\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"3543",leadTitle:null,fullTitle:"Melanoma - From Early Detection to Treatment",title:"Melanoma",subtitle:"From Early Detection to Treatment",reviewType:"peer-reviewed",abstract:'The Book "Melanoma - From Early Detection To Treatment" is aiming to present data and knowledge from most experienced experts in the field. The book covers main topics from the fundamental aspects to multiple approaches in the disease treatment as well as related features. It offers a global view concerning one of the most frequent types of cancer to which a substantial high proportion of people worldwide is confronted at some time point in life.',isbn:null,printIsbn:"978-953-51-0961-7",pdfIsbn:"978-953-51-7076-1",doi:"10.5772/50853",price:159,priceEur:175,priceUsd:205,slug:"melanoma-from-early-detection-to-treatment",numberOfPages:732,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"1967c96a87db80e9bbbabf9293f43ad0",bookSignature:"Guy Huynh Thien Duc",publishedDate:"January 30th 2013",coverURL:"https://cdn.intechopen.com/books/images_new/3543.jpg",numberOfDownloads:58680,numberOfWosCitations:30,numberOfCrossrefCitations:16,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:38,numberOfDimensionsCitationsByBook:1,hasAltmetrics:1,numberOfTotalCitations:84,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 18th 2012",dateEndSecondStepPublish:"May 9th 2012",dateEndThirdStepPublish:"August 13th 2012",dateEndFourthStepPublish:"November 11th 2012",dateEndFifthStepPublish:"December 11th 2012",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"50372",title:"Dr.",name:"Guy Huynh Thien",middleName:null,surname:"Duc",slug:"guy-huynh-thien-duc",fullName:"Guy Huynh Thien Duc",profilePictureURL:"https://mts.intechopen.com/storage/users/50372/images/3718_n.jpg",biography:"Guy HUYNH THIEN DUC is Research Director emeritus from the CNRS (Centre National de la Recherche Scientifique). He started his career in the Pasteur Institute where he prepared his Ph.D in the field of Immunopathology. Thereafter, as researcher in the CNRS, he has been mainly involved in fundamental aspects of Immunology, focusing on Transplantation Immunity and Immunomodulation. 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\r\n\tMedicinal herbs and culinary spices are very important sources of bioactive compounds for different kinds of industries. They accompany a person's life from birth to grave almost every day, in various forms is, served to our table as a part of the food. Many plants are necessary for technical and bioenergetic purposes, and a large group of plants is used in medicine, pharmacy, cosmetics as well as in folk medicine, and gastronomy. Approximately one thousand types of medicinal plants grow in Europe – about 800 are used in folk medicine, more than 300 in European officinal medicine. Nowadays, people have started to be more interesting in this kind of plant due to the benefits. The style "return back to tradition" is one of the more popular trends. The aim of this book is brought to information about medicinal herbs and spices – botany characteristics, chemical components, and the possibility of use in different kinds of industries.
