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\\n\\nLaunching 2021
\\n\\nArtificial Intelligence, ISSN 2633-1403
\\n\\nVeterinary Medicine and Science, ISSN 2632-0517
\\n\\nBiochemistry, ISSN 2632-0983
\\n\\nBiomedical Engineering, ISSN 2631-5343
\\n\\nInfectious Diseases, ISSN 2631-6188
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\\n\\nDentistry (Coming Soon)
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\\n\\nNote: Edited in October 2021
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\n\nDesigned to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
\n\nAfter a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
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\n\nIntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
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\n\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\n\nNote: Edited in October 2021
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The purpose of a thin film is to provide distinct optical, electronic, magnetic, chemical, mechanical, and thermal properties that bulk solid materials do not possess. Depending on the materials used and the desired properties, thin films can be fabricated by various deposition processes. These include physical methods (e.g. sputtering, E-beam evaporation, pulsed laser deposition, cathodic arc deposition, molecular beam epitaxy, and evaporation), and chemical methods (e.g. chemical vapor deposition, sol-gel, spray pyrolysis, atomic layer deposition, and electroplating). Thin films are widely used for many industrial applications, including as optical coatings (antireflective, and self-cleaning coatings) for lenses, windows, and optoelectronic devices; for energy generation (e.g. thin-film photovoltaics) and storage (thin-film batteries and supercapacitors); in gas- and bio-sensors; in electronic semiconductor devices (e.g. transistors); as hard coatings on cutting tools, modules and dies; as decorative coatings; and as bio-compatible coatings for medical implants and thin-film drug delivery. The prevalence of thin films across so many fields of research leads to a rapidly evolving technology where many impactful strides to optimize deposition processes and realize novel applications have been made recently.
\r\n\r\n\tThis book intends to provide a comprehensive overview of the fundamentals, challenges, and trends in thin-film technologies, the recent advances in thin film deposition techniques, as well as the characterization and applications of thin films.
",isbn:"978-1-80356-456-2",printIsbn:"978-1-80356-455-5",pdfIsbn:"978-1-80356-457-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,hash:"9c10a55203c2f0f7d47c743e6cfa2492",bookSignature:"Dr. Dongfang Yang",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11484.jpg",keywords:"Thin-Film Photovoltaics, Thin-Film Batteries, Plasmonic Devices, Semiconductors, Organic Electronics, Superconductor Oxide Films, Growth Mechanisms, Epitaxy, Uniformity, Grain Size, Sputtering, Pulsed Laser Deposition",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 2nd 2022",dateEndSecondStepPublish:"March 30th 2022",dateEndThirdStepPublish:"May 29th 2022",dateEndFourthStepPublish:"August 17th 2022",dateEndFifthStepPublish:"October 16th 2022",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr. Yang is a distinguished senior researcher and expert in laser materials processing, pulsed laser, and e-beam deposition of thin films. Previously affiliated with the University of Ottawa, University of Brunswick, and the University of Guelph, where he was awarded his Ph.D. degree in 1995. Dr. Yang was awarded the title of World's Top 2% Scientists by Stanford University and IAAM Scientist Award and Medal in 2021.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"177814",title:"Dr.",name:"Dongfang",middleName:null,surname:"Yang",slug:"dongfang-yang",fullName:"Dongfang Yang",profilePictureURL:"https://mts.intechopen.com/storage/users/177814/images/system/177814.jpg",biography:"Dongfang Yang received his Ph.D. in Physical Chemistry from the University of Guelph in 1995. He joined the National Research Council Canada in London Ontario in 2001 and is now a Senior Research Officer. His current research interests include laser materials processing; pulsed laser, sputtering and e-beam deposition of thin films; new materials development for energy storage devices; chemical and optical sensors development; and electrochemical studies of organic adsorption and self-assembly monolayer. He is currently serving as an editor or editorial board member for ten scientific journals and was listed among the top 2% most-cited scientists according to a Stanford study in 2020. He also holds an adjunct professorship at Western University, Ontario, Canada.",institutionString:"National Research Council Canada",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"4",institution:{name:"National Research Council Canada",institutionURL:null,country:{name:"Canada"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"14",title:"Materials Science",slug:"materials-science"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"444315",firstName:"Karla",lastName:"Skuliber",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/444315/images/20013_n.jpg",email:"karla@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6426",title:"Titanium Dioxide",subtitle:"Material for a Sustainable Environment",isOpenForSubmission:!1,hash:"5626c0fe0b53330717e73094946cfd86",slug:"titanium-dioxide-material-for-a-sustainable-environment",bookSignature:"Dongfang Yang",coverURL:"https://cdn.intechopen.com/books/images_new/6426.jpg",editedByType:"Edited by",editors:[{id:"177814",title:"Dr.",name:"Dongfang",surname:"Yang",slug:"dongfang-yang",fullName:"Dongfang Yang"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5376",title:"Applications of Laser Ablation",subtitle:"Thin Film Deposition, Nanomaterial Synthesis and Surface Modification",isOpenForSubmission:!1,hash:"7ea5104a7037f15e68fcc05be277fa37",slug:"applications-of-laser-ablation-thin-film-deposition-nanomaterial-synthesis-and-surface-modification",bookSignature:"Dongfang Yang",coverURL:"https://cdn.intechopen.com/books/images_new/5376.jpg",editedByType:"Edited by",editors:[{id:"177814",title:"Dr.",name:"Dongfang",surname:"Yang",slug:"dongfang-yang",fullName:"Dongfang Yang"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5168",title:"Alkali-ion Batteries",subtitle:null,isOpenForSubmission:!1,hash:"2ffb06f3e5dbad9167428c4c443e3a5e",slug:"alkali-ion-batteries",bookSignature:"Dongfang Yang",coverURL:"https://cdn.intechopen.com/books/images_new/5168.jpg",editedByType:"Edited by",editors:[{id:"177814",title:"Dr.",name:"Dongfang",surname:"Yang",slug:"dongfang-yang",fullName:"Dongfang Yang"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10481",title:"Practical Applications of Laser Ablation",subtitle:null,isOpenForSubmission:!1,hash:"e9f235e98a88813c08a9dba80525b195",slug:"practical-applications-of-laser-ablation",bookSignature:"Dongfang Yang",coverURL:"https://cdn.intechopen.com/books/images_new/10481.jpg",editedByType:"Edited by",editors:[{id:"177814",title:"Dr.",name:"Dongfang",surname:"Yang",slug:"dongfang-yang",fullName:"Dongfang Yang"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6320",title:"Advances in Glass Science and Technology",subtitle:null,isOpenForSubmission:!1,hash:"6d0a32a0cf9806bccd04101a8b6e1b95",slug:"advances-in-glass-science-and-technology",bookSignature:"Vincenzo M. Sglavo",coverURL:"https://cdn.intechopen.com/books/images_new/6320.jpg",editedByType:"Edited by",editors:[{id:"17426",title:"Prof.",name:"Vincenzo Maria",surname:"Sglavo",slug:"vincenzo-maria-sglavo",fullName:"Vincenzo Maria Sglavo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6802",title:"Graphene Oxide",subtitle:"Applications and Opportunities",isOpenForSubmission:!1,hash:"075b313e11be74c55a1f66be5dd56b40",slug:"graphene-oxide-applications-and-opportunities",bookSignature:"Ganesh Kamble",coverURL:"https://cdn.intechopen.com/books/images_new/6802.jpg",editedByType:"Edited by",editors:[{id:"236420",title:"Dr.",name:"Ganesh",surname:"Kamble",slug:"ganesh-kamble",fullName:"Ganesh Kamble"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6517",title:"Emerging Solar Energy Materials",subtitle:null,isOpenForSubmission:!1,hash:"186936bb201bb186fb04b095aa39d9b8",slug:"emerging-solar-energy-materials",bookSignature:"Sadia Ameen, M. Shaheer Akhtar and Hyung-Shik Shin",coverURL:"https://cdn.intechopen.com/books/images_new/6517.jpg",editedByType:"Edited by",editors:[{id:"52613",title:"Dr.",name:"Sadia",surname:"Ameen",slug:"sadia-ameen",fullName:"Sadia Ameen"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6188",title:"Solidification",subtitle:null,isOpenForSubmission:!1,hash:"0405c42586170a1def7a4b011c5f2b60",slug:"solidification",bookSignature:"Alicia Esther Ares",coverURL:"https://cdn.intechopen.com/books/images_new/6188.jpg",editedByType:"Edited by",editors:[{id:"91095",title:"Dr.",name:"Alicia Esther",surname:"Ares",slug:"alicia-esther-ares",fullName:"Alicia Esther Ares"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6656",title:"Phase Change Materials and Their Applications",subtitle:null,isOpenForSubmission:!1,hash:"9b257f8386280bdde4633d36124787f2",slug:"phase-change-materials-and-their-applications",bookSignature:"Mohsen Mhadhbi",coverURL:"https://cdn.intechopen.com/books/images_new/6656.jpg",editedByType:"Edited by",editors:[{id:"228366",title:"Dr.",name:"Mohsen",surname:"Mhadhbi",slug:"mohsen-mhadhbi",fullName:"Mohsen Mhadhbi"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6805",title:"Electrical and Electronic Properties of Materials",subtitle:null,isOpenForSubmission:!1,hash:"f6b6930e7ae9d0704f68b5c180526309",slug:"electrical-and-electronic-properties-of-materials",bookSignature:"Md. Kawsar Alam",coverURL:"https://cdn.intechopen.com/books/images_new/6805.jpg",editedByType:"Edited by",editors:[{id:"199691",title:"Dr.",name:"Md. Kawsar",surname:"Alam",slug:"md.-kawsar-alam",fullName:"Md. Kawsar Alam"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"78427",title:"Pathogenicity Mechanism of Candida albicans",doi:"10.5772/intechopen.99737",slug:"pathogenicity-mechanism-of-em-candida-albicans-em-",body:'Candida is a diploid parasite that as often as possible causes mucosal and fundamental contaminations in people [1]. Candida species can colonize a few particular anatomical locales. Greater part of diseases by commensal microorganisms comes from endogenous colonization. Notwithstanding, exogenous pollution, for example, diseases communicated through emergency clinic workers, medical clinic air, and biofilm-debased intrusive gadgets like catheters, can likewise happen [2, 3, 4]. Diseases brought about by Candida can be delegated shallow, cutaneous, mucosal, and fundamental infection. At the point when Candida spp. taint the oral cavity, skin, genitalia, respiratory framework, and the remainder of the gastrointestinal lot, the disease is delegated the shallow sort. Intrusive candidiasis is a disease portrayed with very extreme conditions, for example, candidemia, meningitis (influencing the mind), and endocarditis (influencing the heart) [5]. In hospitalized patients and those with bedraggled safe framework, intrusive contamination is a huge reason for dismalness and mortality along with increased frequency as well as pervasiveness rates.
Candida species pathogenesis is a complex cycle including numerous instruments and pathways. It is likewise a mind boggling and multifactorial system, including highlights of both the host and the microorganism [6]. For contamination to be set up, the pioneering microorganism should avoid, duplicate in the host climate, and make do in the safe arrangement of the host. The living being must likewise have the option to scatter to other body tissues and organs, most particularly in foundational disease [7]. Problem in skin or gastrointestinal boundaries can prompt dispersed or profound organ candidiasis. In more significant circumstances, circulatory system intrusion may some time possible which hence will disperse to various organs of the body.
Candida contaminations in a great many people are asymptomatic. This is because of the capacity of the immunological framework to checkmate the life form as it endeavors to spread in the body. In any case, consumption in resistant systemor changes in microbiota balance, combined with different elements, can work with the spread of Candida which is regularly deadly in 42% of announced cases [8, 9, 10].
As anyone might expect, it is the destructiveness and pathogenic qualities and components that have gotten the most consideration from specialists throughout the long term. As of late, much have been found out about the components of Candida pathogenesis. Studies have shown that at the core of the capacity of Candida to multiply, change from non-destructiveness commensal to pioneering pathogenic organism and build up disease in the host lie profoundly interconnected elements made out of transcriptional circuits, morphology-related/harmfulness encoding qualities, metabolic versatility, genome pliancy, phenotypic exchanging, biofilm arrangement, tissue harming extracellular hydrolytic catalysts, and a few different variables that work with destructiveness and pathogenesis in Candida species [15]. Changes in ecological pH, vigorous supplement procurement framework, escape from phagocytosis, avoidance from have insusceptible framework, have microbiome coaggregation, protection from antifungal specialists, and the capacity to productively react to numerous anxieties are other crucial characteristics that upgrade endurance and pathogenesis.
In order to be capable of inducing such a diversity of infections
The pathogenicity of
S/no. | Pathways | Functions | Reference(s) |
---|---|---|---|
1 | Mitogen-activated protein kinase (MAPK) pathways | Important regulator of morphogenesis. | [22, 23] |
Involved in sensing and transmitting stress signals and other environmental signals | |||
Three main MAP kinase pathways are the following:
| [24]. | ||
2 | Ras-CAMP-PKA pathways | Regulate adhesion, dimorphism. Also involved in the formation of biofilms. | [23, 25, 26] |
Control hyphal formation and white-to-opaque change | [27, 28] | ||
Involved in drug tolerance and in the maintenance of cell wall integrity | |||
3 | RIM 101 signal transduction | Enables | [29] |
4 | Stress response pathways | Contribute to virulence and pathogenesis Facilitate adaptation to ever-changing environmental conditions. Protect against host-derived stresses | [30] |
5 | Ergosterol biosynthetic pathways | Link between hyphae formation and virulence in | [31] |
Enhance cell adhesion and damage to the tissues | [32] | ||
ERG3 and ERG11 play major roles in azole drug resistance; thus, it is the target of fluconazoleantifungals | |||
6 | Genome plasticity | Triggers adaptation to fluctuating host environment. Leads to the generation of recombinant progeny with increased fitness. Induces natural mutations that alter the balance between commensalism and pathogenicity. | [33, 34] |
Facilitates resistance to stressors including antifungal agents and pathogenicity during systemic and mucosal infections | [35] | ||
Triggers polarized filamentous growth Involved in the generation/evolution of new pathotypes or strains Enhances the utilization of several nutrients. Facilitates Candida growth rate, as well as its morphology and behaviors at the host interface | |||
7 | Calcium-calcineurin pathways | Major mediator of stress responses | [36] |
Essential for survival in the presence of stressors | [37] | ||
Play crucial roles in virulence | [38, 39] |
Major pathogenicity inducing pathways/responses in Candida species.
The greater part of the flagging pathways are amazingly fundamental for protecting Candida spp. against immunological assault [40]. They assume different parts in the declaration of morphology related qualities. The co-articulation of morphology-connected proteins brings about synergistic association among quality items fundamental for biofilm foundation and development inside the host [41]. Along these lines, for hindering Candida endurance in have tissues, impedance with Candida species capacity to incorporate quality articulation to changes in morphology could be surely a potential restorative technique [42]. Also, distinguishing flagging segments saved among Candida species is vital for recognizing potential medication targets. During the interaction of pathogenesis, actuated endocytosis happens. It for the most part happens inside 4 h of starting contact to epithelial cell. Candida uses prompted endocytosis to sidestep invulnerable acknowledgment. The acknowledgment of invasins communicated on the contagious cell surface triggers prompted endocytosis. Until this point, only A1s3p and Ssa1p (invasins) are known for
Adhesion to the cellular epithelium.
Colonization.
Penetration to epithelium/hyphal invasion.
Dissemination of vasculature.
Endothelial colonization/penetration.
Systemic candida infection only occurs by immune system escape than vasculature penetration and invading the blood components. Entry to the bloodstream occurs via two routes:
Natural routes.
Artificial routes.
Above subsequent course is worked with biofilm arrangement as pathogens can get away and invade the blood. For Candida to endure and spread in the blood, various qualities are upregulated: qualities engaged with protein amalgamation, glycolytic cycle, glycolysis, and reaction to oxidative pressure. The presence of Candida in the blood prompts a condition called candidemia. From the blood, the yeast is dispersed to different fundamental organs in the body where it causes foundational contaminations. Dispersed candidiasis is profoundly worked with by extracellular hydrolytic compounds, adhesins, phenotypic exchanging, and cytolytic proteins. Candida in the blood can likewise bring about candiduria by antegrade contamination. Albeit most diseases include biofilm arrangement, a few contaminations can happen without the development of biofilm. Indeed, hyphae development and development are the beginning stages in the pathogenicity of Candida species, with the exception of
Notwithstanding, questions actually remain with respect to the instruments controlling its union, the receptors, and its carrier. In outline, the exchanging of Candida spp. from commensal to artful microbe is ascribed to destructiveness factors that are specifically communicated under reasonable inclining conditions. The majority of these destructiveness factors are under close guideline. More examinations in their administrative instruments could be fundamental in the mission for new antifungal specialists. Figure 1 is the significant organization of Candida destructiveness and pathogenesis showing the associations between the different pathogenic determinants and harmful variables.
