accuracy always comes at a higher cost, which translates to more expensive healthcare delivery. There is dire requirement for better clinical validation among the various contenders in each disease process A biomarker based evaluation system, though more accurate, may not suit each and every healthcare facility, but needs to be tailored based on the adaptability and cost effectiveness suited to the society it caters to. Given the vast array of biomarker assays, clinicians should keep in mind that these should always be used as tools that compliment your clinical decision making process rather than replacing the process itself.
I would like to acknowledge the role of my wife, Aparna, who has been a pillar of support throughout the writing of this chapter just like she has been throughout our life together. I would also like to acknowledge the support given by my parents, friends as well as colleagues in my department, who made me what I am.
I have no conflict of interest to declare.
ACC | American College of Cardiology |
ACS | Acute Coronary Syndrome |
AST | Aspartate aminotransferase |
BNP | B type natriuretic peptide |
CABG | Coronary Artery Bypass Grafting |
CHF | Congestive Heart Failure |
CNS | Central Nervous System |
COPD | Chronic Obstructive Pulmonary Disease |
CT | Computed Tomography |
ECG | Electrocardiogram |
ED | Emergency Department |
H-FABP | Heart Fatty Acid Binding Protein |
ICU | Intensive Care Unit |
IL | Interleukin |
IMA | Ischemia modified albumin |
LDH | Lactate dehydrogenase |
LVF | Left Ventricular Failure |
MI | Myocardial Infarction |
MR-proADM | Mid-regional Proadrenomedullin |
NACB | National Academy of Clinical Biochemistry |
NGAL | Neutrophil gelatinase-associated lipocalin |
NSTEMI | Non ST Elevation Myocardial Infarction |
NT pro BNP | N-Terminal pro B type natriuretic peptide |
PCI | Percutaneous Coronary Intervention |
POCT | Point of Care Testing |
QC | Quality Control |
STEMI | ST Elevation Myocardial Infarction |
TNF | Tumour Necrosis Factor |
TNF-alpha | Tumour necrosis factor-alpha |
The use of mechanical energy to promote chemical reactions has become a fast-growing area of green chemistry research in the last decade. With the realization of its practical potentials by chemists and researchers in academia and industry, in recent years, the number of published accounts on mechanosynthesis in various research fields is increasing, ranging from inorganic, metal-organic to organic reactions. Mechanochemistry also become widely exploited for synthesis of drug solid forms [1]. The topic of mechanochemistry was the subject of several review articles [2, 3, 4, 5, 6, 7, 8, 9] and books [10, 11]. In this review, the most recent accounts on the mechanochemical organic synthesis are covered.
Multi-step synthesis is applicable to ball milling solid-state conditions, which is documented by the increasing number of one-pot, multi-step reactions. In the initial milling process, compatible second reagents were added, and milling was continued. Among them are one-pot two-step Negishi C▬C cross-coupling which applies different physical forms of zinc to generate organozinc reagent which was coupled with aryl halide and palladium catalyst in the second milling step. This reaction was also carried out as one-pot one-step reaction [12]. Further examples are one-pot two-step synthesis of thioureas from amines employing thiocarbamoyl benzotriazoles [13], one-pot two-step synthesis of pyrazolones [14], two-step synthesis of paracetamol and procainamide [15], and three-step, two-pot Gabriel synthesis of amines [16]. For illustration, reductive cyclization of fullerene was carried out by three consecutive ball milling reactions (Figure 1) [17]. This solvent-free Michael reaction of fullerene anion to enones (chalkones) was carried out in a two-step, one-pot procedure, starting by zinc reduction of fullerene to carbanion, with water additive used to protonate generated carbanions. The mechanochemical conditions led to the formation of C60-substituted cyclopentanol
Reductive cyclization of C60 with enones by three-step milling.
One-pot, three-step synthesis of pyrroles from amines, alkyne esters, and chalkones saves time and increases the practicality of synthesis (Figure 2) [18]. The first step is reaction of amines with alkyne esters which affords β-enaminoesters
Three-step synthesis of substituted pyrroles.