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She is the author/co-author of 453 publications and 2 patents.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"352448",title:"Dr.",name:"Eva",middleName:null,surname:"Ivanišová",slug:"eva-ivanisova",fullName:"Eva Ivanišová",profilePictureURL:"https://mts.intechopen.com/storage/users/352448/images/system/352448.jpg",biography:"Ing. Eva Ivanišová, Ph.D. assistant professor at the Institute of Food Sciences, Faculty of Biotechnology and Food Sciences, Slovak University of Agriculture Nitra, head of Laboratory of Fats and Oils in Research Centrum AgroBioTech in SUA Nitra. She solved resp. it addresses 14 research home projects but also educational and 2 international projects. She is the author, resp. co-author of 453 publications. Her works, especially in foreign journals, are a guarantee of international acceptance. Awards: 2011 – Rector's Award for best student; 2015 and 2019, 2020 – Dean's Award for the Best of publication activity. Under her leadership, 29 Bachelors and 55 diplomats successfully defended their work. She is a member of the international network AgroBioNet; Member of EFSA; CASEE; Member of Evaluation Commission for Start-up projects EIT Food Hub; Member of Examining Commissions for State Examinations; member of scientific committees of international conferences \"Meeting of Young Researches from V4 Countries\", University of Rzeszow, Poland. She is a head of graduation commission in secondary school in Nitra (SOŠ Slančíková Nitra). She is a reviewer of the journals – Natural Product Research (IF 1.999), Journal of Food Science (IF 2.478), Acta Scientiarum Polonorum Technologia Alimentaria, Journal of Agricultural Science and Technology, BMC Complementary Medicine and Therapies (IF 2.833), Food Chemistry (IF 6.306), Journal of Food Science and Technology (IF 1.849), SN Applied Sciences, RSC Advances (IF 3.070), PLoS One (2.740), Open Life Sciences (IF 0.690), Journal of Microbiology, Biotechnology and Food Sciences, Journal of Central European Agriculture et al.",institutionString:"Slovak University of Agriculture",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Slovak University of Agriculture",institutionURL:null,country:{name:"Slovakia"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"5",title:"Agricultural and Biological Sciences",slug:"agricultural-and-biological-sciences"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"478197",firstName:"Veronika",lastName:"Radosavac",middleName:null,title:"Dr.",imageUrl:"//cdnintech.com/web/frontend/www/assets/author.svg",email:"veronika@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"6418",title:"Hyperspectral Imaging in Agriculture, Food and Environment",subtitle:null,isOpenForSubmission:!1,hash:"9005c36534a5dc065577a011aea13d4d",slug:"hyperspectral-imaging-in-agriculture-food-and-environment",bookSignature:"Alejandro Isabel Luna Maldonado, Humberto Rodríguez Fuentes and Juan Antonio Vidales Contreras",coverURL:"https://cdn.intechopen.com/books/images_new/6418.jpg",editedByType:"Edited by",editors:[{id:"105774",title:"Prof.",name:"Alejandro Isabel",surname:"Luna Maldonado",slug:"alejandro-isabel-luna-maldonado",fullName:"Alejandro Isabel Luna Maldonado"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10359",title:"Landraces",subtitle:"Traditional Variety and Natural Breed",isOpenForSubmission:!1,hash:"0600836fb2c422f7b624363d1e854f68",slug:"landraces-traditional-variety-and-natural-breed",bookSignature:"Amr Elkelish",coverURL:"https://cdn.intechopen.com/books/images_new/10359.jpg",editedByType:"Edited by",editors:[{id:"231337",title:"Dr.",name:"Amr",surname:"Elkelish",slug:"amr-elkelish",fullName:"Amr Elkelish"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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The most used and successful therapy for this condition is L-3, 4 dihydroxyphenylalanine (L-DOPA), a precursor in the synthesis of dopamine. However long-term treatment leads to disabling abnormal involuntary movements known as L-DOPA-induced Dyskinesia (LID), which are uncontrolled and repetitive movement in the axis, arms, legs and oro-facial zone [1-2]. The LID is a serious limitation in the usage of L-DOPA and it can be thought that solving the diskinesia by new therapeutic targets could extend the time of treatment with L-DOPA in the parkinsonian patients with an acceptable quality of life. To propose new alternatives is necessary to know the pathogenesis and pathophysiology of this phenomenon.
According with the classical basal ganglia model [3], PD is the result of an imbalance in the motor networks that stimulate and/or inhibit the initiation of movements. There are two main pathways that have been studied in the basal ganglia. The direct pathway, which is associated with D1-like dopamine receptors, and the indirect pathway that it has been related with D2-like dopamine receptors. The adequate balance between the direct (stimulatory) and indirect (inhibitory) networks facilitates the execution of movements [4]. In PD the loss of dopaminergic control leads to a hyperactivity of the inhibitory pathway, which produces bradykinesia the main symptom of this disease [5]. The restoration of dopamine with L-DOPA counteract the unbalance of the two pathways, nevertheless several cellular and molecular changes caused by L-DOPA move the system toward the opposite side, producing a hyperactivity of the direct pathway and originating the dyskinesia phenomenon [5]. Many changes in basal ganglia circuitry have been associated with dyskinesia [6]; one of the most studied is the hyperactivity of direct pathway that produces an increased GABAergic neurotransmission on striato-nigral neurons, which are controlled by dopamine D1 receptors, and it seems to be the most relevant finding. The dopamine D3 receptors have been involved in dyskinesia since was reported that L-DOPA treatment increases its expression in basal ganglia [7], suggesting the use of ligands of these receptors as a target for dyskinesia, but the neurobiological basis of these changes and the site of action is not well understood since conflicting results in experimental assays have been reported [8-12]. The recent finding of co-existence and interaction between D1 and D3 dopamine receptors in the direct pathway [13-16] could contribute to solve this question.