Simplified diagram illustrating the network of Candida virulence and pathogenicity. (1) planktonic yeast cells attach to surfaces. Favorable conditions facilitate overgrowth; adherence (2): The cells attach to host cells via adhesins; hyphae formation/extension (3): Environmental constrains induce the HSPs, signaling and adaptation pathways which induce morphology-associated genes. The formation of the hyphae marks the beginning of Candida pathogenesis. Epithelial/endothelial adhesion/invasion (4 and 6): This is facilitated by hydrolytic enzymes and it is achieved via two ways: Induced endocytosis and active penetration. Some species such as
Host insusceptible acknowledgment of Candida happens through a few instruments involving intrinsic and versatile insusceptibility. The versatile insusceptible framework perceives explicit antigenic moieties, prompting the advancement of a focused on safe reaction. Interestingly, inborn insusceptible acknowledgment is vague and wide and is the primary line of host protection against possibly hazardous organisms. These vague reactions are promptly endless supply of an organism in a pre-modified design and assume a fundamental part in controlling contagious weights and forestalling infection. Natural invulnerability includes a progression of dissolvable (supplement) and cell (neutrophil, macrophage) parts that act in show to keep by far most of microbes from setting up an intrusive disease. Further, it has become progressively clear that these reactions capacity to enact versatile insusceptibility just as acting along with other homeostatic cycles to give further security. Natural invulnerable acknowledgment of Candida happens through the acknowledgment of microorganism related atomic examples (PAMPs).
PAMPs are themes or particles that are regular between various sorts of growths. In contrast to antigens, individual PAMPs are not explicit to a solitary Candida animal variety but instead are divided among various species and contagious genera. These microbial PAMPs are perceived by have germline encoded design acknowledgment receptors (PRRs) [45] and give a pre-customized method of parasitic acknowledgment, taking into consideration moment acknowledgment of normal contagious parts. Most of contagious PAMPs are cell divider related and incorporate 𝛽-glucans, 𝑁-and 𝑂-connected mannans, and phospholipomannans [46]. These are perceived by three key PRR families: cost like receptors (TLRs), C-type lectin receptors (CLRs), and nucleotide-restricting area leucine-rich receptors (NLRs) [46, 47, 48, 49, 50, 51, 52]. Dendritic cells, monocytes, macrophages, polymorphonuclear leukocytes (PMNs), Tcells, Bcells, and epithelial cells all transmit PRRs on a surface level, in endosomes or in the cytoplasm of host cells. Sanctioning of these PRRs by PAMPs prompts setting off of intracellular hailing pathways, as MAPK (mitogen-started protein kinase) and NF-𝜅B (nuclear factor kappa-light-chain-enhancer of incited B cells) pathways, and finally to further developed record of countless characteristics drew in with have safe protections, including chemokines, cytokines, provocative center individuals, and antimicrobial peptides. Appropriately, PRRs are fundamental center individuals among intrinsic and adaptable safe responses.
While comparing the human genome with murine genome; human genome encodes for ten TLR characteristics (TLR1–10) and murine genome encodes 12 i.e. TLR1 to TLR9 and TLR11 to TLR13. Each TLRs depicted as transmembrane type-1receptors having an enriched lucine extracellularly intermittent region which sees target PAMP and a Toll/interleukin-1 receptor-(TIR-) space containing cytoplasmic region that imparts the institution stimuli, which having closeness to the sort 1 interleukin-1 (IL-1) receptor. TLR family is a developmentally monitored gathering of PRRs that react to an assortment of bacterial, viral, and contagious PAMPs just as some endogenous components delivered when have cells are harmed. The extracellular areas of TLRs perceive an assortment of microbial PAMPs, including lipopolysaccharide (LPS), peptidoglycan, proteins (counting triacylated proteins and flagellin), and changed nucleic acids [53, 54, 55, 56, 57, 58].
Key part for TLRs in host protection against fungal infection was initially identified when Drosophila inadequate in Toll receptor were seen to profoundly helpless to A. fumigatus disease [59]. Therefore by far most of the underlying antifungal insusceptibility research focused on how contagious cells were perceived. This provoked the distinctive verification of a couple of PRRs related with affirmation of different cell divider polysaccharides of parasites and
At last, these investigations finished in the disclosure of another PRR, dectin-1 (dendritic cell associated C-type lectin-1), who perceives parasitic 𝛽-1,3 glucan [61]. Outstandingly, these parasitic PRRs can work both freely and related to each other. For instance, dectin-1 and TLR2 act additionally to perceive contagious yeasts, with dectin-1 prompting phagocytosis while TLR2 initiates cytokine creation [62, 63, 64]. Dectin-1 likewise synergises with TLR4 flagging [64]. Moreover, TLR1 and TLR6 structure heterodimers with TLR2 [65] however do not seem to assume a significant part in
Even so these are standard receptors utilized by macrophages and neutrophils to see
Curiously, galectin-3 coimmunoprecipitates accompanied by dectin-1 [74], which recommends that galectin-3 can work with associations among TLR2 and dectin-1 flagging. TLR acknowledgment of other medicinally significant growths have likewise been concentrated yet are less very much described, despite the fact that apparently TLR3 perceives A. fumigatus conidia and TLR4 perceives
PAMP acknowledgment of TLRs brings about enactment of flagging cascade intracellularly (Figure 2) through connection of the cytoplasmic TIR spaces with various connector proteins: myeloid separation essential reaction quality (88) (MyD88), MyD88-connector like (MAL), TIR-area containing connector initiating interferon-𝛽 (TRIF), and TRIF-related connector atom (TRAM) [53, 54, 55, 56, 57, 58, 76, 77, 78, 79]. This TLR-adapter interaction ends up in the activation of the IRAK ( IL-I receptor associated kinase) proteins and TRAF6 (TNF receptor associated factor-6). As a result it ends up in activation of the main signaling pathways together with NF-𝜅B, MAPK, and IRF (interferon regulative factor) pathways. MAPK activation contains 3 alleyways: p38, JNK (c-Jun N-terminal kinase), and ERKI/2 (extracellular signal-regulated kinaseI/2). Finally, signaling pathway induction ends up in the activation and nuclear localisation of transcription factors as well as NF-𝜅B, AP-I (activating macromolecule I), and IRF-3 and IRF-7. the result of this activation cascade is to induce organic phenomenon and secretion of varied proteins concerned in immune defense as well as cytokines, chemokines, antimicrobial peptides, and alternative inflammatory mediators, all of that operate to stimulate innate and reconciling responses of immune system. It thought to be noted that the overwhelming majority of studies shaping the TLR-mediated pathways are performed victimization myeloid or humor cells, however elaborated analysis of TLR- mediated pathways in alternative cell varieties, and specifically animal tissue cells, could nonetheless establish novel and strange mechanisms of infectious agent (fungal) recognition and management at membrane surfaces.
Signal pathway activation by TLRs and CLRs. TLRs and CLRs activate MAPK and NF-𝜅B signal pathways to varying extents, thereby allowing different innate immune responses to be generated. TLRs utilize TIR-domain containing adapter proteins such as MyD88, mal, TRAM, and TRIF. CLRs signal using ITAM domains within their cytoplasmic region (e.g., dectin-1) or associate with an ITAM-containing transducing protein (e.g., dectin-2 with FcR𝛾). Dectin-1 utilizes Src kinases and Syk kinase to activate a complex containing CARD9, MALT1, and Bcl1o to activate the downstream signal pathways. Figure adapted from [
Although animals missing the TLR signaling adaptor protein MyD88 are vulnerable to fungal infection [46, 80, 81, 82], the exact role of particular TLR receptors in fighting Candida infections is unclear. This is most likely because of contrasts in examination plan, where diverse contagious species, morphotypes, and courses of contamination have been surveyed [52]. Thusly, contemplates utilizing TLR knockout mice have uncovered critical contrasts in the putative jobs of various TLRs in fundamental or mucosal insusceptible reactions against contagious contaminations [83]. For instance, while a few examinations demonstrate that TLR2 and TLR4 impact vulnerability to murine scattered candidiasis [82, 84, 85, 86], not all investigations support this attestation [87, 88]. TLR7 might be needed for parasitic RNA acknowledgment in the autophagosome, which is needed for IFN-𝛽 discharge and is related with delayed
A few examinations have related normal hereditary variations (polymorphisms) in TLR qualities with vulnerability or inclination to foundational candidiasis or constant mucocutaneous candidiasis (CMC). These recollect polymorphisms for TLRI (R80T , N248S , and S602I) [94, 95] and TLR3 (L4I2F) [96, 97]. Polymorphisms in TLR4 (D299G) and TLR2 (D753Q) have moreover been perceived as possible frailty markers for basic candidiasis [98] yet these could not be approved in a greater report [95]. As of now, a large portion of the information accessible recommends a solid part for TLRs in antifungal protection however recognizing explicit jobs for each TLR has been over shadowed by repetitive signs instigated by other PRRs [94].
CLRs (C-type lectin receptors) are a diverse restriction protein family defined by the presence of an extracellular carb acknowledgment space (CRD) or a C-type lectin like area (CTLD) [99]. The job of CLRs in antifungal insusceptibility has been the subject of serious investigation as of late and a few key CLRs have now been shown to show basic capacities in Candida acknowledgment, take-up, and executing and furthermore add to the commencement and additionally tweak of the resistant reaction to organisms [46, 100, 101]. By and by, the key CTLs in Candida affirmation appear, apparently, to be dectin-I, dectin-2, and MR. CLRs signal through incitation of ITAM/ITIM (immunoreceptor tyrosine-based actuation/restraint theme) cytoplasmic areas (Figure 3). This can be done by using their own cytoplasmic area, as dectin-I does, or by using coreceptor cytoplasmic spaces, as DAPI2 (DNAX actuation protein of I2 kDa) and FcR (Fc receptor gamma chain) do, as dectin-2 does. The activation of numerous connections to those activated by TLRs, most notably Src family kinases including Src, Lyn, and Fyn, is triggered when CLRs are ligated. If we talk about dectin-I , it prompts initiation of spleen tyrosine kinase (SYK) and the downstream actuation of the CARD9/BclI0/MALTI (caspase enlistment space family/B cell CLL-lymphoma I0/mucosa related lymphoid tissue lymphoma movement quality I) flagging complex. Independent of the CLR pathways and connectors utilized, a definitive outcome is the enactment of comparative flagging pathways as those initiated by TLRs, overwhelmingly NF-𝜅B and MAPK, that are discussed below point.
Signaling and damage pathways activated by C. albicanshyphae. C. albicanshyphal cells, when in sufficient quantities, are recognized by an unknown PRR mechanism that results in the activation of NF-𝜅B, MAPK, and PI3K pathways. MAPK signaling via p38 and ERK1/2 appears to discriminate between yeast and hyphal cells. Activation of p38 by hyphae leads to activation of the c-Fos transcription factor, which, in conjunction with the p65/p50 NF-𝜅B heterodimers and PI3K/AKT results in upregulation of cytokine and inflammatory mediator expression. Concurrently, activation of ERK1/2 signaling, results in stabilization of the MKP1 phosphatase, which deactivates p38 and JNK, hence acting as part of a negative feedback loop and preventing a potentially deleterious overreaction of theimmune system. Damage induced by hyphae appears to be mediated via JNK activation and prevented via the PI3K/AKT/mTor pathway.
Dectin-I, (also called CLEC7a) is that the main CLR known as taking part in a serious role in fungous recognition by the host system [102] and may be a sort II transmembrane macromolecule that belongs to a subgroup of CLRs referred to as natural killer (NK) receptor-like CLRs. The target ligands of dectin-I are 𝛽-I,3 glucan polymers, that comprise a serious part (∼60%) of fungous cell walls. The intracellular region of dectin-I contains a changed ITAM motif containing one amino acid residue rather than the standard 2 (hence the terms hem-ITAM or hemi- ITAM). Activation of the dectin-I results in phosphorylation of this domain and phosphorylation of SYK and activation of the BclI0- CARD9-MALTI complicated as mentioned on top of. This results in activation of each the canonical and noncanonical NF-𝜅B pathways [103] further as nuclear issue of activated T cells (NFAT) pathway [104]. Dectin-I can even induce signaling via Raf-I in an exceedingly SYK -dependent fashion [103] and is related to phospholipase C and A2 activation [50]. one in all the most important functions of dectin-I binding seems to be the induction of bodily process [105]. However, a singular feature of dectin-I is its ability to be activated or suppressed by its target matter. to completely activate dectin-I, cells got to be exposed to insoluble 𝛽-glucan particles. Notably, exposure of dectin-I to soluble 𝛽-glucan seems to dam activation. This appears to ensue to the apparent form type a vegetative cell conjunction,“whereby phosphatases that usually suppress ITAM motifs are accumulated. This exclusion later permits the phosphorylation of the intracellular hem-ITAM motif [106], thereby sanctioning bodily process. Dectin-I has additionally been shown to synergise with each TLR2 and TLR4, leading to the induction of tumor necrosis factor (TNF), IL-I0, transforming growth factor (TGF) and dendritic cell maturation [107, 108, 109]. In view of the fact that the 𝛽 - I,3 glucan polymers that are the main components of the fungal cell wall, and a strong activation of the immune system, dectin-I plays an important role in inducing antifungal activity of the host. This may also explain why some of the mold surface structure of “the mask” -I.3 glucan from the immune system. For example, Histoplasma capsulatum, masks are 𝛽-I,3 glucan, with a low - 𝛼-I,3 glucan [110] and it seems likely that the
Although some studies have shown that the expression of dectin-I in the epithelial cells of the gastro- intestinal tract [112], and lung [113, 114], in oral epithelial cells express dectin-1 [115, 116]. What’s interesting is that dectin-I expression appears to be reduced in the presence of live
Dectin-2 (otherwise called CLEC6a) is a sort II transmembrane protein however is enacted contrastingly to dectin-I. Dectin-2 comes up short on an intracellular flagging area [128] and requirements to dimerise with FcR𝛾, which has an intracellular flagging space, to send a sign [69]. In myeloid cells and fiery monocytes, dectin-2 perceives high mannose structures that are normal to numerous parasites and ties to hyphae with higher proclivity than to yeast [129, 130]. This may clarify why dectin-2 inadequate mice are helpless to
Dectin-3 (additionally called CLECsf8, MCL, or CLEC4d) was as of late distinguished and seems to shape heterodimers with dectin-2 to perceive 𝛼-mannans on the outside of
DC-SIGN (otherwise called CD209) is another sort II transmembrane receptor that is communicated dominatingly on dendritic cells and macrophages. Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) also known as CD209 (Cluster of Differentiation 209) is a protein which in humans is encoded by the CD209 gene. DC-SIGN is a C-type lectin receptor present on the surface of both macrophages and dendritic cells Nonetheless, the part of DC-SIGN in antifungal invulnerability is muddled [101], in spite of the fact that DC-SIGN seems to perceive high (𝑁-connected) mannose containing glycoproteins and actuate IL-6 creation [71, 136]. Albeit the part of DC-SIGN in the endocytosis and take-up of microbes to advance antigen show is all around recorded [136, 137], its job in phagocytosis is sketchy [71, 136].