Some novel variants and reagents were recently applied for reactions which were previously carried out in ball mill such as the formation of peptide bond and imines; Michael, Mannich, and Wittig reactions; porphyrin metalation; halogenations; and various multicomponent reactions. For instance, amide bond formation by one-pot two-step procedure, followed by polymerization in mill [19], application of PhI(OAc)2 cross dehydrogenative coupling for the amidation of aldehydes via C▬H activation [20], formation of phosphinecarboxamides [21], Rh catalyzed amidation [22] or via Ritter reaction [23] and amination to prepare sulfonamides employing Ir catalyst [24] were reported. In addition, a mechanistic study for amide bond formation is published [25].
Some of the traditional transition metal catalysts used in solution reactions can be replaced with elementary metals as catalysts under mechanochemical conditions. For this purpose, different materials for balls and milling vessels were used by Mack, including silver, copper [26], and nickel, even aluminum jars and balls for amorphization [27] and silicon nitride for Scholl reaction [28]. An exemplary reaction is cyclopropenation of alkynes with diazoacetates carried out in ball mill using various materials for vial and balls. Silver foil was found to be a recyclable metal catalyst which does not loose activity and diastereoselectivity after several reaction cycles [29]. The optimal results of [2+1] cycloadditions for internal alkynes were achieved with stainless steel vials and balls, with the addition of silver foil (Figure 3), whereas copper foil showed much better performance in cyclopropanations of terminal alkynes [30]. Silver foil in conjunction with PdCl2(PPh3)2 catalyst was also employed as the effective co-catalyst for mechanochemical Sonogashira coupling of aliphatic alkynes with aryl iodides.
Cyclopropenation of alkenes and alkynes with diazoacetates.
On the other hand, catalysis of [2+2+2+2] cycloaddition of alkynes to cyclooctatetraenes (Figure 4) with Nickel foil was ineffective (SS vial/ball) and with Tungsten carbide balls was moderate, whereas with nickel powder (SS vial/ball), it was moderately active, and pellets were used to obtain high conversion. Nickel vial in combination with nickel balls provided low conversion [31]. Nickel powder generated in situ is responsible for the catalytic activity and, by using the neodymium magnet to separate nickel pellets from crude reaction mixture, makes the catalyst recyclable.
Nickel-catalyzed [2+2+2+2] cycloaddition of alkynes.
Metal catalyst additives such as Pd foil, Cr, and Ni powder showed the activity in alkyne hydrogenation using water as hydrogen source. Efficient mechanochemical hydrogenation method employs SUS304 stainless steel which contains zero-valent Cr and Ni constituents for balls and vial [32]. Alkene and alkyne bonds and nitro, azido, and keto groups were reduced in 62–100% yield by in situ hydrogen generation (Figure 5). Furthermore with SUS304 steel vials as catalyst, alkanes and Et2O were used as hydrogen sources for hydrogenation of aromatic compounds, alkenes, alkynes, and ketones [33].
Nickel-catalyzed hydrogenation reactions.
Novel mechanochemical C▬C bond forming reactions include Friedel-Crafts acylation [34] and alkylation which was also employed in polymer synthesis [35]. Porphyrin synthesis in which mechanochemical procedure was reported earlier was extended to bulkier aromatics [36] and the solventless metalation of porphyrins [37, 38].
Mack has shown that different products could be obtained in enolate addition reactions, when solution procedure was replaced by solvent-free conditions (Figure 6) [39]. Whereas in solution 3-hydroxy-1,3-diphenylbutan-1-one and dypnone were formed by base-catalyzed aldol condensation of acetophenone, in ball mill 1,5-pentadione
Aldol condensation of acetophenone.
Dehydrogenative C▬H/C▬H arylation of oximes and anilides as directing groups was carried out by Xu (Figure 7) [40]. The mechanochemical process is fast (1 h, 6 × (10 min + 1 min break)) and mild, with less amount of arenes, and highly para-selective. A variety of functional groups could be tolerated in LAG (DMF) conditions with TfOH as an additive in conjunction with Pd catalyst and oxidant. Optimal reaction conditions were also applied to olefinic C▬H arylation with simple arenes. Kinetic isotope effects of experiments using deuterated substrates showed KIE data which are consistent with those reported in the similar transformation using arenes as solvents. Slightly different mechanochemical conditions were employed by Su in oxidative C▬H dehydrogenative homocoupling of
Dehydrogenative C▬H/C▬H arylation.