The aim of this review is provide a global view of the pathophysiology of dyskinesia based on the changes reported in animal models and parkinsonian patients that involve the direct pathway and the dopamine D1 and D3 receptors, the understanding of this changes could result in a potential novel therapeutic approaches to treat the dyskinesia.
Basal ganglia are organized in four segregated circuits: motor, oculo-motor, limbic and associative [17]. In PD the motor loop is altered in these structures. The basal ganglia circuit originates in glutamatergic cortical neurons from motor and premotor areas that project to caudate (C) and putamen (P), the striatum in rats (Str). The main phenotype of striatum is the GABAergic medium-size spiny neurons (MSNs), which projects to the direct and indirect pathways. The substance P/Dynorphyn positive MNSs GABAergic neurons project to substantia nigra pars reticulata (SNr) and/or to the internal segment of globus pallidus (GPi), the entopeduncular nucleus (EPn) in rats. SNr and GPi is the output nucleus of the motor loop to the thalamic glutamatergic nucleus, which in turn stimulates the motor cortex; this network is called the direct pathway. While the striatal enkephaline positive MNSs GABAergic neurons project to the external segment of the globus pallidus (GPe), pallidal GABAergic neurons which in turn project their axons to the glutamatergic neurons of the Subthalamic nucleus (Sth) and this neurons project to the output nuclei forming the indirect pathway [17]. (See Fig. 1).
Neurons of the thalamic relay nucleus are subject to a tonic inhibitory control from GABAergic GPi/SNr neurons, the removal of this control leads to the activation of thalamus that in consequence activates the motor cortex facilitating the movement. The activity of GPi/SNr neurons is maintained by a tonic stimulatory action of the Sth controlled reciprocally by the GPe. Stimulation of the MNSs GABAergic striatal neurons by the cortex in the direct pathway produces inhibition of the output nucleus through the release of GABA. The remotion in the inhibition of the thalamus toward to the cortex turns in the initiation of the movement, thus the activation of the direct pathway allows the movement. In contrast the activation of MNSs GABAergic neurons from the indirect pathway inhibits GPe neurons, which removes the tonic inhibitory action on Sth, the increased activity of the glutamatergic neurons stimulates the output nuclei, producing inhibition of thalamus and in consequence inhibit the motor cortex, which means that the activation of the indirect pathway inhibits the movements.
Simultaneous activation of the direct and indirect pathway will produce an antagonistic action on movement. The adequate balance between direct and indirect pathway is maintained by dopamine. The Substantia nigra pars compacta (SNc) is the source of dopamine in the basal ganglia since SNc neurons project to all the basal ganglia nuclei (Fig.1A) in normal conditions [18].
The basal ganglia motor circuits in normal (A), parkinsonism (B) and L-DOPA-induced dyskinesia (C). GPe, external globus pallidus; Sth, subthalamic nucleus; GPi, internal globus pallidus; SNr, substantia nigra pars reticulata; SNc, substantia nigra pars compacta, D1, dopamine D1 receptor and D2, dopamine D2 receptor.