The MR (or called CD206) is a prototypical kind I transmembrane protein that is transcendently communicated on macrophage and dendritic cells. MR receptor ties a few starch particles, including extended 𝑁-connected mannans, N-acetylglucosamine, glucose, and fucose [138]. Thus, MR can perceive numerous contagious, bacterial, and viral pathogens. MR needs regular intracellular flagging spaces despite the fact that ligation actually prompts an assortment of cell reactions, including signal pathway acceptance, phagocytosis, advancement of antigen show to T cells, and cytokine discharge [63, 136, 137, 138, 139, 140]. For instance, the MR is enlisted to the phagosome after
NLRs are a group of intracellular PRRs portrayed by leucine rich rehashes and a nucleotide-restricting area that identify PAMPs present in the cell cytoplasm. Like TLRs and CTLs, NLRs perceive microbial items yet they additionally perceive have determined threat signals or alarmins [145]. There are now 23 human NLRs and 34 mouse NLRs identified [146]. Inflammasomes are huge multimeric protein structures framed by NLRs and two distinct proteins, ASC (apoptosis-related spot like protein containing a CARD) and procaspase-I (procysteine-subordinate aspartate-coordinated protease I). The inflammasome’s main function is to convert procaspase-I to dynamic caspase-I, which causes young cells that are friendly to IL-I and supportive of IL- I8 to produce IL-I and IL-I8 [147]. Despite the fact that
Surprisingly, NLRP3 is strongly expressed in nonkeratinizing epithelia, such as the oral cavity and throat [151], suggesting a possible role for NLRP3 in parasitic recognition in oral epithelial cells, which is supported by studies showing increased IL- I and IL- I8 levels in response to
Mincle (also known as CLEC4e or CLECsf9) is a type II transmembrane protein that transmits its signal after dimerizing with the FcR connector protein [128]. Macrophages, monocytes, neutrophils, myeloid dendritic cells, and certain B cell subsets all communicate mincle, while plasmacytoid dendritic cells, T cells, and NK cells do not [133]. Mincle binds -mannans-containing starch structures [143, 163] and detects
The supplement course assumes a significant part in have protection against parasitic microorganisms and is quickly enacted in light of host attack by Candida [168, 169, 170]. Candida actuates each of the three known pathways (old style, elective, and mannose-restricting lectin (MBL)) with nobody clear pathway overwhelming the reaction [171]. Given that the Candida cell surface is covered with a bounty of manno proteins, it is not astonishing that Candida microorganisms are viable at actuating the MBL pathway, which seems significant for opsonisation, phagocytosis, and other supplement capacities [172, 173]. The connection between enacted C3b and the supplement receptor CR3 is generally needed for the uptake of Candida cells by phagocytes [174].
Neutrophils are a key effector cell in intrinsic insusceptibility, and they play a dual role in antifungal responses. First, they phagocytose and destroy contaminated Candida cells (below), and then, via cross communication with epithelial cells, they indirectly assist in mucosal protection (tended to above). TLRs and CTLs help neutrophils phagocytose nonopsonized Candida, while CR3 and the Fc receptor (FcR) help them phagocytose opsonized Candida [193]. Once phagocytosed, Candida is killed both inside and outside the cell through oxidative and nitrosative mechanisms, but fungicidal movement varies across Candida species [194, 195]. Preformed cytoplasmic granules interweave with the phagosome intracellularly, although unlike macrophages, no substantial pH changes occur [196]. Antimicrobial proteins found in neutrophil granules include defensins, lactoferrin, lysozyme, myeloperoxidase, and elastase [197], all of which can be transported into the extracellular environment. Candida’s phagocytic execution requires oxidative processes. During the oxidative burst, neutrophils create reactive oxygen species (ROS), which needs the NADPH oxidase catalyst complex to assemble in the cytoplasmic and phagosomal film [198]. First, the superoxide extremist is formed, which is subsequently dismutated to hydrogen peroxide, an oxidative and harmful particle [199].
Then, myeloperoxidase uses hydrogen peroxide to create hypochlorous acid, which is moreover an exceptionally oxidative particle that responds with natural amines to frame chloramines that have further antimicrobial stuffs [193, 200]. Candida’s phagocytic execution is further aided by reactive nitrogen species (RNS) [193]. When neutrophils are activated, they produce nitric oxide (NO) from arginine and oxygen via an enzyme called inducible nitric oxide synthase (iNOS). NO is extremely sensitive, and it is converted to peroxynitrite, which is then reduced to nitrogen dioxide and a hydroxyl radical. Because iNOS is restricted to the intracellular compartment, RNS production is restricted to the intracellular compartment [199]. The creation of neutrophil extracellular catches (NETs) [201, 202], which are formed during a unique sequence of neutrophil cell death known as NETosis, is another more recently found way of Candida executing. Similar to serine proteases, antimicrobial peptides (e.g., calprotectin), and other microbicidal chemicals, the neutrophil “explodes,” unleashing a snare of chromatin fibrils coated with the neutrophil’s material. Candida spp. are well-versed in surviving the oxidative, nitrosative, osmotic, and restorative nerves encountered during interactions with neutrophils. Because of the weights, many cycles, features, and proteins are altered within the organism. These include upregulation of transporters (e.g., oligopeptide, ammonium, and iron), use of alternative carbon and nitrogen sources and metabolic cycles (e.g., glycolysis, glyoxylate, unsaturated fat, and amino destructive), and detoxification of neutrophil oxidative/nitrosative butchering instruments. (e.g., catalase, superoxide dismutases, and nitric oxide dioxygenase). In any event, these nuances are beyond the scope of this examination, and the reader is directed to a later examination that focuses on the Candida reaction to neutrophils [193, 203].
Macrophages can function as phagocytic cells as well as antigen-presenting cells capable of activating T lymphocytes. Upon activation, macrophages divide into two phenotypically and functionally distinct subsets, M1 and M2, based on the cytokine milieu in which they are initiated [204, 205, 206]. The M1 total is derived from receptiveness to the T colleague (Th)1 cytokine IFN, whereas the M2 total is derived from receptiveness to Th2 cytokines, IL-4 and IL- 13. M1 macrophages are microbic and proinflammatory, whereas M2 macrophages are involved in wound healing and extracellular network upgradation. Macrophages, like neutrophils, see and phagocytoze nonopsonised Candida via TLRs and CTLs, and opsonised Candida via CR3 and FcR [193, 207]. Nonetheless, macrophage phagosome formation differs from neutrophil phagosome development in that macrophage phagosomes follow the endocytic development route and grow into phagolysosomes with a distinctive acidic pH that promotes compound activity, such as cathepsin D [208]. M1 macrophages use both oxidative and nitrosative executing components (as seen above for neutrophils), but they also use the RNS, NO, to directly kill phagocytosed Candida via the translocation of iNOS. TNF and the chemokines CXCL9 and CXCL10 are also released by M1 macrophages [209]. These chemokines act as ligands for the CXCR3 receptor, which is found on Th1 cells and NK cells, attracting resistant cells to contamination sites.
M2 macrophages, then again, advance contagious ingenuity inside the macrophage, giving an instrument to invulnerable avoidance. M2 macrophages additionally express more significant levels of MR (CD206) bringing about expanded phagocytosis of Candida [210]. Correspondingly, the arginase-1 (Arg1) quality is additionally expanded in articulation, which rivals iNOS for a similar substrate (arginine), consequently diminishing NO levels [211]. This is additionally exacerbated by decreased degrees of TNF𝛼 creation in M2 macrophages. In light of this, macrophages anticipate playing an important role in Candida protection, but this is contingent on the Candida strain assisting the macrophage [212]. Candida spp., like neutrophils, are believed to rely on relative adaptations to survive in macrophages.
Besides these receptors molecules, actively participated proteins and cellular mechanism system there is a lot of others factors in these mechanisms are linked like adhesins and invasins, biofilm formation, contact sensing and thigmotropism, secreted hydrolases, pH-sensing and its regulation, environment and metabolic adaptation, small HSPs, metal acquisition. So, for a complete understanding these factors also play significant role in pathogenicity mechanism of
This chapter has discussed the pathogenicity mechanism along with host and cellular responses in Candida species. Host reactions to Candida are profoundly assorted because of the assortment of contagious PAMPs and antigens perceived by various safe cells at different disease destinations. Many inquiries have been conducted on this important topic, particularly with
About 7% of the population >65 years suffer from a painful heel, even though younger people are often affected, too [1]. The most common cause of this symptom is the so‐called “plantar fasciitis” [2]. This term is widely used, although “plantar fasciopathy” or “plantar fasciosis” would be a better description to point out the degenerative nature of the disease. However, as more than 1100 citations in Pubmed quote “plantar fasciitis” (in comparison with only 50), we will use the traditional term in the following.
Plantar fasciitis has been associated with obesity, with acute or chronic work overload, or with work on hard surfaces [2, 3]. It seems that physiological degeneration of the fascia at the calcaneal insertion exacerbates due to repetitive microtraumas caused by vertical compression [4]. This causes inflammatory tissue reactions. As a result, the fascia is thickened with an associated fluid collection to 4.0 mm and more in ultrasonography [5]. Furthermore, this inflammation may trigger bone formation, the so‐called “plantar heel spur.” This process has been studied intensively by Kumai and Benjamin [6]. They proposed three stages of spur growth: “(a) an initial formation of cartilage cell clusters and fissures at the plantar fascia enthesis; (b) thickening of the subchondral bone plate at the enthesis as small spurs form; and (c) development of vertically oriented trabeculae buttressing the proximal end of larger spurs” [6]. The first description of this spur formation and correlation with the clinical symptoms was carried out by Plettner in 1900 [7]. However, not every heel spur is associated with heel pain, as these spurs are found in 11–16% of the normal asymptomatic population [4]. On the other hand, some patients with painful plantar fasciitis do not have a radiographic confirmation of a spur formation.
A similar mechanism (although caused by longitudinal traction and not by vertical compression) of bone formation has been described at the insertion of the Achilles tendon [8].
According to the American clinical practice guidelines from 2010, diagnosis is established by the typical anamnesis and the characteristic localizations of tenderness. Still, weight‐bearing radiographs are also recommended [9].
Single doses of external beam radiotherapy (EBRT) in the range of 0.3–1 Gy are called “low dose EBRT” (LD‐EBRT). These single fractions are applied two or three times a week until a total dose of about 3–6 Gy is reached. Such radiotherapeutic concepts are used for diverse nonmalignant conditions, e.g., osteoarthrosis, tendinopathy, epicondylitis, or bursitis. A comprehensive review of the historical developments in LD‐EBRT for benign diseases is given by Trott [10].
In contrast, EBRT in oncology is characterized by much higher single and total doses. “Normofractionation” describes single doses of 1.8–2 Gy, applied about five times a week. To treat breast cancer, the total doses of about 62 Gy are necessary, in prostate cancer even more than 72 Gy. From a radiobiological point of view, these high cumulative doses are used to induce DNA double strand breaks. Due to errors in a repair mechanism (nonhomologous end joining), dicentric chromosomes can occur. These can result in unfinished mitoses, the so‐called “mitotic catastrophe,” the main mechanism to reduce clonogenic survival in tumor cells [11]. High doses of EBRT induce local inflammation and tissue reactions.
The much lower doses of LD‐EBRT act via different mechanisms. In the last two decades, several anti‐inflammatory effects have been discovered, contrary to the effects of the above‐mentioned high EBRT doses.
Furthermore, doses between 0.1 and 0.5 Gy reduced the adhesion of PBMC significantly to endothelial cells (ECs)
A third mechanism was the suppression of nitric oxide (NO) production in activated macrophages by LD‐EBRT between 0.3 and 1.25 Gy [18]. As the expression of inducible nitric oxide synthases (iNOS) proteins was not altered, the LD‐EBRT seemed to act at the translational or posttranslational level. Furthermore, a dose of 0.5 Gy significantly reduced oxidative burst and superoxide production of stimulated macrophages [19]. A diminished release of reactive oxygen species (ROS) can also contribute to the anti‐inflammatory effects of LD‐EBRT.
Taken together, all of these pathways and mechanisms showed a similar dose dependence with a maximum effect between 0.3 and 0.7 Gy regarding a discontinuous dose‐effect relation [20].
There are several
Since 1937 [21] for decades, large retrospective studies on the efficacy of LD‐EBRT in calcaneodynia have been published (overview in 22). In 1970, one negative randomized trial was reported and heavily criticized but had not been repeated [23]. Starting in the 1980s, patients were systematically clinically examined and interrogated in a structured manner to try to control for diverse risk factors and to compare the efficacy of different fractionation schemes and total doses [24].
It took until the past decade to perform and report prospectively randomized trials to proof the efficacy of LD‐EBRT and to identify the optimal dose fractionation schedule. In the following, we report the design and the results of these trials. Table 1 gives a short overview of the studied dose concepts and the results. Due to methodological reasons, we will describe the studies not following their publications dates, but according to a systematic order.
Since the publication of the first randomized trial on LD-EBRT in 1970, the efficacy of LD‐EBRT was questioned [23]. Goldie et al. randomized 399 patients, however, only nine patients suffered from calcaneodynia. This is why these results cannot be extrapolated to LD‐EBRT of a painful heel spur. Furthermore, endpoints were not clearly defined, and therapy was started in an acute stage of the disease [25].
The landmark study to prove the efficacy of LD‐EBRT was performed by the German cooperative group on the radiotherapy for benign diseases (GCGBD) under the responsibility of Niewald et al. [26]. A very low dose EBRT (6 × 0.1 Gy applied twice a week up to a total dose of 0.6 Gy) was randomized to a standard dose LD‐EBRT (6 × 1 Gy twice a week up to a total dose of 6 Gy). In the case of an unfavorable response after 3 months, the patient was offered a second treatment series (“reirradiation”) applying a standard dose. The dosage of the experimental arm was chosen to examine if very low doses are effective at all. Second, it acted as a placebo irradiation, as a sham irradiation was regarded unethical. LD‐EBRT was applied using a linear accelerator (4‐ to 6‐MV photons) using lateral parallel opposing fields.
Inclusion criteria were tenderness of the calcaneus with a limitation of the painless walking distance and duration of the symptoms for more than 6 months. Furthermore, a radiological proof of a heel spur was required, and the patients had to be least 40 years of age. Patients with previous traumata to the foot, rheumatic or vascular diseases, lymphatic edema, pregnancy, or breastfeeding were excluded. Concomitant therapy with oral analgesics was not limited. However, local injections with steroids during the study period were not permitted.
Initially, 200 patients were planned [27] to detect a difference of 10% in the quality of life (QOL) sum score (SF‐12) [28] and calcaneodynia sum score (CS) [29] (Table 2) with a power of 80% and an error probability of 5%. Furthermore, the visual analogue scale (VAS) to evaluate pain intensity was used. However, after randomization of 66 patients and interim analysis of 62 patients (4 had to be excluded due to a withdrawal of informed consent or violation of the inclusion criteria), the differences in efficacy between the two treatment arms were so pronounced, that the trial was closed early.
Author | Year | N | Standard arm | Experimental arm | Results | Conclusions |
---|---|---|---|---|---|---|
2012 | 66 | 6 × 1 Gy twice a week | 6 × 0.1 Gy | 3 months: VAS/CS/SF12 sig. better with standard | 1. Dose‐response relationship | |
1 year: less second treatment series with standard | 2. Proof of therapeutic effect of LD‐EBRT | |||||
2007 | 130 | 6 × 1 Gy twice a week | 6 × 0.5 Gy | 6 months: CS no sig. differences | 6 × 0.5 Gy as standard fractionation | |
2014 | 457 | 6 × 1 Gy twice a week | 6 × 0.5 Gy | 6 weeks, 2.5 years: VAS/CS no sig. differences | 6 × 0.5 Gy as standard confirmed | |
2015 | 127 | 6 × 1 Gy twice a week | 12 × 0.5 Gy thrice a week | 3 months: VAS/CS/SF12 no sig. differences | Efficacy not increased with 12 × 0.5 Gy standard still 6 × 0.5 Gy |
Summary of contemporary randomized trials on LD‐EBRT of painful heel spurs: tested schedules, results, and conclusions.
Criteria | Extent of symptoms/alteration | Points |
---|---|---|
S = Pain at | 6 / 4 / 2 / 0 | |
(total: 30%) | N = Pain during D = Pain during R = Pain at I = Pain at none = 6 ; slight = 4 ; moderate = 2 ; severe = 0 points ⇨ | 6 / 4 / 2 / 0 6 / 4 / 2 / 0 6 / 4 / 2 / 0 6 / 4 / 2 / 0 |
per single criterion | ||
(total: 15%) | None Orthopedic shoe, insoles, heel cushion One cane or crutch Two canes or crutches ⇨ | 15 10 5 0 |
(total: 20%) | No limitation, maximum professional strain possible Slight limitation, normal professional work possible Moderate limitation, reduced professional activity Severe limitation, daily professional work impossible ⇨ | 20 10 5 0 |
(total: 15%) | No limitation of daily and leisure activities and sports Slightly limitation/reduced leisure activities and sports Moderate limitation/no leisure activities and sports Complete limitation of any daily and leisure activities ⇨ | 15 10 5 0 |
(total: 20%) | No limp, normal walking is possible without a limitation Slightly altered, limp after walking Moderately altered, limp after walking Severely altered, normal walking is impossible ⇨ | 20 10 5 0 |
The mean age of patients was 54 years in the standard dose group and 58 years in the 6 × 0.1 Gy group. Sixty‐one patients had a plantar, one patient a dorsal heel spur. In mean, patients in the standard dose group suffered for 15.3 months before the start of LD‐EBRT, in the 6 × 0.1 Gy group for 18.8 months. Twenty‐one patients had symptoms on both sides. In 28 patients the pain irradiated into the calf, only in 18 patients it was localized to the sole of the foot. Two patients had received surgery for LD‐EBRT.