The synthesis of benzo[b]furans by electrophilic cyclization of 2-alkynylanisoles
Synthesis of benzo[b]furans by electrophilic cyclization.
C▬N bond forming reactions were paid larger attention to. Mechanochemical nitration reactions of aromatics are extended to various reagents: NaNO3 in conjunction with MoO3 as an additive [43], BiNO3 with MgSO4 [44], as well as BiNO3 alone was applied for nitration of fullerene C60 [45]. Amine guanylation with
Demethylation of alkaloid
Strecker reaction of benzaldehyde with benzylamine and KCN in simple reaction conditions using unusual material (stones as ball bearings) provided a mixture of α-aminonitrile
Strecker reaction.
Palladium-catalyzed Buchwald-Hartwig amination of aryl chlorides in ball mill has provided moderate to high yields of diarylamine products
Buchwald-Hartwig amination.
Efficient spiroimidazoline synthesis by the reaction of 2-substituted 1H-indene-1,3-(2H)-diones
Synthesis of spiroimidazolines.
Another user and environmentally friendly protocol than isocyanide synthesis via Ugi reaction was the development of solid-state Hofmann reaction (synthesis of isocyanides from amines) (Figure 13) [55]. The implementation of the reaction in mechanochemical conditions significantly reduces the amounts of chloroform, from bulk solvent to 2.1 equivalents. Milling in two 15-minute steps, where chloroform was added each time, afforded better yields than one 30-min milling with all chloroform added at once. The addition of NBu3 was beneficial for sterically more hindered substrates.
Hofmann reaction of amines with chloroform.
Enzymes can tolerate ball milling conditions, and enzymatic reactions were successfully carried out for several transformations: esterification of primary alcohols [56], peptide bond formation [57], ester hydrolysis [58], and cleavage of cellulose [59]. An enzymatic kinetic resolution of racemic secondary alcohols
Acylative kinetic resolution of secondary alcohols.
Similar methodology was applied by Juaristi for the mechanoenzymatic resolution of racemic chiral amines. CALB was applied in the combination of isopropyl acetate as acylating agent and dioxane additive (in agate jars), and amide products were obtained with excellent enantiopurity (ee 66–>99%). Enantiopure chiral amines were used in the synthesis of (
Besides hydrogenation reaction facilitated in SUS304 ss and Strecker reaction, gaseous reagents were also in situ generated in transfer hydrogenation of carbonyls with polymethylhydrosiloxane as hydrogen source [62], reduction of NO2 group by catalytic transfer hydrogenation employing Pd and ammonium formate [15], and synthesis of thioureas by generation of ammonia from NH4Cl and Na2CO3 [13].
Among the reactions for the formation of other types of bonds which were not previously carried in ball milling conditions are C▬P bond by phosphonylation with MnOAc [63], O▬P phosphate nucleoside bond using CDI [64], S▬P bond via Arbuzov reaction [65], C▬B bond by borylation using Ir catalyst [66], and P▬S and P▬Se bond formation by milling of phosphines with S and Se [67].
A recent example of mechanochemical enantioselective reactions is the fluorination of aliphatic cyclic and acyclic β-keto esters using
Enantioselective fluorination of β-keto esters.
The epimerization of (3R,6′R,3′R)-lutein to 3′-epilutein was successfully carried out in a stainless steel jar MET-A (composition 84.5% Fe, 13% Cr) in conjunction with acidic cation-exchange resin [69]. This transformation was accompanied with the formation of anhydrolutein, and the best
Some cycloaddition reactions were carried out in ball mill for the first time. A mechanistic study of Diels-Alder reactions of selected anthracenes by Arrhenius kinetics was reported by Andersen and Mack [70]. The array of 1,3-dipolar cycloaddition reactions is recently extended with nitrones [71] and nitrile oxides [72].