Two families of receptors mediate the action of dopamine through the basal ganglia, D1-like (D1 and D5 subtypes) and D2-like (D2short, D2long D3 and D4 subtypes). D1-like receptors are expressed predominantly in substance P/Dynorphyn positive MNSs GABAergic neurons and their activation increases the firing rate at soma and also the GABA release in the terminals [19-22]. It have been reported that some population of striato-nigral neurons also expresses D3 receptors [14, 23]. While the dopamine D2-like receptors are associated to striatal enkephalin positive MNSs GABAergic neurons and their activation decreases the firing at soma and the GABA release at the terminals [20, 24-26]. Some population of striato-palidal neurons also expresses D5 receptors [23]. Dopamine via D1-like receptors potentiates the stimulation of the direct pathway, while via D2-like receptors decreases indirect pathway activity, synergizing the activity of both pathways and facilitating movement [17]. Other association of dopamine receptors subtypes with neuronal elements of these circuits occurs [27-32], however the role of their function in the integral circuitry is not well understood.
The progressive loss of dopaminergic neurons of the SNc causes the neurodegenerative disorder called Parkinson’s disease. The loss of dopamine has serious consequences in the balance of direct and indirect pathways, in fact a hyperactivity of the indirect pathway with a decrease in the activity of the direct pathway coexists and that explains the hypomotility or bradykinesia observed in patients and in animal models of PD (Fig. 1B) [17].
Dopamine replacement therapy with L-DOPA restores the lack of the neurotransmitter in the basal ganglia [33]. It has been shown that L-DOPA (a precursor in dopamine synthesis, Fig. 2) is transformed to dopamine in the central nervous system by decarboxylation via central aromatic acid decarboxilase (DCAA) [34]; also it has been proposed that remaining dopaminergic neurons (Fig. 2) and/or serotoninergic neurons are host candidates for transformation of L-DOPA [35], mediating an ectopic and false transmitter release [36] in fact any cell that express DCAA can eventually transform L-DOPA into dopamine. The dopamine synthesized from L-DOPA activates D1-like and D2-like family of receptors. However it has been also suggested the existence of DOPAergic receptors [37], since direct effects of L-DOPA on dopamine receptors have been reported [19, 38 -39] but also effects are mediated by either L-DOPA or their metabolites [39, 40-41] that could participate in their therapeutic or side effects including dyskinesia [42-43]. Probably the effectiveness of L-DOPA over dopamine receptor agonist is due to a variety of actions in the central nervous system [44].
Synthesis of dopamine from L-DOPA in the dopaminergic nerve terminals. DCAA, aromatic acid decarboxylase; DAT, dopamine transporter, TH, Tyrosine Hydroxylase; D1, D1-like dopamine receptor; D2, D2-like dopamine receptor.
During L-DOPA treatment the activation of dopamine receptors restores the movement in PD patients and the locomotor activity in experimental animal models. L-DOPA treatment produces a priming effect where the brain is sensitized to L-DOPA after chronic administration and finally produces dyskinesia as main side effect [45] with a prevalence of 30-45% in patients [46]. However early age of Parkinsonism onset and severity of disease have been classified as risk factors in the development of LID [47] and more recently the nigral-associated pathology has been related with early onset of LID [48]. It has been shown that pharmacokinetic properties of L-DOPA are also related with the onset of dyskinesia with phenomenological differences in the altered movements. When the higher plasma levels of L-DOPA are reached the maximum antiparkinsonic effect can be achieved. In contrast dyskinesia occurs at intermedium L-DOPA plasma levels either when bioavailability is increasing or decreasing due to metabolism of L-DOPA, interesting when the lower L-DOPA plasma levels are reached generalized dystonic postures occurs [49].
The dyskinesia also has been observed in experimental models of PD under chronic L-DOPA treatment [50], the effect is dose and species dependent, since different population with high and low dyskinesia score have been reported [51-52].
The mechanism of the genesis of dyskinesia is essentially unknown. Initial studies suggested that L-DOPA or metabolites could be responsible of the side effects, however the inhibition of L-DOPA decarboxylation, does not correlate with LID scores [53]. Plenty evidence has been published recently showing that several compensatory effects occur after dopamine denervation and LID.
The changes in nuclear function of striato-nigral and striato-pallidal neurons have been related with denervation, most of them are associated with proteins involved in the dopamine receptors signaling and in the regulation of glutamatergic transmission by dopamine [54], it can be though that L-DOPA therapy should restore these parameters. However that is not the case since the major alterations related to LID occur on these cellular systems [52, 55-60].