Three months after therapy VAS values, CS‐ and QOL‐scores were significantly better after the standard dose in comparison with the very low dose treatment arm. The higher pain relief resulted in a better QOL. Twelve months after therapy about 64% of the patients after 6 × 0.1 Gy had to receive a second treatment series due to insufficient treatment results, in comparison with only 17% of the patients in the standard dose treatment group. As the second series was applied with a standard dose (6 × 1 Gy), patients in the 6 × 0.1 Gy group who were reirradiated showed equally favorable results compared with those in the standard‐dose group who did not receive a second course [26]. This is why the second treatment series in this clinical setting acted as a “salvage therapy.” Another interesting finding was that patients with a good response already at 3 months remained stable or even improved at 12 months. Furthermore, this underlines the long‐lasting efficacy of LD‐EBRT.
Acute side effects or long‐term toxicity did not occur.
In conclusion, this randomized trial established a dose‐response‐relationship of the analgesic effect of LD‐EBRT, thus providing a clinical and methodological proof of the efficacy of 6 × 1 Gy LD‐EBRT on the clinical course of painful heel spurs. The early termination of the study was justified due the interim analysis showing significant differences in the clinical outcome between both treatment arms. Still, the trial was not blinded, so both the patients and the staff were aware of the received dose. With modern linear accelerators, a complete blinding of the staff is nearly impossible. The only option would be a shame irradiation with closed collimator jaws, reducing the dose to the unavoidable “leakage” radiation. A much easier and straight forward way was used in the above‐mentioned study by application of a minimal physical dose with 0.1 Gy. Another critical point might be that only half of the patients were examined 12 months after therapy (
Another potential confounder not only in this study but also in all other published prospective and retrospective case series might be that a lot of the patients had received diverse and other conservative therapies before being referred to LD‐EBRT. An interaction between one of these other treatments and LD‐EBRT cannot be ruled out due to methodological reasons. This reflects clinical reality. Still, an interaction between one of these therapies and LD‐EBRT is rather unlikely and counter‐intuitive, as patients were referred to LD‐EBRT after the clinical failure of all the other conservative treatments.
Two randomized studies investigated the efficacy of 0.5 Gy single dose in comparison to 1 Gy.
The first trial was conducted by Heyd et al. [30]. They randomized 130 patients between 6 × 0.5 Gy twice weekly (low dose) and 6 × 1 Gy (standard dose). A linear accelerator was used, applying a single field technique.
Inclusion criteria were clinical signs of a painful heel spur, radiological evidence of spur formation, patient age ≥30 years and a relapse after previous conservative treatments, in patients >45 years LD‐EBRT could be used as the primary treatment. Endpoints of the study were changes in the “original” calcaneodynia score [31], that was documented before LD‐EBRT, at the end of the course, and 6 weeks and 6 months afterward.
One hundred and thirty patients were randomized. Mean age was 58.4 years. A 102 patients suffered from a plantar, one patient from a dorsal, and 27 patients from combined spurs. In mean, patients had been suffering from symptoms for 9.8 months. The symptoms had been present in 58 patients for less than 6 months, in 72 patients for a longer time. In 7 heels LD‐EBRT was the first therapeutic approach.
At the end of LD‐EBRT, 66% in the low dose group vs. 59% in the standard dose experienced an improvement in symptoms, 6 weeks later 80 vs. 85%. At this time point, 1.5% in each group reported an increase in symptoms, 19 vs. 14% no change. No statistically significant differences were noted. In case of insufficient treatment results patients were offered a second EBRT series. Thus 26 vs. 37% were treated a second time. Six weeks after that, 71 vs. 79% of these patients reported a further improvement. Six months after LD‐EBRT 88% of the patients in both groups had an amelioration of their symptoms, the remaining patients reported no change. During the EBRT series a slight increase in pain was reported by 26 vs. 29% of the patients. No other acute or late toxicity occurred.
In conclusion, 6 × 0.5 Gy twice weekly was as effective as 6 × 1 Gy.
These results were confirmed by a second randomized trial [32, 33]. Ott et al. randomized 457 patients between 6 × 0.5 Gy (low dose) and 6 × 1 Gy (standard dose). In contrast to the above‐cited “Heyd‐study” [30] an X‐ray unit (orthovoltage) and not linear accelerators was used. Patients received a single field (6 × 8 cm on the plantar calcaneus) with 150 kV, 15 mA, 1 mm Cu‐filter, with source‐to‐skin distance (SSD) of 40 cm. Six weeks after the LD‐EBRT a second series was offered to patients with an insufficient response. The endpoint was pain reduction. CS score and VAS values were measured before and at the end of LD‐EBRT (early response), 6 weeks (delayed), and 2.5 years (long‐term) afterward.
With a median follow‐up of 32 months the mean VAS values before treatment, for early, delayed, and long‐term response for the 0.5 and 1.0 Gy groups were 65.5 ± 22.1 and 64.0 ± 20.5 (
Taken together, the above‐mentioned studies proofed an equivalent clinical efficacy of 6 × 0.5 Gy in comparison to 6 × 1 Gy, thus defining a new clinical treatment standard with six times 0.5 Gy twice weekly as the minimum effective dose.
Before proofing 0.5 Gy as the new standard single dose, another randomized study tried to increase efficacy in reaching the “old” cumulative dose of 6 Gy with a single dose of 0.5 Gy. Niewald et al. randomized between 6 × 1 Gy twice a week (old “standard dose”) and 12 × 0.5 Gy three times a week (“experimental dose”) [25]. The aim was not just to get comparable results, but to further improve the analgesic effects. Linear accelerators (6 MV photons) applying a lateral opposing field technique were used.
Inclusion and exclusion criteria were quite similar to the ones used in the landmark study [26]: Clinical evidence of a painful heel spur, and duration of the symptoms for more than 6 months; radiological proof of a spur formation; age at least 40 years; Karnofsky‐Index at least 70%. Patients with previous radiotherapy or previous trauma to the foot, rheumatic or vascular diseases, lymphatic edema, pregnancy, breastfeeding, or severe psychiatric disorders were excluded. Concomitant therapy with analgesics was allowed. However, patients receiving surgery or shock wave therapy after randomization were excluded.
Endpoints were the SF‐12 sum score, the CS sum score (Table 2), and VAS. Follow‐up was scheduled every 6 weeks for 1 year.
Two‐hundred and forty patients were calculated to detect a difference of 15% in the VAS and CS score, with a power of 80%, and an error probability of 5%. After randomization of 127 patients and an interim analysis of 107 patients, the study was closed early, as the intended increase in analgesic efficacy by the experimental treatment was very unlikely to be achieved.
The mean age of the patients in the standard group was 56.1 Gy in comparison with 58.1 Gy in the experimental group. The mean duration of symptoms before initiation of LD‐EBRT was 17 vs. 16 months. In 98% of the standard group and 93% of the experimental group a plantar spur was treated, in 2 and 7% a combined (plantar and dorsal) spur.
Results after 3 months have been issued so far [25], longer follow‐up has yet to be published. After 3 months, there were no significant differences neither in the VAS (standard 42.3 vs. experimental 44.4) nor the CS sum score (28 vs. 28.4) nor in the QOL (SF‐12) scores. Although longer follow‐up has to be awaited, a further increase in the analgesic effect by applying 12 × 0.5 Gy three times a week is unlikely. This is why this fractionation schedule is currently not recommended, as it does not follow the “as low as reasonable achievable” principle of radiation protection.
Further reduced single doses in LD‐EBRT (with the exception of 0.1 Gy [26]) have never been tested in a prospectively randomized clinical trial. In radiotherapy of degenerative joint disorders, single doses of about 0.3–0.4 Gy were established by von Pannewitz in the late 1920s and published in 1933 and 1970 [34, 35]. However, two studies on calcaneodynia have raised serious concerns on single doses as low as 0.3 Gy.
Seegenschmiedt et al. analyzed treatment efficacy in 141 patients (170 irradiated heels), who were treated from 1984–1994 with X‐ray units (250 kV/200 kV, 20 mA, 40 cm SSD), applying a single field of 6 × 8 cm [24]. Seventy‐two heels received 12 Gy with 6 × 1 Gy (three times a week) –6 weeks break – 6 × 1 Gy (group A), 50 heels were treated with 10 × 0.3 Gy every day (group B1), and 38 heels 10 × 0.5 Gy every day (group B2). The endpoint was the value of a semiquantitative pain score 3 months and in mean 4 years after LD‐EBRT.
The median age of patients was 55 years in group A and 59 years in group B1/B2. The mean duration of symptoms before LD‐EBRT was 8 months, in one‐third, the symptoms persisted for more than 6 months.
Complete pain remission was achieved in 68–71% of the patients without significant differences between the treatment groups. However, there were differences in the clinical course of patients with partial remission of the symptoms: The best results in these patients were achieved during longer follow‐up in group B1 (10 × 0.5 Gy), followed by group A (6 × 1–6 × 1 Gy), followed by group B2 (10 × 0.3 Gy). The latter group showed a significantly worse amelioration of symptoms than the other groups.
A reduced efficacy was also reported in another retrospective case series, comprising 673 heels treated with a single dose of 0.3 Gy three times weekly up to 1.5 Gy (X‐ray) [36]. In case of insufficient treatment results the patients were offered a second course. After the first treatment, only 13% reported CR, nearly all patients had undergone a second LD‐EBRT.
Taken together, to the best of our current knowledge a single dose of 0.5 Gy is standard of care and should only be modified in controlled clinical trials.
In Table 3 selected contemporary randomized trials and patient series are shown broken down into several factors that might be correlated with treatment efficacy. For a better overview, we did not differentiate between univariate and multivariate analyses. We did not try to collect all ever published data.
Duration of symptoms before start of LD‐EBRT has been shown to be correlated with treatment efficacy in numerous studies.
Muecke et al. analyzed in a retrospective multicenter study 502 patients [22]. Duration of symptoms ≤6 months was associated with 76% treatment success vs. 44% after a history >6 months. Also Seegenschmiedt et al. found in their large collectives a correlation between the duration of heel pain and treatment outcome [24]. A significant influence of duration of symptoms before LD‐EBRT was also reported in 73 heels by Schneider et al. [37]. With a history of 3–6 months, the VAS value was reduced by 85%, 28 months after LD‐EBRT in comparison with a reduction of 58% with a history > 6 months. Similar results were obtained by Hermann et al. in 285 heels comparing <12 month history of pain vs. >12 months [38].
In contrary, another study could not confirm these results [30].
To the best of our knowledge, in no study, an influence of gender on treatment outcome has been confirmed [22, 24, 30, 38, 39]. In contrast to radiotherapy for oncological indications with high doses, efficacy and tolerability of LD‐EBRT seems to be the same concerning gender.
Several studies described a correlation between older age and better treatment results, at least 6 weeks after LD‐EBRT [37]. Age somewhat over 50 years seems to be important: >50 years [40], > 53 [38], or > 58 [22]. For a possible explanation see Section 2.3.7.
However, other studies found no influence of this patient characteristic on treatment outcome [24, 30, 39].
A very precise registration of changes in pain intensity (VAS) was done by Schneider at al. [37]. Sixty‐two patients (73 treated heels) were prospectively scored every week during LD‐EBRT, at the end of therapy, 6 weeks, 28 months, and 40 months later. Additionally, subjective mechanical heel stress during LD‐EBRT was estimated. A linear accelerator (10 MV) was used, applying one single field with a size of 12 × 17 cm. Patients were treated twice a week to a total dose of 5 Gy, with increasing single fraction doses (0.25 – 0.25 – 0.5 – 1 – 1 – 1 – 1 Gy). Mean patient age was 54 years, and all had a radiologically proven plantar spurn, mean symptom duration before LD‐EBRT was 6.5 months. Nearly all patients had received other conservative therapies before LD‐EBRT with insufficient results.
Interestingly, VAS scores decreased continuously during LD‐EBRT: before treatment the mean value was 6.3 ± 1.5, after the first week of LD‐EBRT 6.2 ± 1.8, after the second week 5.5 ± 2 (
In standard schedules with fixed single doses a slight increase in pain during the treatment series was reported by 26% (during 6 × 0.5 Gy) vs. 29% (6 × 1 Gy) of the patients [30]. Unfortunately, a possible correlation of this phenomenon with definite treatment results was not investigated.
Without further quantification, another study (6 × 1 vs. 6 × 0.1 Gy) stated, that this initial increase in symptoms “had no influence on the final pain relief 3 and 12 months after treatment” [26]. Older studies postulated a temporary reduction of the pH value in the irradiated tissues at the beginning of the treatment series, without consequences for the long‐term efficacy of LD‐EBRT [41].
This is contrasted by observations of LD‐EBRT in peritendinitis humeroscapularis [42]. In 73 patients (86 shoulders) initial increase of pain during the treatment course was significantly associated with a good response.
Muecke et al. analyzed in a retrospective multicenter study the influence of different treatment techniques in 502 patients [22]. Treatment failure was defined as pain persistence after LD‐EBRT and recurrence of pain during follow‐up. Treatment with MV (6–10 MV) was a significant prognostic factor for pain relief in multivariate analysis, as MV was associated with an eight‐year event‐free probability of 68 vs. 61% after X‐ray beams (175 kV). There are two possible explanations for this finding: besides the possibility of a random result, the authors postulate a more homogenous dose distribution with MV treatment in comparison with KV [22].
Schneider et al. reported an efficacy of just one‐third after a second LD‐EBRT course (so‐called “re‐irradiation”) in comparison with the effects of the first course [37]. Out of 73 heels treated with 5 Gy LD‐EBRT 18 heels received reirradiation due to insufficient treatment response. However, pain reduction measured by means of changes in VAS shortly after the second course and during long‐term follow‐up was significantly diminished in comparison with the efficacy of the first course (about 30% reduction in pain at the last evaluation vs. 86%).
Similar results were obtained in the large retrospective series (502 patients) by Muecke et al. [22]. Treatment failure was significantly associated with the number of treatment series: eight‐year event‐free probability was about 70% after the first course in comparison with just about 30% after reirradiation.
A systematic study on the efficacy of a reirradiation has been published by Hautmann et al. [43]. Eighty‐three patients (101 heels) with insufficient response to the first course or recurrent pain afterward due to plantar fasciitis (83 heels), or achillodynia (28 heels) received a second LD‐EBRT course in median 10 weeks (range 4 weeks to 63 months) after the first LD‐EBRT. About 75% of the patients were treated with 6 × 1 Gy, the others 6 × 0.5 Gy. The pain was assessed using the numeric rating scale (NRS) before and at the end of LD‐EBRT, 6, and 12 weeks, and 6, 12, and 24 months thereafter.
Before reirradiation NRS values were 6 (interquartile range 5–8), at the end of LD‐EBRT 5 (2–6), 6 weeks later 2 (1–4), at 12 weeks 1 (0–3), at 6 months 0 (0–2), at 12 and 24 months 0 (0–1). Interestingly, not only the patients with recurrent pain after the first course but also patients with insufficient responses to the first course experienced a profound and long‐lasting amelioration of their symptoms after the second course.
This is why a second treatment course should be recommended in case of insufficient efficacy of the first course.
A significant correlation between avoidance of heel stress during LD‐EBRT and efficacy of LD‐EBRT 6 weeks after therapy was reported by Schneider et al. in 73 heels [37]. With a Pearson\'s correlation coefficient of -0.467 (
An intuitive explanation is given by the authors [37]: As patient age was associated with positive treatment results, too, they proposed that older patients are often retired, thus being able to take more care of their heels.
Interestingly, all randomized trials required the radiological proof of a heel spur before including patients into the studies. Furthermore, most of the prospective and retrospective series warranted such an objective sign. However, as a substantial part of the patients suffers from plantar heel pain without having developed a heel spur, LD‐EBRT should be effective in these patients, too.