Among the recent examples of oxidation/reduction reactions are Cannizzaro disproportionation of furfural [73] and benzylic oxidation of lignin by oxone and TEMPO [74]. Nitro group was reduced by Ni2B-NaBH4 system [75] and by AuNPs-catalyzed reaction with cyclodextrins as additives [76].
Ionic liquids as novel promoter/additive which could be regenerated were employed for the synthesis of imines [77] and in multicomponent synthesis of 4
Solvent-free mechanochemical conditions were also used in synthesis of reactive species. Synthesis of naphthalenediimide radical ions was achieved by milling of naphthalenediimides with trialkyl and triarylphosphines and Et3N base [79]. The ArSN reaction provides bistrialkyl(aryl)phosphonium naphthalenediimide radical anions which were isolated, and automated ball milling procedure was superior to manual grinding and sonication conditions. The formation of free radicals was also obtained from glucose-based polysaccharides [80].
Several examples of advantageous application of mechanochemistry in supramolecular chemistry are given in recent literature. The encapsulation of fullerene C60 in mechanochemical conditions was extended from γ-cyclodextrin, cucurbit [15], uril and sulfocalix [16], arene hosts to molecular cages [81]. Other molecular guests were encapsulated by ball milling in calixarene (fluorene) [82], cyclodextrins (steroids) [83], as well as daidzein and genistein [84]. Synthesis of metal-organic framework in the presence of guest was used for the entrapment of boron dipyrromethene dyes in MOF. This complex could not be obtained by direct milling of MOF with BODIPY dyes [85]. Furthermore, the size of mechanochemically prepared hemicucurbituril macrocycles was effectively controlled by anion templating [86]. Pseudorotaxanes which were prepared in solution were transformed into diamide rotaxanes [2] by solvent-free reaction of amine and acyl chloride terminus forming amide stoppers [87]. On the other hand, for the synthesis of rotaxanes [2], a one-pot, two-step mechanochemical protocol was used. It involves the preparation of pseudorotaxane and stoppering by 1,3-dipolar alkyne-azide cycloaddition in the second step.
While the photochemical activation of molecules in solution is a well-known phenomenon, its integration with milling mechanochemistry has largely remained unexplored. The first step in this direction was made by MacGillivray who described the photochemical [2+2] dimerization of 4,4′-di(pyridyl)ethylene molecules, pre-assembled in a cocrystal by template-directed solid-state cocrystallization, into a cyclobutane product [88]. The milling, achieved by shaking a glass vial in a vortex machine, was required for the cocrystallization step, while the broadband UV lamp from a laboratory photoreactor was used to affect the dimerization in the solid state. This approach, named “vortex grinding,” requires the vortex shaker to be placed inside the photoreactor chamber and is not compatible with standard milling equipment. Recently, visible light photoredox catalysis has grown into an exciting and very productive research field, but the challenge of combining it with solid-state milling remained. Further investigations by König showed that solvent-free visible light-induced photocatalytic reactions could be realized in thin liquid films by means of a rod mill, consisting of a test tube containing the reaction mixture and a glass rod attached to a stirrer [89] or by a “rotating film reactor” where a glass vial is rotated at 1200 rpm to form a film exposed to blue light [90]. In this way, alcohol oxidations using riboflavin tetraacetate photocatalyst and coupling of aryl halides with pyrroles and phosphites in the presence of rhodamine 6G were accomplished (Figure 16a).
(a) Rod mill and rotating film reactors for solvent-free photocatalysis. (b) MASSPC reactor for simultaneous ball milling and LED irradiation. (c) A multiposition jar adapter for planetary ball milling and the lunar motion of vials in the adapter. (d) Resonant acoustic mixing device and the effect of acceleration on the cocrystallization of carbamazepine and nicotinamide.