It has been reported alteration in gene expression during L-DOPA therapy particularly on transcription factors. Early gene expression which are markers of neural activity has been studied and increased expression of the transcription factor ΔFosB has been associated with L-DOPA induced dyskinesia in rats and related with sensitization process [61-64], while accumulated ΔJunD has been shown drop the severity of LID in monkeys without reduction of antiparkinsonian effects [63]. Also zif-268 has been related with a persistent stimulation of D1 receptors by L-DOPA and has been proposed like a potential marker for the onset of the dyskinetic phenomena [65]. On the other hand histone activation mediated by D1 receptors it has also been related with dyskinesia [66-67] suggesting that changes in gene transcription factors are altered, then is plausible suggest that many alterations in signaling molecules activated by dopaminergic receptors could contribute to the leading of motor disabilities. The resulting changes of the altered activity culminates with expression of proteins related with the activity of D1-associated neurons like the increased expression of prodynorhin, glutamic acid decarboxylase, adenylyl cyclase, PKA, DARPP-32 and CDk5 [52, 54-60].
Nevertheless LID can be also pathophysiologically explained by a change in the balance of the direct/indirect pathway. In this condition an increase in the activity of the direct pathway that facilitates movements can explain the phenomena (Fig. 1C) [5]; since the direct pathway stimulates movement, dyskinesia can be considered a pathologic condition with over-activation of this pathway generated by pulsatile activity of striato-nigral neurons. In fact experimental data supports this idea; a higher release of GABA in SNr/EP has been shown in experimental models of LID [52,68], which in turns facilitates the inhibition of the output neurons and removes the inhibition of premotor nuclei leading activation of the movement.
The role of the indirect pathway and dopamine D2-like receptors is less understood and explored. An over-activity of the GPe is associated with LID [55], and dopamine D2 receptors [69- 71]; however pallidotomy does not modify significantly LID in hemiparkinsonian monkeys [72]. Some D2-like agonist has beneficial effect on L-DOPA induced dyskinesia [73], but the genetic inactivation of dopamine D2 receptor expression in striatum does not modify the development of LID [66]. On the other hand D2 dopamine receptor agonist treatment in PD models produce lower LID compared with D1 receptor agonist treatment suggesting a predominantly role of dopamine D1 receptors [65,74]. Interesting recent reports have shown that L-DOPA restores spine density in D2-expressing striatal neurons of LID mice [75], suggesting an undefined role of striato-pallidal in the dyskinetic phenomenon. On the other hand adenosine A2A receptors are selectively expressed in the indirect pathway and an increased expression of these receptors was found in patients with LID [76], the A2A/D2 receptor heterodimer interaction has been suggested is modified during LID in the indirect pathway [77]. All this data suggested a role of the indirect pathway in LID development; however further studies are needed to clarify the role of D2 receptor and the indirect pathway in the dyskinesia phenomenon.
Other non-dopaminergic alterations have been involved in LID, which contributes to this phenomenon. The idea of a role of the glutamatergic system in LID comes from the use of amantadine in Parkinson’s disease and as an adjuvant in the management of LID [78], in fact amantadine increases extracellular dopamine from L-DOPA in parkinsonian rats [79]. Dopaminergic denervation decreases the expression and phosphorilation of NR1 subunit of the NMDA receptor without change in NR2 subunit. L-DOPA restores the expression of the subunit but also increases the phosphorilation level of the NR2A subunit with a consecutive high activity of the NMDA channel [80-81]. It has been shown also that D1-like receptors increase the phosphorylation of the channel subunits through the PKA signaling pathway [82-83]. Furthermore D1 receptor promotes the expression of NMDA in membrane [80] and can interact at the level of protein [84], in consequence if a generalized hypersensitivity of D1-like receptor activity occurs, the NMDA receptor activity will also be potentiated [80, 85]. Dopamine modulates long-term potentiation (LTP) of the glutamatergic system, in consequence in dyskinesia, L-DOPA could contribute to the prolongation of this effects [78, 86]. It has been shown in dyskinetic rats an increased levels of PSD-95 and SAP97 proteins of the postsynaptic density, those proteins are involved in the interaction of NMDA and AMPA receptors in the membrane, but their participation in the phenomenon has not been completely determined [87-89]. The consequence in all these alterations of the glutamatergic system is a higher excitatory transmission to the direct pathway. An interesting review on the role of D1/NMDA interaction and LID is found in Fiorentini et al., 2008 [90]. Changes in synaptic plasticity induced by L-DOPA also occur in the output nuclei [91].