Hermann et al. analyzed treatment efficacy in 250 patients (285 heels), who received LD‐EBRT predominantly with 6 × 1 Gy [38]. In this series, 33% of the treated heels were without radiological evidence of a spur. In 185 patients a spur was confirmed with a mean length of 6.5 mm (range 0.6–25 mm). Patients without evidence of a plantar heel spur had a significantly higher chance of CR after LD‐EBRT (43 vs. 35%). Furthermore, the length of the spurs correlated directly with treatment outcome. Spurs >6.5 mm had just a 30% chance of experiencing CR in comparison with shorter ones. No statistical differences were found between treatment results of heels without spurs and those with spurs ≤6.5 mm.
Miszczyk et al. reported on 327 patients (623 LD‐EBRT series) mostly treated with X‐ray (180 kV, usually 1mm Cu filters) with single doses of 1.5 Gy (range 1–3 Gy) up to a total dose between 9 and 12 Gy (range 1–45 Gy) [39]. Mean spur size was 9 mm (range 1–30 mm). With a mean follow‐up of 74 months, no correlation between spur size and duration of pain relief was found. Analysis concerning spur length and treatment outcome in itself were unfortunately not reported.
Multivariate logistic regression enables the identification of factors independently predicting treatment outcome. By combining these factors, models can be calculated, that predict treatment outcome with a high probability. An example from the study of Hermann et al. is given in Table 4: in 285 heels treated with 6 × 1 Gy/6 × 0.5 Gy the influences of the patient characteristics age, spur length, and duration of symptoms before LD-EBRT alone and in combination were calculated [38]. The best results were obtained for patients > 53 years, spur length <6 mm, and a duration of symptoms <12 months with a probability for CR of 55% (CI 36–73%) and PR of 38% (CI 22–58%). Without these characteristics, the chance for CR was just 18% (CI 9–33%), for PR 31% (17–48%).
Study (citation) | [30] | [26] | [24] | [37] | [39] | [22] | [38] | [40] | [83] |
---|---|---|---|---|---|---|---|---|---|
Rand | Rand | Prospect | Prospect | Retrospect | Retrospect | Retrospect | Retrospect | Retrospect | |
130 | 66 | 170 | 73 | 623 | 502 | 285 | 161 | 7947 | |
MV | MV | KV | MV | KV | MV, KV | MV | KV | MV, KV | |
calcaneus | calcaneus | calcaneus | entire dorsal and middle foot | insertion of plantar fascia | calcaneus | calcaneus vs. insertion of calcaneus | calcaneus | entire dorsal foot vs. calcaneus vs. insertion of plantar fascia | |
6 × 1 vs. 6 × 0.5 Gy | 6 × 1 Gy vs. 6 × 0.1 Gy | 12, 3, 5 Gy | 5 Gy (increasing single dose) | 1.5 (1–3) up to 9–12 Gy (1–45) | 5–10 × 0.5–1 Gy | 6 × 1 Gy6 × 0.5 Gy | 6 × 1 Gy | 0.3–1.5 Gy; 2–3x weekly 2.5–18.76 Gy | |
History of symptoms | 0 | n.i. | + | + | 0 | + | + | + | + |
Gender | 0 | n.i. | 0 | n.i. | 0 | 0 | 0 | n.i. | n.i. |
Patient\'s age | 0 | n.i. | 0 | + | 0 | + | + | + | n.i. |
Initial worsening of pain during LD‐EBRT | n.i. | n.i. | n.i. | n.i. | n.i. | n.i. | n.i. | n.i. | n.i. |
MV vs. KV | n.i. | n.i. | n.i. | n.i. | n.i. | + | n.i. | n.i. | 0 |
Number of therapy series | n.i. | n.i. | n.i. | + | n.i. | + | n.i. | n.i. | + |
Heel stress during LD‐EBRT | n.i. | 0 | n.i. | + | n.i. | n.i. | n.i. | n.i. | n.i. |
Factors associated with treatment efficacy in contemporary studies.
Patient\'s age >53 | No spur or spur ≤6.5 mm | Duration of symptoms <12 months | Probability of | ||
---|---|---|---|---|---|
No change | Partial remission | Complete remission | |||
1 | 1 | 1 | 0.07 (0.03–0.14) | 0.38 (0.22–0.58) | 0.55 (0.36–0.73) |
1 | 1 | 0 | 0.13 (0.07–0.28) | 0.37 (0.21–0.57) | 0.50 (0.30–0.70) |
1 | 0 | 1 | 0.15 (0.06–0.24) | 0.53 (0.33–0.72) | 0.32 (0.17–0.53) |
1 | 0 | 0 | 0.25 (0.13–0.45) | 0.48 (0.27–0.69) | 0.27 (0.13–0.48) |
0 | 1 | 1 | 0.17 (0.10–0.31) | 0.33 (0.19–0.50) | 0.50 (0.33–0.66) |
0 | 1 | 0 | 0.34 (0.20–0.53) | 0.40 (0.24–0.59) | 0.26 (0.13–0.45) |
0 | 0 | 1 | 0.30 (0.20–0.46) | 0.29 (0.18–0.43) | 0.41 (0.27–0.56) |
0 | 0 | 0 | 0.51 (0.35–0.69) | 0.31 (0.17–0.48) | 0.18 (0.09–0.33) |
Probabilities (95%‐CI) for NC, PR and CR calculated by polytomous logistic regression in dependence of the risk factors age, spur length, and duration of symptoms before LD‐EBRT according to Hermann et al. in a collective of 285 heels treated with 6 × 1/6 × 0.5 Gy (taken from [38]).
In modern radiotherapeutic departments, X‐ray sources are less and less available. This is why nowadays most patients are treated with linear accelerators, which were initially developed for the treatment of oncological diseases. However, these machines can be used in the treatment of benign diseases without any modifications or problems. Due to the high efforts in physical, technical, and organizational quality assurances for the operation of an accelerator or an X-ray source, the concentration on accelerators and their use for all indications is recommended.
For irradiation of the heel, the patient has to be placed on the treatment couch with the feet toward the gantry of the accelerator (so‐called “feet first”). Two different patient positions are widely used. He can be placed in supine position, with the irradiated leg is stretched out, while the other leg is angled. Another option is to place the patient in a lateral decubitus position on the side of the involved heel. Again, the symptomatic leg is stretched, while the contralateral leg is bent, with a cushion placed beneath the knee. Using X‐rays, the ipsilateral knee is bent by 90% and the foot is positioned on the treatment table. One anterior‐posterior (AP) beam is usually applied in this technique.
For the treatment itself, there are also two different options. Irradiation may be given as a single stationary field (SSD 100cm by convention). Alternatively, parallel opposing fields from 0° and 180° gantry position (in decubitus position) or lateral opposing fields (90° and 270° in supine position) are also applicable but take a little bit longer in daily clinical practice. The hypothetical advantage of using two opposing fields is a uniform dose distribution in the entire beam path in the calcaneus (Figure 1). However, there has never been a clinical proof, whether this theoretical assumption translates into any clinical advantage for the patient. When applying opposing fields, the dose is specified according to the ICRU 50 report, normally in the center of the calcaneus.
Dose distribution of two different treatment techniques generated in a treatment planning system (XIO®). In A and B just one single 6 MV photon field (8 × 8 cm) is applied, while C and D shows the dose distribution with two opposing fields from 0 and 180°. In the upper row, the so‐called “beams eye views” are given, while in the lower row the respective dose distributions on an axial CT scan directly at the calcaneal insertion are shown. Note the more uniform dose distribution with opposing fields. The 95% isodose is given as a green line (2.85 Gy). This dose encompasses larger parts of the calcaneal bone in D (opposing fields) than in B (single field). More information is given in Section 2.4.
A third option is the so‐called “plantar field” with the patient lying in prone position. A single field is positioned directly over the plantar insertion/calcaneus, potentially with rotations of the patient table and the gantry to compensate for inclinations of the patients surface in the irradiated field. However, this technique is regarded problematic when using linear accelerators due to the dose build‐up effect in the critical tissue depth. This problem is illustrated in Figure 2: photons with 6 MV reach just the half of the prescribed dose at the skin level, 100% is reached at 1.5 cm tissue depth. This would result in an insufficient dose in the critical structures (plantar fascia and heel spur). To overcome this problem, a silicone flap of about 1 cm diameter must be positioned on the skin before radiation.
Depth curves of different megavoltage energies. Blue 6 MV photons, red 15 MV photons. At the surface of the body/skin (depth 0 mm), only half (or even less with 15 MV) of the prescribed dose is applied. By physical interactions between photons and the tissue/water, there is a steep increase in dose. A 100% is reached at 1.5 cm depth with 6 MV and at about 3 cm depth with 15 MV. KV‐radiation reaches the maximum dose directly under the surface/skin (not shown). More information is given in Section 2.4.
Patients are often sent to the radiotherapist after a long unsuccessful history of diverse conservative treatments. The reason for this is a widespread fear among general practitioners that LD‐EBRT might be associated with severe side effects and risks. These fears are not substantiated, as reactions of the nerves or vessels require much higher doses than used for LD‐EBRT. For example, a dose of 45 Gy in normofractionated oncological therapy is considered to be safe for the spinal cord and therefore daily clinical practice [44]. Peripheral nerves are even more radioresistant. Acute or chronic side‐effects have never been reported in all contemporary studies on LD‐EBRT.
Acute side effects are negligible, as very low doses of ionizing radiation (in comparison with oncological treatments) are applied to a distal extremity. The total dose of LD‐EBRT with 3 or 6 Gy is far too low to cause any acute or late reactions on the skin overlaying the calcaneus. During normofractionated EBRT (single doses of 1.8–2 Gy, treatment on 5 days a week) erythema and mild edema develop at about 30 Gy [45]. Hyperpigmentation occurs at about 45 Gy, moist epitheliolyses at about 50 Gy. A 50–60 Gy might cause telangiectasias years after the therapy. This is why there is no report on acute treatment side effects in LD‐EBRT until now to the best of our knowledge.
About one‐third of the patients might experience a slight increase in pain during LD‐EBRT. In the randomized trial by Heydt et al. this phenomenon was seen in 26% (during 6 × 0.5 Gy) vs. 29% (6 × 1 Gy) [30]. It does not seem to be correlated with treatment outcome; further detailed information is given in Section 2.3.4.
The dose scattered to the male gonads is somewhat higher than to the ovaries. Jansen et al. calculated for 6 × 0.5 Gy about 1.5 mSv received by the testes and 0.75 mSv to the ovaries [46]. Comparable results have repeatedly been measured in the past [47, 48].
Taken together, the dose received by the gonads is insignificant. As the distal extremity is irradiated, scattered dose to the gonads is comparable to normal diagnostic radiological imaging [49]. The hereditary effects of these doses are very small and very likely negligible [46].
Although spermatogonial cells are very radiosensitive, a single dose of at least 100 mSv is needed to induce a temporary failure of spermatogenesis [50]. A single dose of 1000 mSv (equivalent to 1 Gy photon irradiation) results in an azoospermia for 9–18 months [51]. Interestingly, fractionated doses harm these cells even more. A temporary oligospermia is reported after receiving several fractions up to a cumulative dose of 160 mSv [52]. An azoospermia lasting for 14–22 months has been reported for fractionated doses of 620–860 mSv [53]. The actually during LD‐EBRT received testicular dose is about 100 times smaller than the lowest dose causing temporary changes in testicular tissues.
The dose to the testicles can be further reduced by utilizing a special testicular shielding. However, clinically meaningful dose reductions have been only measured in MV treatment of subdiaphragmatic/pelvine lymphatic regions or tumors [54, 55].
The mean lethal dose for human oocytes has been estimated at 2 Gy (2000 mSv) [56]. Permanent ovarian failure after radiotherapy is age dependent: in perimenopausal women, a dose of 6 Gy is sufficient [57], while in younger women up to 20 Gy are tolerated. The dose scattered to the ovaries during LD‐EBRT for calcaneodynia cannot cause such sequelae (0.75 mSv).
Naturally, pregnancy has to be excluded in all premenopausal women before beginning with LD‐EBRT, to avoid any risk to the fetus.
So far, no studies with long‐term observation periods have been published, describing a case of malignancy induced by LD‐EBRT for calcaneodynia. However, induction of malignancies is a stochastic effect of ionizing radiation. This means that there is no threshold dose—in contrast for example to the above‐mentioned reactions of the skin. A photon can accidentally trigger a mutation, which in turn leads to tumor formation many years later. The higher the radiation dose, the higher the probability of such an event occurring.
The best available data on tumor induction of full dose EBRT in oncology has been collected in patients treated with breast cancer. Almost 11,000 patients have been followed for over 20 years. The risk of a radiation‐induced tumor was approx. 1% per decade after radiotherapy [58].
To estimate the risk associated with much lower doses of LD‐EBRT, mathematical models on the basis of epidemiological long‐term observations of atomic bomb victims have been developed by the ICRP [59].
Jansen et al. applied the ICRP model on LD‐EBRT of a painful heel spur [46]. Assumed was a single field entering at the foot sole with a size of 8 × 10 cm, 200 kV photons, SSD 40 cm. For an LD‐EBRT series with 6 × 1 Gy the average attributable lifetime risk for induction of a fatal tumor was calculated to be about 0.5 in a thousand patients. An important risk factor for radiogenic‐induced cancer is the patient\'s age by the time the radiation exposure occurs. The risk is already reduced in the 3rd decade of the patient\'s life, it starts to decrease steadily from the age of 40 [60]. Applying these calculations, the estimated lifetime risk per one thousand patients for a fatal tumor accounts for the age of 25 0.6 (male)/0.8 (female), for the age of 50 0.2/0.3, for the age of 75 0.07/0.1 [46].
However, it must be critically noted that this mathematical model was developed for radiation protection and relates to the exposure of complete organ systems with approx. 1 Gy. Therefore, other groups argue that a significantly lower risk of radiogenic cancer induction— approx. ten times less—should be adopted [49, 61]. Furthermore, taken the new standard scheme with 6 × 0.5 Gy into account, these risks are additionally halved.
This risk (max. 1/1000, very likely much lower) must be seen in relation to the tumor risk of the not additionally radiotherapeutical‐treated population. In 2008, the lifetime risk of a man in Germany to suffer from cancer was 50.7% (25.9% to die from malignancy), in women 42.8% and 20.2% respectively [62].
By limiting the application of LD‐EBRT treatment to patients > 30 years of age, an exposure of the juvenile “relatively higher risk” patient population is avoided.
Traditionally target volume definition has been quite large. Field sizes of 12 × 17cm were treated, including the entire dorsal and middle foot, and not just the calcaneus [37, 82] (Figure 3A).
Field definitions in LD‐EBRT of a painful plantar heel spur/fasciitis. (A) traditional field definition including the entire dorsal and middle foot. (B) In randomized trials and large prospective series commonly used field definition encompassing the entire calcaneus, including insertion of the plantar fascia and the Achilles tendon. (C) Proposed small field definition for localized painful plantar fasciitis/plantar spur, encompassing only the painful area with 2 cm margins extending into the neighboring areas (calcaneus, fascia, fat pad).
In the recent randomized trials and prospective observational studies target volume definition was more restricted and confined to the calcaneus (Figure 3B). “The target volume consisted of the calcaneus and the region of the plantar aponeurosis” [26]. “The ventral margin is corresponding to the ventral surface of the calcaneus, the plantar and dorsal margins are surrounding the soft‐tissue border, and the cranial margin is below the ankle” [30]. “Target volume is the calcaneus, normally with a field size of 6 cm × 8 cm” [32]. “The calcaneus and the plantar aponeurosis were included in the target volume” [25].
In a German national survey 2001 on LD‐EBRT of painful heel spurs the target volume definition “large” (dorsal and middle foot) vs. “small” (entire calcaneus) was not correlated with treatment outcome [83]. Consequently, very large field definitions should be regarded as obsolete.
However, as the pathophysiological cause of calcaneodynia is thought to be a localized inflammatory process (see Section 1), it is questionable, whether the entire calcaneus has to be irradiated (as long as there are not a plantar as well as a painful dorsal spurs). There are some clinical data that support a further restriction of target volume definition.
Field sizes have been given in the study by Miszczyk et al. on 327 patients treated with X‐ray beams [39]. Target volume was “… the insertion of the plantar fascia with a calcaneal spur and a reasonable margin. The field size varied from 27 to 150 cm2 (mean 47 cm2).” However, although not explicitly stated, no correlation was found between field size and duration of pain relief after LD‐EBRT. Treatment efficacy in itself was apparently not investigated.