In 2017, our group reported on the first successful implementation of mechanochemical ball milling in a commercial shaker mill with visible light photocatalysis, named the “mechanochemically-assisted solid-state photocatalysis” or “MASSPC” [91]. The major obstacle in employing photochemical activation in mechanochemical reactions is the nontransparency of milling jars typically made of stainless steel, tungsten carbide, or Teflon. To overcome this issue, custom-made Duran glass jars completely translucent to visible light were designed. Plastic jars made of polymethylmethacrylate (PMMA), extensively used in real-time in situ monitoring of mechanochemical reactions [92], were found to be inadequate for this purpose due to the insufficient transparency caused by the wear of the plastic material during milling. In parallel, a photochemical reactor that would enable simultaneous high-speed vibrational milling and irradiation of the milled sample was constructed. While the initial experiments with LED strips wrapped around the glass jars showed promise as the simplest solution, prolonged exposure to high-frequency vibrations led to breakage of the strip, and this approach was eventually abandoned. Instead, an LED reactor that would fit around the oscillating glass jar was devised and successfully used in the aerobic thiophenol-promoted photocatalytic oxidation of diphenylacetylene to a diketone benzil (Figure 16b).
The obtained results suggested that singlet oxygen (1O2) was involved in the transformation of an alkyne into the diketone product, while the gas chromatographic analysis allowed reaction quantification and the detection of intermediate isomeric vinyl sulfides as the photoactive species that react with singlet oxygen. The formation of 1O2 under these conditions was also demonstrated by the MASSPC approach by synthesizing anthracene-9,10-
One practical limitation of using conventional ball mills for synthetic purposes is their low throughput, i.e., the inability to process more than a few samples simultaneously. To address this problem, Cravotto and Colacino resorted to modification of a standard jar for planetary ball milling by transforming it to a multiposition jar adapter capable of processing up to 12 samples at the same time [94]. The adapter can be made in different sizes to accommodate 4 vials of 100 mL, 8 vials of 20 mL, or 12 vials of 2 mL volume. In the case of a planetary ball mill equipped with four milling stations, this technical modification enables fast screening and optimization for up to 48 different reaction conditions. Besides high-throughput operation mode and time- and cost-effectiveness, “mechanochemical parallel synthesis” (1)avoids cleaning and cross contamination as the reaction mixtures can be stored or analyzed directly in the vial, (2) it allows reactions on a milligram scale (ca. 10 mg), (3) aluminum adapters serve as heat sinks and prevent reaction mixtures from overheating, and (4) the vials can be periodically loaded/unloaded to enable processing a large number of samples. Vials loaded into a multiposition adapter/jar experience the so-called
The development of mechanochemical parallel synthesis was successfully employed in the synthesis of a library of 3,4-dihydro-2H-benzo[e][1, 3] oxazines by a one-pot three-component reaction between a phenol, a paraformaldehyde, and a primary amine. More than 60 experiments per week were performed, as opposed to expected 6–8 weeks required for the same output using conventional milling. A typical experiment in a 2 mL vial was done on 0.53 mmol scale using 60 stainless steel balls (1 mm diameter), while 20 mL vials were charged with 3.19 mmol of a phenol/amine along with 60 glass beads (3 mm diameter). The reaction mixtures were milled at 550 rpm for 4 h affording yields comparable to solution synthesis.
The traditional paradigm of mechanochemistry is the use of milling balls to introduce mechanical and thermal energy into a system through mechanisms such as impact, shear, or their combination, depending on the milling mode. The number, mass, size, or material the balls are made of, as well as their relation to the volume of a milling jar, are all important variables in determining the outcome of a mechanochemical ball milling reaction. However, in a technique called the “resonant acoustic mixing” or RAM, solid-state reactions can be performed in the absence of milling bodies [95]. Unlike conventional ball milling, where the introduced energy causes physical damage to particles, generates defects, and often leads to aggregation of particulates, compaction, the so-called “snow balling,” or even complete amorphization, RAM is a much softer technique for mixing solids with minimal damage to particles. It is therefore particularly convenient in cases where mixing of impact-sensitive materials such as explosives and propellants is required. In a resonant acoustic mixer device, effective mixing is accomplished by transferring the mechanical energy of a vibrating plate connected to a bed of springs to a sample container placed on top of the plate. The plate and the container are set into an oscillating motion at a fixed resonance frequency, resulting in local zones of intense mixing (Figure 16d). Since the frequency of plate vibration is fixed (ca. 61 Hz), the intensity of mixing is simply adjusted by changing the amplitude of the oscillation; hence the acceleration or the “G-force” exerted on a powder sample in the container can be controlled.