The role of the serotoninergic system on LID comes from the hypothesis of conversion of L-DOPA to dopamine in serotoninergic neurons and nerve terminals within the basal ganglia [92, 93]. It has been suggested a false-transmitter release of dopamine from this neurons [36, 94], in consequence a higher dopaminergic activity would be the responsible of LID. According with this hypothesis the role of serotonin system in LID is related with effects on dopamine formed in the terminals. Some studies indicates that increasing serotonin levels suppress LID, the effect seem to be mediated by 5-HT1A receptors [95], since these receptors are also located at cortico-striatal glutamatergic terminals is plausible that blockade of D1 receptor activity explains the therapeutically effect [96]. Moreover blockade of serotonin transporter also attenuates LID suggesting that a reduce turnover [95] and activation of serotonin receptors is involved in its beneficial effect.
Dopamine denervation and L-DOPA treatment increases mRNA codifying opioid precursors pro-enkephaline A and B, which correlates with the development of dyskinesia [55, 97]. This effect has been observed in striato-nigral neurons [98] and has been postulated participate in LID due to an enhanced coupling of opioid receptors to G protein [99]. However the blockade of these receptors in dyskinetic rats does not prevent symptoms and in fact there is an increase in the dyskinesia score [100, 101]. It seems that the over-expression is just consequence of denervation, recent studies have been shown that modification of δ-opiod receptor modify dyskinesia in hemiparkinsonian rats [102], but the role of opioids in LID remains unclear and needs further study. Finally the role of noradrenergic system in LID is poorly studied but it has been suggested that an increased norepinephrine transmission in Str could be related with dyskinesia since the blockade of norepinephrine receptors reverts LID [103].
Since the direct pathway of the basal ganglia and D1 receptors activity is associated with dyskinesia, the research has been focusing on changes in these neurons, their activity, neurochemical tracers and their receptors particularly dopamine D1 and D3 receptors, in order to propose alternatives to the therapeutic management of the Parkinson patients.
D1-like family of dopamine receptors includes D1 and D5 subtypes. D1 has 466 amino acids and D5 has 477 with a homology of 80% located mainly in the transmembrane domains [104]. D1 and D5 receptors have a differential distribution in the central nervous system; moreover there is a controversy of their signaling pathway. Initially was proposed that both receptors stimulate adenylyl cyclase; however some dopamine effects on PLC activity seem to be mediated by the D5 type [105].
Dopamine D1 receptors are members of the G protein coupled receptors family (GPCRs) stimulates adenylyl cyclase trough Gαolf or Gαs proteins [106]. In the D1-like receptors associated to the striato-nigral neurons, the subunit Gαolf interacts with the catalytic domain of adenylyl cyclase V [107], increasing the activity and therefore cAMP formation [108]. It have been reported Gαolf is expressed in the direct pathway and the level of expression can change after dopamine denervation [52].
The cAMP formed by D1 receptor activation stimulates PKA, and recent studies suggested the activation of the GEF (nucleotide interchange factor) EPAC and the consequence activation of Rap1 a low weight G protein that activates MAPK [109]. The activation of PKA phosphorylates several substrates that include: Na+, voltage depending K+ and GIRKs channels, producing inhibition; whereas Ca2+ L, N, P, Q, NMDA, AMPA and GABAA channels are stimulated by the phosphorylation. PKA also phosphorylates DARPP-32 at threonine 34, DARPP-32 phosphorylated inhibits protein phosphate 1 (PP1). Phosphorilation of NMDA channels by D1 receptor signaling through DARPP-32, synergize their stimulatory action, whereas by the same pathway attenuates GABAA inhibitory currents. PP1 has several substrates such as Ca2+ L, N, P and AMPA channels (for references see Udieh, 2010 [105]).