In the above‐mentioned series of 285 heels Hermann et al. analyzed treatment efficacy in dependence of field sizes, too [38]. The mean field size was 74 cm2. No correlation between field size (smaller vs. larger than 74 cm2) with treatment efficacy was found. Further analyses of small fields (< 6 × 6 cm), medium‐sized fields (36–64 cm2) and larger fields revealed no significant differences.
This is why it seems to suffice to encompass the painful region with 2 cm margins extending into the neighboring areas (calcaneus, fascia, fat pad; Figure 3C). However, this recommendation is deducted from pathophysiological considerations and the above‐mentioned case series. A randomized trial is necessary to proof clinical equivalence of a field definition “entire calcaneus” (Figure 3B) vs. “insertion of the plantar fascia” (Figure 3C).
The optimal fractionation schedule has not been elucidated yet. All randomized trial used twice weekly treatments. Only one experimental arm was scheduled three times a week [25]. In a National Survey in Germany with 146 answering institutions, about 45% applied two fractions and 37.5% three fractions weekly [83].
Interestingly, in the landmark study by von Pannewitz a fractionation schedule of only once per week was established [34]. Until now, there is no proof of a higher efficacy applying LD‐EBRT twice or three times per week.
In radiotherapy of another benign disease (endocrine orbitopathy) a 1 Gy per week over 20 weeks schedule was more effective than the standard schedules (10 × 2 Gy or 10 × 1 Gy every working day) [84]. Although other immunological mechanisms cause endocrine orbitopathy in comparison with plantar fasciitis, there is sufficient clinical evidence to test in a randomized trial different fractionation schedules (twice a week vs. once a week, possibly thrice a week).
Other therapies than LD‐EBRT have been applied in painful heel spur. In the following, just a rough overview can be given.
Different kinds of insoles and foot orthoses have been developed. The goal was to reduce plantar contact pressure and to distribute the pressure uniformly over the whole rearfoot [63]. Magnetic insoles do not seem to provide additional benefit [64]. As a short‐term treatment, low‐Dye taping techniques are often used. However, in a randomized trial only a modest improvement in ‘first‐step’ pain was seen in comparison with sham‐intervention [65].
Manual stretching is often recommended. A systematic review of six studies found only statistically significant differences in comparison with the control in one study combining calf muscle and plantar fascia stretches [66].
Several trials have investigated acupuncture. A systematic review from 2010 showed (limited) evidence for the effectiveness [67]. A randomized trial published in 2014 recruited 84 patients [68]. The authors concluded, that “dry needling provided statistically significant reductions in plantar heel pain, but the magnitude of this effect should be considered against the frequency of minor transitory adverse events.”
Ultrasound therapy has led to questionable results [69], but a randomized trial on cryo‐ultrasound with about 100 patients published in 2014 showed good effectiveness [70].
Low‐level laser light (635 nm), given twice a week for a total of six applications, reduced in a randomized trial VAS scores significantly after 8 weeks in comparison with placebo [71]. However, the study comprised of just 69 patients; other similar studies have not been reported so far.
Extracorporeal shock waves are widely applied. Three metaanalyses comprising at least five randomized trials found significant short‐term pain relief and improved functional outcomes for this therapeutic option [72–74]. Another study compared the analgesic efficacy of ultrasound and shock wave therapy in 47 patients [75]. The results suggested that the shock wave therapy had greater analgesic efficacy.
Another basic approach is the oral administration of nonsteroidal anti‐inflammatory drugs (NSAID) to achieve a symptomatic relief. Injections into the painful area are also recommended. A recent review summarized ten randomized trials on corticosteroid injections into the plantar fascia [76]. A significant effect of the steroids on the pain has been shown. However, it was usually short‐term, lasting 4–12 weeks in duration. No advantage of ultrasound‐guided injection techniques in comparison with palpation guidance was found, and no superiority of one type of corticosteroid over another was seen. A longer lasting pain relief has been suggested by a small randomized trial of botulinum toxin injections [77]. Another option is the injection of autologous platelet‐rich plasma. A recent review identified three randomized trials, all showing promising results [78]. However, a very small trial challenged this method of plasma preparation, as the same clinical effectivity was observed after the injection of whole blood [79].
Different surgical approaches have been developed. Releases of the plantar fascia are done, in some studies combined with a spur resection [80]. Due to a probably faster recovery after surgery with comparable functional results endoscopic procedures are recommended nowadays [81]. Surgery is usually indicated after failure of conservative therapies as the ultimate “salvage‐therapy.”
There is only a limited amount of studies randomizing patients between LD‐EBRT and the above‐mentioned alternative therapies.
Canyilmaz et al. randomized 123 patients between LD‐EBRT (6 × 1 Gy, three times a week) and 1 ml injection of 40 mg methylprednisolone and 0.5 ml 60 mg 1% lidocaine under the guidance of palpation [85]. After 3 and 6 months, VAS values and CS‐scores were compared between both groups. After 3 months, the results in the radiotherapy arm were significantly superior compared with those after injections.
To corroborate these findings, similar studies should be conducted. Furthermore, more studies randomizing LD‐EBRT against other therapies (e.g. extracorporeal shock waves) are needed. A minimum size of 50 patients per treatment arm should be assured to gain more statistically relevant results. Recruiting patients without prior excessive other therapies for these studies would be optimal.
The goal must be an evidence‐based algorithm defining the therapeutic sequence of the different conservative treatment modalities for plantar fasciitis.
LD‐EBRT for painful plantar fasciitis/heel spur is an effective and safe treatment option for patients over 30 years of age and after exclusion of pregnancy. A fractionation of 6 × 0.5 Gy twice weekly up to a total dose of 3 Gy is currently recommended. In the case of an insufficient response a second course can be offered to the patient.
Randomized trials on target volume definition and further optimization of LD‐EBRT fractionation are currently in the process of planning. Further trials to compare the different conservative therapies for plantar fasciitis with each other are necessary to allow the development of an evidence‐based treatment algorithm.
This chapter is dedicated to Professor Gisela Hermann‐Brennecke on the occasion of her 70th birthday.
AP | anterior‐posterior |
CI | confidence interval |
CR | complete remission |
CS | Calcaneodynia score |
Cu | chemical element symbol for copper |
EC | endothelial cells |
GCG‐BD | German Cooperative Group on Radiotherapy for Benign Diseases |
Gy | Gray |
ICRP | International Commission on Radiological Protection |
IL | interleukin |
iNOS | inducible nitric oxide synthases |
KV | kilovoltage |
LD‐EBRT | low dose external beam radiotherapy |
mA | milliampere |
mRNA | messenger ribonuclein acid |
mSv | milliSievert |
MV | megavoltage |
NC | no change |
NF‐κB | nuclear factor kappa B |
NO | nitric oxide |
NSAID | non‐steroidal anti‐inflammatory drug |
PBMC | peripheral blood mononuclear cells |
PR | partial remission |
QOL | quality of life |
ROS | reactive oxygen species |
SSD | skin‐to‐source distance |
TGF‐β1 | transforming growth factor β1 |
VAS | visual analogue scale |
If you are associated with any of the institutions in our list below, you can apply to receive OA publication funds by following the instructions provided in the links.
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However, it can only be activated under ultraviolet light irradiation due to its wide bandgap, high recombination, and weak separation efficiency of carriers. Doping is an effective method to extend the light absorption to the visible light region. In this chapter, we will address the importance of doping, different doping modes, preparation method, and photocatalytic mechanism in TiO2 photocatalysts. Thereafter, we will concentrate on Ti3+ self‐doping, nonmetal doping, metal doping, and codoping. Examples of progress can be given for each one of these four doping modes. The influencing factors of preparation method and doping modes on photocatalytic performance (spectrum response, carrier transport, interfacial electron transfer reaction, surface active sites, etc.) are summed up. The main objective is to study the photocatalytic processes, to elucidate the mechanistic models for a better understanding the photocatalytic reactions, and to find a method of enhancing photocatalytic activities.",book:{id:"5139",slug:"semiconductor-photocatalysis-materials-mechanisms-and-applications",title:"Semiconductor Photocatalysis",fullTitle:"Semiconductor Photocatalysis - Materials, Mechanisms and Applications"},signatures:"Fei Huang, Aihua Yan and Hui Zhao",authors:[{id:"178389",title:"Dr.",name:"Fei",middleName:null,surname:"Huang",slug:"fei-huang",fullName:"Fei Huang"},{id:"185126",title:"Dr.",name:"Aihua",middleName:null,surname:"Yan",slug:"aihua-yan",fullName:"Aihua Yan"},{id:"185127",title:"Ms.",name:"Hui",middleName:null,surname:"Zhao",slug:"hui-zhao",fullName:"Hui Zhao"}]},{id:"17184",doi:"10.5772/17039",title:"Polymer Nanocomposites: From Synthesis to Applications",slug:"polymer-nanocomposites-from-synthesis-to-applications",totalDownloads:17288,totalCrossrefCites:31,totalDimensionsCites:68,abstract:null,book:{id:"1045",slug:"nanocomposites-and-polymers-with-analytical-methods",title:"Nanocomposites and Polymers with Analytical Methods",fullTitle:"Nanocomposites and Polymers with Analytical Methods"},signatures:"S. Anandhan and S. Bandyopadhyay",authors:[{id:"27050",title:"Prof.",name:"Sri",middleName:null,surname:"Bandyopadhyay",slug:"sri-bandyopadhyay",fullName:"Sri Bandyopadhyay"},{id:"44992",title:"Prof.",name:"Anandhan",middleName:null,surname:"Srinivasan",slug:"anandhan-srinivasan",fullName:"Anandhan Srinivasan"}]},{id:"9725",doi:"10.5772/8508",title:"Biosynthesis and Application of Silver and Gold Nanoparticles",slug:"biosynthesis-and-application-of-silver-and-gold-nanoparticles",totalDownloads:27927,totalCrossrefCites:23,totalDimensionsCites:58,abstract:null,book:{id:"3621",slug:"silver-nanoparticles",title:"Silver Nanoparticles",fullTitle:"Silver Nanoparticles"},signatures:"Zygmunt Sadowski",authors:null},{id:"17194",doi:"10.5772/21694",title:"Properties of Nanofillers in Polymer",slug:"properties-of-nanofillers-in-polymer",totalDownloads:20385,totalCrossrefCites:9,totalDimensionsCites:56,abstract:null,book:{id:"1045",slug:"nanocomposites-and-polymers-with-analytical-methods",title:"Nanocomposites and Polymers with Analytical Methods",fullTitle:"Nanocomposites and Polymers with Analytical Methods"},signatures:"Damien M. Marquis, Éric Guillaume and Carine Chivas-Joly",authors:[{id:"44307",title:"Dr",name:"Damien",middleName:"Michel",surname:"Marquis",slug:"damien-marquis",fullName:"Damien Marquis"},{id:"44317",title:"Prof.",name:"Carine",middleName:null,surname:"Chivas-Joly",slug:"carine-chivas-joly",fullName:"Carine Chivas-Joly"}]},{id:"52860",doi:"10.5772/65937",title:"Cerium Oxide Nanostructures and their Applications",slug:"cerium-oxide-nanostructures-and-their-applications",totalDownloads:5365,totalCrossrefCites:23,totalDimensionsCites:55,abstract:"Due to excellent physical and chemical properties, cerium oxide (ceria, CeO2) has attracted much attention in recent years. This chapter aimed at providing some basic and fundamental properties of ceria, the importance of oxygen vacancies in this material, nano‐size effects and various synthesis strategies to form diverse structural morphologies. Finally, some key applications of ceria‐based nanostructures are reviewed. We conclude this chapter by expressing personal perspective on the probable challenges and developments of the controllable synthesis of CeO2 nanomaterials for various applications.",book:{id:"5510",slug:"functionalized-nanomaterials",title:"Functionalized Nanomaterials",fullTitle:"Functionalized Nanomaterials"},signatures:"Adnan Younis, Dewei Chu and Sean Li",authors:[{id:"191574",title:"Dr.",name:"Adnan",middleName:null,surname:"Younis",slug:"adnan-younis",fullName:"Adnan Younis"}]}],mostDownloadedChaptersLast30Days:[{id:"38951",title:"Carbon Nanotube Transparent Electrode",slug:"carbon-nanotube-transparent-electrode",totalDownloads:3985,totalCrossrefCites:3,totalDimensionsCites:5,abstract:null,book:{id:"3077",slug:"syntheses-and-applications-of-carbon-nanotubes-and-their-composites",title:"Syntheses and Applications of Carbon Nanotubes and Their Composites",fullTitle:"Syntheses and Applications of Carbon Nanotubes and Their Composites"},signatures:"Jing Sun and Ranran Wang",authors:[{id:"153508",title:"Prof.",name:"Jing",middleName:null,surname:"Sun",slug:"jing-sun",fullName:"Jing Sun"},{id:"153596",title:"Ms.",name:"Ranran",middleName:null,surname:"Wang",slug:"ranran-wang",fullName:"Ranran Wang"}]},{id:"49413",title:"Electrodeposition of Nanostructure Materials",slug:"electrodeposition-of-nanostructure-materials",totalDownloads:3733,totalCrossrefCites:1,totalDimensionsCites:7,abstract:"We are conducting a multi-disciplinary research work that involves development of nanostructured thin films of semiconductors for different applications. Nanotechnology is widely considered to constitute the basis of the next technological revolution, following on from the first Industrial Revolution, which began around 1750 with the introduction of the steam engine and steelmaking. Nanotechnology is defined as the design, characterization, production, and application of materials, devices and systems by controlling shape and size of the nanoscale. The nanoscale itself is at present considered to cover the range from 1 to 100 nm. All samples prepared in thin film forms and the characterization revealed their nanostructure. The major exploitation of thin films has been in microelectronics, there are numerous and growing applications in communications, optical electronics, coatings of all kinds, and in energy generation. A great many sophisticated analytical instruments and techniques, largely developed to characterize thin films, have already become indispensable in virtually every scientific endeavor irrespective of discipline. Among all these techniques, electrodeposition is the most suitable technique for nanostructured thin films from aqueous solution served as samples under investigation. The electrodeposition of metallic layers from aqueous solution is based on the discharge of metal ions present in the electrolyte at a cathodic surface (the substrate or component.) The metal ions accept an electron from the electrically conducting material at the solid- electrolyte interface and then deposit as metal atoms onto the surface. The electrons necessary for this to occur are either supplied from an externally applied potential source or are surrendered by a reducing agent present in solution (electroless reduction). The metal ions themselves derive either from metal salts added to solution, or by the anodic dissolution of the so-called sacrificial anodes, made of the same metal that is to be deposited at the cathode.",book:{id:"4718",slug:"electroplating-of-nanostructures",title:"Electroplating of Nanostructures",fullTitle:"Electroplating of Nanostructures"},signatures:"Souad A. M. Al-Bat’hi",authors:[{id:"174793",title:"Dr.",name:"Mohamad",middleName:null,surname:"Souad",slug:"mohamad-souad",fullName:"Mohamad Souad"}]},{id:"54226",title:"Localized Surface Plasmon Resonance for Optical Fiber-Sensing Applications",slug:"localized-surface-plasmon-resonance-for-optical-fiber-sensing-applications",totalDownloads:2265,totalCrossrefCites:2,totalDimensionsCites:5,abstract:"It is well known that optical fiber sensors have attracted the attention of scientific community due to its intrinsic advantages, such as lightweight, small size, portability, remote sensing, immunity to electromagnetic interferences and the possibility of multiplexing several signals. This field has shown a dramatic growth thanks to the creation of sensitive thin films onto diverse optical fiber configurations. In this sense, a wide range of optical fiber devices have been successfully fabricated for monitoring biological, chemical, medical or physical parameters. In addition, the use of nanoparticles into the sensitive thin films has resulted in an enhancement in the response time, robustness or sensitivity in the optical devices, which is associated to the inherent properties of nanoparticles (high surface area ratio or porosity). Among all of them, the metallic nanoparticles are of great interest for sensing applications due to the presence of strong absorption bands in the visible and near-infrared regions, due to their localized surface plasmon resonances (LSPR). These optical resonances are due to the coupling of certain modes of the incident light to the collective oscillation of the conduction electrons of the metallic nanoparticles. The LSPR extinction bands are very useful for sensing applications as far as they can be affected by refractive index variations of the surrounding medium of the nanoparticles, and therefore, it is possible to create optical sensors with outstanding properties such as high sensitivity and optical self-reference. In this chapter, the attractive optical properties of metal nanostructures and their implementation into different optical fiber configuration for sensing or biosensing applications will be studied.",book:{id:"5721",slug:"nanoplasmonics-fundamentals-and-applications",title:"Nanoplasmonics",fullTitle:"Nanoplasmonics - Fundamentals and Applications"},signatures:"Pedro J. Rivero, Javier Goicoechea and Francisco J. Arregui",authors:[{id:"69816",title:"Dr.",name:"Javier",middleName:null,surname:"Goicoechea",slug:"javier-goicoechea",fullName:"Javier Goicoechea"},{id:"188796",title:"Dr.",name:"Pedro J.",middleName:null,surname:"Rivero",slug:"pedro-j.