In 2018, Michalchuk and Boldyreva reported the first in situ study of a RAM-induced cocrystallization of nicotinamide (
Since the introduction of real-time in situ techniques for monitoring mechanochemical reactions [92], based on synchrotron PXRD, Raman spectroscopy, and their combination, mechanistic details for a number of organic transformations, metal-organic framework (MOF) systems, and solid-state cocrystallizations have been studied and revealed [96]. These in situ studies also allow for kinetic considerations of solid-state milling reactions under LAG conditions [97], as well as investigations of the effect of milling parameters such as frequency [98], number of milling balls [99], or the ball to reactant ratio on the course of mechanochemical reactions [100]. On a technical side, such investigations go hand in hand with the development of equipment necessary to conduct them. In this respect, accessories such as milling jars for in situ studies deserve special attention. Filinchuk et al. have employed a 3D printer as a low-cost and rapid way to fabricate several types of plastic jars made of PMMA or polylactic acid (PLA) transparent to X-rays and showed how different geometries and material of the jars can reduce background (due to scattering) and minimize absorption, as well as improve the angular resolution during PXRD measurements [101]. In comparison with standard jars used in most experiments (type 0 and its modification type 1), jars with thinner walls (type 2) and added grooves (type 3) or physically separated X-ray probing area in the “two-chamber” jar (type 4) displayed significantly lower background and absorption (Figure 17a). In designs 3 and 4, the size of the groove or the opening between the two chambers is smaller than the ball size, which eliminates the problem of X-ray scattering on milling balls and detection of the corresponding diffraction peaks. The sampling efficiency of 3D-printed jars was tested on the solvent-free mechanochemical PbO polymorph interconversion from β-PbO to α-PbO phase, as a suitable model system. The results showed that the jar design generally affects the rate of β-PbO to α-PbO conversion, with the lowest rate expectedly recorded in the type 4 “two-chamber” jar where the analyzed sample resides in the bottom chamber, while ball milling and intensive mixing take place in the upper chamber. The authors also noted that types 3 and 4 jars are not compatible with liquid-assisted grinding since wet powder materials would probably stick and aggregate in the groove or in the chamber corners.
(a) Different types of 3D-printed plastic jars. (b) Casati’s design of a probing jar and a dual motion ball mill. (c) Twin-screw extruder and its components.
Besides improving the design of milling jars, the development of instrumentation for mechanistic studies is essential, as exemplified by Casati’s design of a new type of in situ ball mill intended for real-time probing of reactions in solids [102]. The new setup, characterized by a dual motion during milling in the form of vertical shaking (up to 50–80 Hz) and continuous slow rotation of the jar, is capable of collecting PXRD data with significantly reduced background and sharper Bragg reflections, which becomes important if high-resolution measurements are desired. Such a design also prevented the aggregation of powder material in the grooves, often encountered in devices where the only motion is shaking insufficient to push the powder out of the groove. In combination with the new design of a two-part milling chamber surrounded by a continuous probing ring where the milling balls cannot enter, it provides opportunities for collecting better resolved PXRD data, reaction monitoring, phase quantification, and line profile analysis (Figure 17b).
An interesting recent contribution to real-time in situ monitoring of organic transformations is the detection of a cocrystal between barbituric acid and vanillin that precedes the formation of C〓C bond in the final Knoevenagel product [103]. The reactant molecules in the cocrystal are positioned to allow nucleophilic attack of the methylene group in barbituric acid to the carbonyl group in vanillin. LAG using ethanol accelerated the reaction, while acetonitrile or nitromethane prolonged the life span of the cocrystal, the structure of which was elucidated from the laboratory PXRD data. Using
Since mechanochemical synthesis in ball mills is inherently associated with thermal effects accompanying the mechanical activation through impact or shear, a complete understanding of milling processes on a microscopic level must also take into consideration the corresponding evolution of heat. The Emmerling group described a combined in situ study of the Knoevenagel reaction between
One of the main drawbacks of mechanochemical synthesis is the lack of ability to perform milling reactions on large scales and in a continuous fashion. Industrial ball mills, which are typically used on these scales, can process tons of materials, whereas for laboratory use, planetary ball mills can deliver products up to several hundred grams. Currently, the most efficient way to increase the product output of mechanochemical reactions is the twin-screw extrusion (TSE), which has been successfully demonstrated in the large-scale solvent-free production of MOFs, cocrystals, and deep eutectic solvents, in space time yields (kg m−3 day−1) three to four times greater than the corresponding solution methods. In a typical TSE design, powdered reactants are fed into the instrument at a certain rate and conveyed by a pair of co- or counter-rotating screws encased in the extruder barrel. As the material moves along the barrel, mixing and kneading elements incorporated into the TSE design exert shearing and compression forces on the reactants, resulting in the product phase which is collected at the exit port (Figure 17c). Besides the screw speed and feed rate, the extruder barrel temperature is another processing parameter that can be modified [106].