-rivero",fullName:"Pedro J. Rivero"},{id:"197277",title:"Dr.",name:"Francisco",middleName:null,surname:"Arregui",slug:"francisco-arregui",fullName:"Francisco Arregui"}]},{id:"25297",title:"Nanofabrication of Metal Oxide Patterns Using Self-Assembled Monolayers",slug:"nanofabrication-of-metal-oxide-patterns-using-self-assembled-monolayers",totalDownloads:3443,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"860",slug:"nanofabrication",title:"Nanofabrication",fullTitle:"Nanofabrication"},signatures:"Yoshitake Masuda",authors:[{id:"12385",title:"Dr.",name:"Yoshitake",middleName:null,surname:"Masuda",slug:"yoshitake-masuda",fullName:"Yoshitake Masuda"}]},{id:"77225",title:"Piezoelectricity and Its Applications",slug:"piezoelectricity-and-its-applications",totalDownloads:510,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The piezoelectric effect is extensively encountered in nature and many synthetic materials. Piezoelectric materials are capable of transforming mechanical strain and vibration energy into electrical energy. This property allows opportunities for implementing renewable and sustainable energy through power harvesting and self-sustained smart sensing in buildings. As the most common construction material, plain cement paste lacks satisfactory piezoelectricity and is not efficient at harvesting the electrical energy from the ambient vibrations of a building system. In recent years, many techniques have been proposed and applied to improve the piezoelectric capacity of cement-based composite, namely admixture incorporation and physical. The successful application of piezoelectric materials for sustainable building development not only relies on understanding the mechanism of the piezoelectric properties of various building components, but also the latest developments and implementations in the building industry. Therefore, this review systematically illustrates research efforts to develop new construction materials with high piezoelectricity and energy storage capacity. In addition, this article discusses the latest techniques for utilizing the piezoelectric materials in energy harvesters, sensors and actuators for various building systems. With advanced methods for improving the cementations piezoelectricity and applying the material piezoelectricity for different building functions, more renewable and sustainable building systems are anticipated.",book:{id:"10511",slug:"multifunctional-ferroelectric-materials",title:"Multifunctional Ferroelectric Materials",fullTitle:"Multifunctional Ferroelectric Materials"},signatures:"B. Chandra Sekhar, B. Dhanalakshmi, B. Srinivasa Rao, S. Ramesh, K. Venkata Prasad, P.S.V. Subba Rao and B. Parvatheeswara Rao",authors:[{id:"335022",title:"Dr.",name:"B. Chandra",middleName:null,surname:"Sekhar",slug:"b.-chandra-sekhar",fullName:"B. Chandra Sekhar"},{id:"422021",title:"Dr.",name:"B.",middleName:null,surname:"Dhanalakshmi",slug:"b.-dhanalakshmi",fullName:"B. Dhanalakshmi"},{id:"422022",title:"Dr.",name:"B.Srinivasa",middleName:null,surname:"Rao",slug:"b.srinivasa-rao",fullName:"B.Srinivasa Rao"},{id:"422023",title:"Dr.",name:"S.",middleName:null,surname:"Ramesh",slug:"s.-ramesh",fullName:"S. Ramesh"},{id:"422024",title:"Dr.",name:"K.Venkata",middleName:null,surname:"Prasad",slug:"k.venkata-prasad",fullName:"K.Venkata Prasad"},{id:"422025",title:"Dr.",name:"P.S.V",middleName:null,surname:"Subba Rao",slug:"p.s.v-subba-rao",fullName:"P.S.V Subba Rao"},{id:"422026",title:"Dr.",name:"B.Parvatheeswara",middleName:null,surname:"Rao",slug:"b.parvatheeswara-rao",fullName:"B.Parvatheeswara Rao"}]}],onlineFirstChaptersFilter:{topicId:"1169",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81438",title:"Research Progress of Ionic Thermoelectric Materials for Energy Harvesting",slug:"research-progress-of-ionic-thermoelectric-materials-for-energy-harvesting",totalDownloads:23,totalDimensionsCites:0,doi:"10.5772/intechopen.101771",abstract:"Thermoelectric material is a kind of functional material that can mutually convert heat energy and electric energy. It can convert low-grade heat energy (less than 130°C) into electric energy. Compared with traditional electronic thermoelectric materials, ionic thermoelectric materials have higher performance. The Seebeck coefficient can generate 2–3 orders of magnitude higher ionic thermoelectric potential than electronic thermoelectric materials, so it has good application prospects in small thermoelectric generators and solar power generation. According to the thermoelectric conversion mechanism, ionic thermoelectric materials can be divided into ionic thermoelectric materials based on the Soret effect and thermocouple effect. They are widely used in pyrogen batteries and ionic thermoelectric capacitors. The latest two types of ionic thermoelectric materials are in this article. The research progress is explained, and the problems and challenges of ionic thermoelectric materials and the future development direction are also put forward.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Jianwei Zhang, Ying Xiao, Bowei Lei, Gengyuan Liang and Wenshu Zhao"},{id:"77670",title:"Thermoelectric Elements with Negative Temperature Factor of Resistance",slug:"thermoelectric-elements-with-negative-temperature-factor-of-resistance",totalDownloads:71,totalDimensionsCites:0,doi:"10.5772/intechopen.98860",abstract:"The method of manufacturing of ceramic materials on the basis of ferrites of nickel and cobalt by synthesis and sintering in controllable regenerative atmosphere is presented. As the generator of regenerative atmosphere the method of conversion of carbonic gas is offered. Calculation of regenerative atmosphere for simultaneous sintering of ceramic ferrites of nickel and cobalt is carried out. It is offered, methods of the dilated nonequilibrium thermodynamics to view process of distribution of a charge and heat along a thermoelement branch. The model of a thermoelement taking into account various relaxation times of a charge and warmth is constructed.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Yuri Bokhan"},{id:"79236",title:"Processing Techniques with Heating Conditions for Multiferroic Systems of BiFeO3, BaTiO3, PbTiO3, CaTiO3 Thin Films",slug:"processing-techniques-with-heating-conditions-for-multiferroic-systems-of-bifeo3-batio3-pbtio3-catio",totalDownloads:96,totalDimensionsCites:0,doi:"10.5772/intechopen.101122",abstract:"In this chapter, we have report a list of synthesis methods (including both synthesis steps & heating conditions) used for thin film fabrication of perovskite ABO3 (BiFeO3, BaTiO3, PbTiO3 and CaTiO3) based multiferroics (in both single-phase and composite materials). The processing of high quality multiferroic thin film have some features like epitaxial strain, physical phenomenon at atomic-level, interfacial coupling parameters to enhance device performance. Since these multiferroic thin films have ME properties such as electrical (dielectric, magnetoelectric coefficient & MC) and magnetic (ferromagnetic, magnetic susceptibility etc.) are heat sensitive, i.e. ME response at low as well as higher temperature might to enhance the device performance respect with long range ordering. The magnetoelectric coupling between ferromagnetism and ferroelectricity in multiferroic becomes suitable in the application of spintronics, memory and logic devices, and microelectronic memory or piezoelectric devices. In comparison with bulk multiferroic, the fabrication of multiferroic thin film with different structural geometries on substrate has reducible clamping effect. A brief procedure for multiferroic thin film fabrication in terms of their thermal conditions (temperature for film processing and annealing for crystallization) are described. Each synthesis methods have its own characteristic phenomenon in terms of film thickness, defects formation, crack free film, density, chip size, easier steps and availability etc. been described. A brief study towards phase structure and ME coupling for each multiferroic system of BiFeO3, BaTiO3, PbTiO3 and CaTiO3 is shown.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Kuldeep Chand Verma and Manpreet Singh"},{id:"78034",title:"Quantum Physical Interpretation of Thermoelectric Properties of Ruthenate Pyrochlores",slug:"quantum-physical-interpretation-of-thermoelectric-properties-of-ruthenate-pyrochlores",totalDownloads:74,totalDimensionsCites:0,doi:"10.5772/intechopen.99260",abstract:"Lead- and lead-yttrium ruthenate pyrochlores were synthesized and investigated for Seebeck coefficients, electrical- and thermal conductivity. Compounds A2B2O6.5+z with 0 ≤ z < 0.5 were defect pyrochlores and p-type conductors. The thermoelectric data were analyzed using quantum physical models to identify scattering mechanisms underlying electrical (σ) and thermal conductivity (κ) and to understand the temperature dependence of the Seebeck effect (S). In the metal-like lead ruthenates with different Pb:Ru ratios, σ (T) and the electronic thermal conductivity κe (T) were governed by ‘electron impurity scattering’, the lattice thermal conductivity κL (T) by the 3-phonon resistive process (Umklapp scattering). In the lead-yttrium ruthenate solid solutions (Pb(2-x)YxRu2O(6.5±z)), a metal–insulator transition occurred at 0.2 moles of yttrium. On the metallic side (<0.2 moles Y) ‘electron impurity scattering’ prevailed. On the semiconductor/insulator side between x = 0.2 and x = 1.0 several mechanisms were equally likely. At x > 1.5 the Mott Variable Range Hopping mechanism was active. S (T) was discussed for Pb-Y-Ru pyrochlores in terms of the effect of minority carrier excitation at lower- and a broadening of the Fermi distribution at higher temperatures. The figures of merit of all of these pyrochlores were still small (≤7.3 × 10−3).",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Sepideh Akhbarifar"},{id:"77635",title:"Optimization of Thermoelectric Properties Based on Rashba Spin Splitting",slug:"optimization-of-thermoelectric-properties-based-on-rashba-spin-splitting",totalDownloads:124,totalDimensionsCites:0,doi:"10.5772/intechopen.98788",abstract:"In recent years, the application of thermoelectricity has become more and more widespread. Thermoelectric materials provide a simple and environmentally friendly solution for the direct conversion of heat to electricity. The development of higher performance thermoelectric materials and their performance optimization have become more important. Generally, to improve the ZT value, electrical conductivity, Seebeck coefficient and thermal conductivity must be globally optimized as a whole object. However, due to the strong coupling among ZT parameters in many cases, it is very challenging to break the bottleneck of ZT optimization currently. Beyond the traditional optimization methods (such as inducing defects, varying temperature), the Rashba effect is expected to effectively increase the S2σ and decrease the κ, thus enhancing thermoelectric performance, which provides a new strategy to develop new-generation thermoelectric materials. Although the Rashba effect has great potential in enhancing thermoelectric performance, the underlying mechanism of Rashba-type thermoelectric materials needs further research. In addition, how to introduce Rashba spin splitting into current thermoelectric materials is also of great significance to the optimization of thermoelectricity.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Zhenzhen Qin"},{id:"75364",title:"Challenges in Improving Performance of Oxide Thermoelectrics Using Defect Engineering",slug:"challenges-in-improving-performance-of-oxide-thermoelectrics-using-defect-engineering",totalDownloads:214,totalDimensionsCites:0,doi:"10.5772/intechopen.96278",abstract:"Oxide thermoelectric materials are considered promising for high-temperature thermoelectric applications in terms of low cost, temperature stability, reversible reaction, and so on. Oxide materials have been intensively studied to suppress the defects and electronic charge carriers for many electronic device applications, but the studies with a high concentration of defects are limited. It desires to improve thermoelectric performance by enhancing its charge transport and lowering its lattice thermal conductivity. For this purpose, here, we modified the stoichiometry of cation and anion vacancies in two different systems to regulate the carrier concentration and explored their thermoelectric properties. Both cation and anion vacancies act as a donor of charge carriers and act as phonon scattering centers, decoupling the electrical conductivity and thermal conductivity.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Jamil Ur Rahman, Gul Rahman and Soonil Lee"}],onlineFirstChaptersTotal:6},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:287,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:10,numberOfPublishedChapters:103,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"7",title:"Biomedical Engineering",doi:"10.5772/intechopen.71985",issn:"2631-5343",scope:"Biomedical Engineering is one of the fastest-growing interdisciplinary branches of science and industry. The combination of electronics and computer science with biology and medicine has improved patient diagnosis, reduced rehabilitation time, and helped to facilitate a better quality of life. Nowadays, all medical imaging devices, medical instruments, or new laboratory techniques result from the cooperation of specialists in various fields. The series of Biomedical Engineering books covers such areas of knowledge as chemistry, physics, electronics, medicine, and biology. This series is intended for doctors, engineers, and scientists involved in biomedical engineering or those wanting to start working in this field.",coverUrl:"https://cdn.intechopen.com/series/covers/7.jpg",latestPublicationDate:"May 13th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:12,editor:{id:"50150",title:"Prof.",name:"Robert",middleName:null,surname:"Koprowski",slug:"robert-koprowski",fullName:"Robert Koprowski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTYNQA4/Profile_Picture_1630478535317",biography:"Robert Koprowski, MD (1997), PhD (2003), Habilitation (2015), is an employee of the University of Silesia, Poland, Institute of Computer Science, Department of Biomedical Computer Systems. For 20 years, he has studied the analysis and processing of biomedical images, emphasizing the full automation of measurement for a large inter-individual variability of patients. Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:7,paginationItems:[{id:"7",title:"Bioinformatics and Medical Informatics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",slug:"slawomir-wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",biography:"Professor Sławomir Wilczyński, Head of the Chair of Department of Basic Biomedical Sciences, Faculty of Pharmaceutical Sciences, Medical University of Silesia in Katowice, Poland. His research interests are focused on modern imaging methods used in medicine and pharmacy, including in particular hyperspectral imaging, dynamic thermovision analysis, high-resolution ultrasound, as well as other techniques such as EPR, NMR and hemispheric directional reflectance. Author of over 100 scientific works, patents and industrial designs. Expert of the Polish National Center for Research and Development, Member of the Investment Committee in the Bridge Alfa NCBiR program, expert of the Polish Ministry of Funds and Regional Policy, Polish Medical Research Agency. Editor-in-chief of the journal in the field of aesthetic medicine and dermatology - Aesthetica.",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"5886",title:"Dr.",name:"Alexandros",middleName:"T.",surname:"Tzallas",slug:"alexandros-tzallas",fullName:"Alexandros Tzallas",profilePictureURL:"https://mts.intechopen.com/storage/users/5886/images/system/5886.png",institutionString:"University of Ioannina, Greece & Imperial College London",institution:{name:"University of Ioannina",institutionURL:null,country:{name:"Greece"}}},{id:"257388",title:"Distinguished Prof.",name:"Lulu",middleName:null,surname:"Wang",slug:"lulu-wang",fullName:"Lulu Wang",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRX6kQAG/Profile_Picture_1630329584194",institutionString:null,institution:{name:"Shenzhen Technology University",institutionURL:null,country:{name:"China"}}},{id:"225387",title:"Prof.",name:"Reda R.",middleName:"R.",surname:"Gharieb",slug:"reda-r.-gharieb",fullName:"Reda R. 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He completed a one-year Post-Doctoral Fellowship awarded by the DFAIT (Foreign Affairs and International Trade Canada) at the Institute of Biomedical Engineering of the University of New Brunswick (Canada) in 2010. Currently, he is Professor in the Faculty of Electrical Engineering (UFU). He has authored and co-authored more than 200 peer-reviewed publications in Biomedical Engineering. He has been a researcher of The National Council for Scientific and Technological Development (CNPq-Brazil) since 2009. He has served as an ad-hoc consultant for CNPq, CAPES (Coordination for the Improvement of Higher Education Personnel), FINEP (Brazilian Innovation Agency), and other funding bodies on several occasions. He was the Secretary of the Brazilian Society of Biomedical Engineering (SBEB) from 2015 to 2016, President of SBEB (2017-2018) and Vice-President of SBEB (2019-2020). He was the head of the undergraduate program in Biomedical Engineering of the Federal University of Uberlândia (2015 - June/2019) and the head of the Centre for Innovation and Technology Assessment in Health (NIATS/UFU) since 2010. He is the head of the Postgraduate Program in Biomedical Engineering (UFU, July/2019 - to date). He was the secretary of the Parkinson's Disease Association of Uberlândia (2018-2019). Dr. Andrade's primary area of research is focused towards getting information from the neuromuscular system to understand its strategies of organization, adaptation and controlling in the context of motor neuron diseases. 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Dr. Villarreal is the editor in chief and founder of the Revista de Ciencias Tecnológicas (RECIT) (https://recit.uabc.mx/) and is a member of several editorial and reviewer boards for numerous international journals. He has published more than thirty international papers and reviewed more than ninety-two manuscripts. 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Carvajal-Gámez, Guillermo Urriolagoitia-Sosa and Alberto J. 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(Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. His research interests include intelligent and embedded systems.",institutionString:"Universidad Autonoma de Queretaro",institution:{name:"Autonomous University of Queretaro",institutionURL:null,country:{name:"Mexico"}}}]},{type:"book",id:"7726",title:"Swarm Intelligence",subtitle:"Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/7726.jpg",slug:"swarm-intelligence-recent-advances-new-perspectives-and-applications",publishedDate:"December 4th 2019",editedByType:"Edited by",bookSignature:"Javier Del Ser, Esther Villar and Eneko Osaba",hash:"e7ea7e74ce7a7a8e5359629e07c68d31",volumeInSeries:2,fullTitle:"Swarm Intelligence - Recent Advances, New Perspectives and Applications",editors:[{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:null}]},{type:"book",id:"7656",title:"Fuzzy Logic",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7656.jpg",slug:"fuzzy-logic",publishedDate:"February 5th 2020",editedByType:"Edited by",bookSignature:"Constantin Volosencu",hash:"54f092d4ffe0abf5e4172a80025019bc",volumeInSeries:3,fullTitle:"Fuzzy Logic",editors:[{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:"Polytechnic University of Timişoara",institution:{name:"Polytechnic University of Timişoara",institutionURL:null,country:{name:"Romania"}}}]},{type:"book",id:"9963",title:"Advances and Applications in Deep Learning",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/9963.jpg",slug:"advances-and-applications-in-deep-learning",publishedDate:"December 9th 2020",editedByType:"Edited by",bookSignature:"Marco Antonio Aceves-Fernandez",hash:"0d51ba46f22e55cb89140f60d86a071e",volumeInSeries:4,fullTitle:"Advances and Applications in Deep Learning",editors:[{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. (Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. His research interests include intelligent and embedded systems.",institutionString:"Universidad Autonoma de Queretaro",institution:{name:"Autonomous University of Queretaro",institutionURL:null,country:{name:"Mexico"}}}]}]},openForSubmissionBooks:{paginationCount:7,paginationItems:[{id:"11667",title:"Marine Pollution - Recent Developments",coverURL:"https://cdn.intechopen.com/books/images_new/11667.jpg",hash:"e524cd97843b075a724e151256773631",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"April 20th 2022",isOpenForSubmission:!0,editors:[{id:"318562",title:"Dr.",name:"Monique",surname:"Mancuso",slug:"monique-mancuso",fullName:"Monique Mancuso"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11664",title:"Recent Advances in Sensing Technologies for Environmental Control and Monitoring",coverURL:"https://cdn.intechopen.com/books/images_new/11664.jpg",hash:"cf1ee76443e393bc7597723c3ee3e26f",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"May 4th 2022",isOpenForSubmission:!0,editors:[{id:"24687",title:"Dr.",name:"Toonika",surname:"Rinken",slug:"toonika-rinken",fullName:"Toonika Rinken"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11662",title:"Limnology - The Importance of Monitoring and Correlations of Lentic and Lotic Waters",coverURL:"https://cdn.intechopen.com/books/images_new/11662.jpg",hash:"f1043cf6b1daae7a7b527e1d162ca4a8",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"May 10th 2022",isOpenForSubmission:!0,editors:[{id:"315689",title:"Dr.",name:"Carmine",surname:"Massarelli",slug:"carmine-massarelli",fullName:"Carmine Massarelli"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"10845",title:"Marine Ecosystems - Biodiversity, Ecosystem Services and Human Impacts",coverURL:"https://cdn.intechopen.com/books/images_new/10845.jpg",hash:"727e7eb3d4ba529ec5eb4f150e078523",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"May 12th 2022",isOpenForSubmission:!0,editors:[{id:"320124",title:"Dr.",name:"Ana M.M.",surname:"Gonçalves",slug:"ana-m.m.-goncalves",fullName:"Ana M.M. 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He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. 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:"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:"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://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNVJQA4/Profile_Picture_2022-03-07T13:23:04.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. His research interests include biochemistry, oxidative stress, reactive species, antioxidants, lipid peroxidation, inflammation, reproductive hormones, phenolic compounds, female infertility.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Associate Prof.",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:"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/15648_n.jpg",biography:"Dr. Mohd Aftab Siddiqui is currently working as Assistant Professor in the Faculty of Pharmacy, Integral University, Lucknow for the last 6 years. He has completed his Doctor in Philosophy (Pharmacology) in 2020 from Integral University, Lucknow. He completed his Bachelor in Pharmacy in 2013 and Master in Pharmacy (Pharmacology) in 2015 from Integral University, Lucknow. He is the gold medalist in Bachelor and Master degree. He qualified GPAT -2013, GPAT -2014, and GPAT 2015. His area of research is Pharmacological screening of herbal drugs/ natural products in liver and cardiac diseases. He has guided many M. Pharm. research projects. He has many national and international publications.",institutionString:"Integral University",institution:null},{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255360/images/system/255360.png",biography:"Dr. Usama Ahmad holds a specialization in Pharmaceutics from Amity University, Lucknow, India. He received his Ph.D. degree from Integral University. Currently, he’s working as an Assistant Professor of Pharmaceutics in the Faculty of Pharmacy, Integral University. From 2013 to 2014 he worked on a research project funded by SERB-DST, Government of India. He has a rich publication record with more than 32 original articles published in reputed journals, 3 edited books, 5 book chapters, and a number of scientific articles published in ‘Ingredients South Asia Magazine’ and ‘QualPharma Magazine’. He is a member of the American Association for Cancer Research, International Association for the Study of Lung Cancer, and the British Society for Nanomedicine. Dr. Ahmad’s research focus is on the development of nanoformulations to facilitate the delivery of drugs that aim to provide practical solutions to current healthcare problems.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"30568",title:"Prof.",name:"Madhu",middleName:null,surname:"Khullar",slug:"madhu-khullar",fullName:"Madhu Khullar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/30568/images/system/30568.jpg",biography:"Dr. Madhu Khullar is a Professor of Experimental Medicine and Biotechnology at the Post Graduate Institute of Medical Education and Research, Chandigarh, India. She completed her Post Doctorate in hypertension research at the Henry Ford Hospital, Detroit, USA in 1985. She is an editor and reviewer of several international journals, and a fellow and member of several cardiovascular research societies. Dr. Khullar has a keen research interest in genetics of hypertension, and is currently studying pharmacogenetics of hypertension.",institutionString:"Post Graduate Institute of Medical Education and Research",institution:{name:"Post Graduate Institute of Medical Education and Research",country:{name:"India"}}},{id:"223233",title:"Prof.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/223233/images/system/223233.png",biography:"Xianquan Zhan received his MD and Ph.D. in Preventive Medicine at West China University of Medical Sciences. He received his post-doctoral training in oncology and cancer proteomics at the Central South University, China, and the University of Tennessee Health Science Center (UTHSC), USA. He worked at UTHSC and the Cleveland Clinic in 2001–2012 and achieved the rank of associate professor at UTHSC. Currently, he is a full professor at Central South University and Shandong First Medical University, and an advisor to MS/PhD students and postdoctoral fellows. He is also a fellow of the Royal Society of Medicine and European Association for Predictive Preventive Personalized Medicine (EPMA), a national representative of EPMA, and a member of the American Society of Clinical Oncology (ASCO) and the American Association for the Advancement of Sciences (AAAS). He is also the editor in chief of International Journal of Chronic Diseases & Therapy, an associate editor of EPMA Journal, Frontiers in Endocrinology, and BMC Medical Genomics, and a guest editor of Mass Spectrometry Reviews, Frontiers in Endocrinology, EPMA Journal, and Oxidative Medicine and Cellular Longevity. He has published more than 148 articles, 28 book chapters, 6 books, and 2 US patents in the field of clinical proteomics and biomarkers.",institutionString:"Shandong First Medical University",institution:{name:"Affiliated Hospital of Shandong Academy of Medical Sciences",country:{name:"China"}}},{id:"297507",title:"Dr.",name:"Charles",middleName:"Elias",surname:"Assmann",slug:"charles-assmann",fullName:"Charles Assmann",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/297507/images/system/297507.jpg",biography:"Charles Elias Assmann is a biologist from Federal University of Santa Maria (UFSM, Brazil), who spent some time abroad at the Ludwig-Maximilians-Universität München (LMU, Germany). He has Masters Degree in Biochemistry (UFSM), and is currently a PhD student at Biochemistry at the Department of Biochemistry and Molecular Biology of the UFSM. His areas of expertise include: Biochemistry, Molecular Biology, Enzymology, Genetics and Toxicology. He is currently working on the following subjects: Aluminium toxicity, Neuroinflammation, Oxidative stress and Purinergic system. Since 2011 he has presented more than 80 abstracts in scientific proceedings of national and international meetings. Since 2014, he has published more than 20 peer reviewed papers (including 4 reviews, 3 in Portuguese) and 2 book chapters. He has also been a reviewer of international journals and ad hoc reviewer of scientific committees from Brazilian Universities.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",country:{name:"Brazil"}}},{id:"217850",title:"Dr.",name:"Margarete Dulce",middleName:null,surname:"Bagatini",slug:"margarete-dulce-bagatini",fullName:"Margarete Dulce Bagatini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217850/images/system/217850.jpeg",biography:"Dr. Margarete Dulce Bagatini is an associate professor at the Federal University of Fronteira Sul/Brazil. She has a degree in Pharmacy and a PhD in Biological Sciences: Toxicological Biochemistry. She is a member of the UFFS Research Advisory Committee\nand a member of the Biovitta Research Institute. She is currently:\nthe leader of the research group: Biological and Clinical Studies\nin Human Pathologies, professor of postgraduate program in\nBiochemistry at UFSC and postgraduate program in Science and Food Technology at\nUFFS. She has experience in the area of pharmacy and clinical analysis, acting mainly\non the following topics: oxidative stress, the purinergic system and human pathologies, being a reviewer of several international journals and books.",institutionString:"Universidade Federal da Fronteira Sul",institution:{name:"Universidade Federal da Fronteira Sul",country:{name:"Brazil"}}},{id:"226275",title:"Ph.D.",name:"Metin",middleName:null,surname:"Budak",slug:"metin-budak",fullName:"Metin Budak",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226275/images/system/226275.jfif",biography:"Metin Budak, MSc, PhD is an Assistant Professor at Trakya University, Faculty of Medicine. He has been Head of the Molecular Research Lab at Prof. Mirko Tos Ear and Hearing Research Center since 2018. His specializations are biophysics, epigenetics, genetics, and methylation mechanisms. He has published around 25 peer-reviewed papers, 2 book chapters, and 28 abstracts. He is a member of the Clinical Research Ethics Committee and Quantification and Consideration Committee of Medicine Faculty. His research area is the role of methylation during gene transcription, chromatin packages DNA within the cell and DNA repair, replication, recombination, and gene transcription. His research focuses on how the cell overcomes chromatin structure and methylation to allow access to the underlying DNA and enable normal cellular function.",institutionString:"Trakya University",institution:{name:"Trakya University",country:{name:"Turkey"}}},{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",slug:"anca-pantea-stoian",fullName:"Anca Pantea Stoian",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",biography:"Anca Pantea Stoian is a specialist in diabetes, nutrition, and metabolic diseases as well as health food hygiene. She also has competency in general ultrasonography.\n\nShe is an associate professor in the Diabetes, Nutrition and Metabolic Diseases Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. She has been chief of the Hygiene Department, Faculty of Dentistry, at the same university since 2019. Her interests include micro and macrovascular complications in diabetes and new therapies. Her research activities focus on nutritional intervention in chronic pathology, as well as cardio-renal-metabolic risk assessment, and diabetes in cancer. She is currently engaged in developing new therapies and technological tools for screening, prevention, and patient education in diabetes. \n\nShe is a member of the European Association for the Study of Diabetes, Cardiometabolic Academy, CEDA, Romanian Society of Diabetes, Nutrition and Metabolic Diseases, Romanian Diabetes Federation, and Association for Renal Metabolic and Nutrition studies. She has authored or co-authored 160 papers in national and international peer-reviewed journals.",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",country:{name:"Romania"}}},{id:"279792",title:"Dr.",name:"João",middleName:null,surname:"Cotas",slug:"joao-cotas",fullName:"João Cotas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279792/images/system/279792.jpg",biography:"Graduate and master in Biology from the University of Coimbra.\n\nI am a research fellow at the Macroalgae Laboratory Unit, in the MARE-UC – Marine and Environmental Sciences Centre of the University of Coimbra. My principal function is the collection, extraction and purification of macroalgae compounds, chemical and bioactive characterization of the compounds and algae extracts and development of new methodologies in marine biotechnology area. \nI am associated in two projects: one consists on discovery of natural compounds for oncobiology. The other project is the about the natural compounds/products for agricultural area.\n\nPublications:\nCotas, J.; Figueirinha, A.; Pereira, L.; Batista, T. 2018. An analysis of the effects of salinity on Fucus ceranoides (Ochrophyta, Phaeophyceae), in the Mondego River (Portugal). Journal of Oceanology and Limnology. in press. DOI: 10.1007/s00343-019-8111-3",institutionString:"Faculty of Sciences and Technology of University of Coimbra",institution:null},{id:"279788",title:"Dr.",name:"Leonel",middleName:null,surname:"Pereira",slug:"leonel-pereira",fullName:"Leonel Pereira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279788/images/system/279788.jpg",biography:"Leonel Pereira has an undergraduate degree in Biology, a Ph.D. in Biology (specialty in Cell Biology), and a Habilitation degree in Biosciences (specialization in Biotechnology) from the Faculty of Science and Technology, University of Coimbra, Portugal, where he is currently a professor. In addition to teaching at this university, he is an integrated researcher at the Marine and Environmental Sciences Center (MARE), Portugal. His interests include marine biodiversity (algae), marine biotechnology (algae bioactive compounds), and marine ecology (environmental assessment). Since 2008, he has been the author and editor of the electronic publication MACOI – Portuguese Seaweeds Website (www.seaweeds.uc.pt). He is also a member of the editorial boards of several scientific journals. Dr. Pereira has edited or authored more than 20 books, 100 journal articles, and 45 book chapters. He has given more than 100 lectures and oral communications at various national and international scientific events. He is the coordinator of several national and international research projects. In 1998, he received the Francisco de Holanda Award (Honorable Mention) and, more recently, the Mar Rei D. Carlos award (18th edition). 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In her research, she had used organisms including bacteriophage T4, Neurospora crassa, Schizosaccharomyces pombe and mice, as well as human cells and tissues. She authored or co-authored more than 140 scientific publications, including articles in major peer reviewed journals, book chapters, invited reviews and one book.",institutionString:"University of Arizona",institution:{name:"University of Arizona",country:{name:"United States of America"}}},{id:"182258",title:"Dr.",name:"Ademar",middleName:"Pereira",surname:"Serra",slug:"ademar-serra",fullName:"Ademar Serra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/182258/images/system/182258.jpeg",biography:"Dr. Serra studied Agronomy on Universidade Federal de Mato Grosso do Sul (UFMS) (2005). He received master degree in Agronomy, Crop Science (Soil fertility and plant nutrition) (2007) by Universidade Federal da Grande Dourados (UFGD), and PhD in agronomy (Soil fertility and plant nutrition) (2011) from Universidade Federal da Grande Dourados / Escola Superior de Agricultura Luiz de Queiroz (UFGD/ESALQ-USP). Dr. Serra is currently working at Brazilian Agricultural Research Corporation (EMBRAPA). His research focus is on mineral nutrition of plants, crop science and soil science. 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