James et al. have shown that organic molecules can be synthesized continuously on a large scale using TSE technique under solvent-free conditions. Four condensation reactions (the Knoevenagel reaction, the imine formation, the aldol reaction, and the Michael addition) were optimized by changing the screw speed, feed rate, and temperature, to provide a quantitative conversion to desired products. High-space time yields of >250,000 kg m−3 day−1 for the vanillin-barbituric acid reaction, 14,900 kg m−3 day−1 for the imine product, 35,000 kg m−3 day−1 for the Michael product, and 32,000 kg m−3 day−1 in the case of the aldol product were achieved [106]. TSE was also applied in the large-scale synthesis of 2,2-difluoro-1,3-diphenylpropane-1,3-dione in the presence of Selectfluor as the fluorine source, with the space time yield of 3395 m−3 day−1 vs. only 29 m−3 day−1 obtained in the mixer mill [107]. The three-component solvent-free Biginelli reaction was successfully carried out using TSE, to afford 3,4-dihydropyrimidin-2-(1H)-ones/thiones in optimized yields of 85–91% [108].
A short review of recent literature dealing with organic mechanochemical synthesis is presented.
The authors acknowledge funding by the Croatian Science Foundation grant No. IP-2018-01-3298, cycloaddition strategies towards polycyclic guanidines (CycloGu).
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But the blood-flow measurement inside the heart is difficult. There are many reasons behind it. The deep range and fast blood-flow are difficult to measure because of limitation of acoustic velocity. Moreover, strong heart valve signals mix into the blood-flow signal. Against such difficulties, the statistics mathematical model was applied to analyze many clinical data sets. The system identification method based on the mathematical model could realize a new blood-flow measurement system that has ultrasound Doppler information as input and electrocardiogram as output.",book:{id:"4655",slug:"applications-of-digital-signal-processing-through-practical-approach",title:"Applications of Digital Signal Processing through Practical Approach",fullTitle:"Applications of Digital Signal Processing through Practical Approach"},signatures:"Baba Tatsuro",authors:[{id:"65121",title:"Dr.",name:"Baba",middleName:null,surname:"Tatsuro",slug:"baba-tatsuro",fullName:"Baba Tatsuro"}]},{id:"24302",title:"Multiple-Membership Communities Detection and Its Applications for Mobile Networks",slug:"multiple-membership-communities-detection-and-its-applications-for-mobile-networks",totalDownloads:4106,totalCrossrefCites:4,totalDimensionsCites:4,abstract:null,book:{id:"599",slug:"applications-of-digital-signal-processing",title:"Applications of Digital Signal Processing",fullTitle:"Applications of Digital Signal Processing"},signatures:"Nikolai Nefedov",authors:[{id:"66756",title:"Dr.",name:"Nikolai",middleName:null,surname:"Nefedov",slug:"nikolai-nefedov",fullName:"Nikolai Nefedov"}]},{id:"49358",title:"Optical Signal Processing for High-Order Quadrature- Amplitude Modulation Formats",slug:"optical-signal-processing-for-high-order-quadrature-amplitude-modulation-formats",totalDownloads:2012,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"In this book chapter, optical signal processing technology, including optical wavelength conversion, wavelength exchange and wavelength multicasting, for phase-noise-sensitive high-order quadrature-amplitude modulation (QAM) signals will be discussed. Due to the susceptibility of high-order QAM signals against phase noise, it is imperative to avoid the phase noise in the optical signal processing subsystems. To design high-performance optical signal processing subsystems, both linear and nonlinear phase noise and distortions are the main concerns in the system design. We will first investigate the effective monitoring approach to optimize the performance of wavelength conversion for avoiding undesired nonlinear phase noise and distortions, and then propose coherent pumping scheme to eliminate the linear phase noise from local pumps in order to realize pump-phase-noise-free wavelength conversion, wavelength exchange and multicasting for high-order QAM signals. 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He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"94311",title:"Prof.",name:"Martins",middleName:"Ochubiojo",surname:"Ochubiojo Emeje",slug:"martins-ochubiojo-emeje",fullName:"Martins Ochubiojo Emeje",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94311/images/system/94311.jpeg",biography:"Martins Emeje obtained a BPharm with distinction from Ahmadu Bello University, Nigeria, and an MPharm and Ph.D. from the University of Nigeria (UNN), where he received the best Ph.D. award and was enlisted as UNN’s “Face of Research.” He established the first nanomedicine center in Nigeria and was the pioneer head of the intellectual property and technology transfer as well as the technology innovation and support center. Prof. Emeje’s several international fellowships include the prestigious Raman fellowship. He has published more than 150 articles and patents. He is also the head of R&D at NIPRD and holds a visiting professor position at Nnamdi Azikiwe University, Nigeria. He has a postgraduate certificate in Project Management from Walden University, Minnesota, as well as a professional teaching certificate and a World Bank certification in Public Procurement. Prof. Emeje was a national chairman of academic pharmacists in Nigeria and the 2021 winner of the May & Baker Nigeria Plc–sponsored prize for professional service in research and innovation.",institutionString:"National Institute for Pharmaceutical Research and Development",institution:{name:"National Institute for Pharmaceutical Research and Development",country:{name:"Nigeria"}}},{id:"436430",title:"Associate Prof.",name:"Mesut",middleName:null,surname:"Işık",slug:"mesut-isik",fullName:"Mesut Işık",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/436430/images/19686_n.jpg",biography:null,institutionString:null,institution:{name:"Bilecik University",country:{name:"Turkey"}}},{id:"268659",title:"Ms.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/268659/images/8143_n.jpg",biography:"Dr. Zhan received his undergraduate and graduate training in the fields of preventive medicine and epidemiology and statistics at the West China University of Medical Sciences in China during 1989 to 1999. 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. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. 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. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a scientist and Principal Investigator at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering the lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via artificial intelligence-based analyses of exosomal Raman signatures. Dr. Paul also works on spatial multiplex immunofluorescence-based tissue mapping to understand the immune repertoire in lung cancer. Dr. Paul has published in more than sixty-five peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award and the 2022 AAISCR-R Vijayalaxmi Award for Innovative Cancer Research. He is a senior member of the Institute of Electrical and Electronics Engineers (IEEE) and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. 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. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. 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. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. 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. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",slug:"md.-faheem-haider",fullName:"Md. Faheem Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329248/images/system/329248.jpg",biography:"Dr. Md. Faheem Haider completed his BPharm in 2012 at Integral University, Lucknow, India. In 2014, he completed his MPharm with specialization in Pharmaceutics at Babasaheb Bhimrao Ambedkar University, Lucknow, India. He received his Ph.D. degree from Jamia Hamdard University, New Delhi, India, in 2018. He was selected for the GPAT six times and his best All India Rank was 34. Currently, he is an assistant professor at Integral University. Previously he was an assistant professor at IIMT University, Meerut, India. 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. His area of research is the pharmacological screening of herbal drugs/natural products in liver cancer and cardiac diseases. He is a member of many professional bodies and has guided many MPharm and PharmD research projects. Dr. Siddiqui has many national and international publications and one German patent to his credit.",institutionString:"Integral University",institution:null}]}},subseries:{item:{id:"2",type:"subseries",title:"Prosthodontics and Implant Dentistry",keywords:"Osseointegration, Hard Tissue, Peri-implant Soft Tissue, Restorative Materials, Prosthesis Design, Prosthesis, Patient Satisfaction, Rehabilitation",scope:"