D1 receptors also induce activation of anti-apoptotic signals. PKA phosphorylates Akt (also known like PKB), which phosphorylates CREB that translocate to the nucleus inducing gene expression related with cellular survival. D1 receptors interact with other receptors, ionic channels and cytoskeleton proteins. Protein-protein interaction between NMDA at the level of NR1 subunit produces signaling via PI3K, interaction with NR2 subunit decreases NMDA current [105]. D1 receptors form heterodimers with adenosine A1 receptors producing decrease in GABA release [110], while D5 receptor interacts with GABAA channels decreasing Cl- current [111]. Neurofilament M, COP gamma and DIRP78 are cytoskeleton proteins related with expression, sensitization, and transport of D1 receptors [105].
D1 receptor interactions with other dopamine receptors have been described. Dimmers between D1-D2 receptors induce an increased intracellular Ca2+ probably mediated by the Gαq →PLC pathway [112]. It has also been reported the interaction of dopamine D1/D3 receptors, here we will discuss latter the role of this dimmer in PD and LID.
The adenylyl-cyclase→PKA stimulated by D1-like receptors induces GABA release in the Str and SNr [19, 22, 113] and increases the firing rate MNSs [21], mechanism that has been related with the facilitation of movement in the direct pathway. Dopamine D1 receptor effects on firing rate and GABA release are mediated by DARPP-32 and PP1 [21, 83, 113, 114]. The effects on firing rate and release have been associated to modulation of L-type and P/Q calcium channels [21, 113-116].
As we discuss before the loss of dopamine innervation induces molecular and signal transduction changes in the neurons of the basal ganglia attributed to a compensatory response. Most of the experimental studies have been assessed using toxins to induce experimental models of PD like 6-hydroxydopamine (6-OHDA) for rats or 1-metyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) for mice or non-human primates, because their ability to induce the degeneration of dopaminergic neurons [117-118]. The changes after dopamine denervation have been studied in particular on striato-nigral (direct pathway) and pallido-nigral (indirect pathway) neurons and plenty evidence shows that cellular and functional changes occurs, this phenomenon is called supersensitivity to dopamine denervation [119, 120]. The supersensitivity has been shown in expression levels of mRNA for enkephalins, substance P and dynorphins [121] but also up-regulation of more than 30 genes including zif 268, c-fos, c-jun and MAPK-1, most of them related with neuronal activity [54, 122]. Interesting several of those genes and changed proteins convey to D1 dopamine receptors and their signal transduction pathways [54].
Perhaps one of the most studied effects of denervation is the altered expression of dopamine receptors in the basal ganglia [20]. D2-like dopamine receptors increase in number, sensibility and consistently with that the mRNA in the striato-palidal neurons[20], which explain the hypomotolity. In contrast despite some contradictory results [56, 123], there is evidence that not only the mRNA of D1-like dopamine receptors decreases in the striatal neurons [20] but also the expression [124-125], with no changes in the affinity studied by radioligand binding techniques in SNr [125]. Proteasome altered activity observed in L-DOPA treatment produces an altered D1-like receptor abnormal trafficking that might be responsible for this changes [126]. Contrary to the decrease of D1-like dopamine receptors an increased response to their activation is observed in the striatum [120, 122, 127], and also a substantial increase in GABA release in the striato-nigral terminals [68, 125]. However despite the supersensitivity phenomenon the lack of endogenous dopamine in PD to activate the receptors explains the poor activation of basal ganglia pathways and therefore the hypomotility.
The activation of dopamine receptors would be the target in order to restore the balance in the circuit of the basal ganglia. The gold-standard therapy in PD is L-DOPA, because is converted to DA, or even can activate dopamine receptors directly increasing firing rate in striatal neurons and inducing GABA release in SNr. In addition the activation of D1 receptors leads an increase of GABA release in striato-nigral terminals promoting the activation of the direct pathway related with the movement, which is the main purpose of the pharmacological approach to treat PD.
It can be thought that replacement of DA with L-DOPA should restore the number, sensitivity and response of the activation of dopamine receptors observed in experimental conditions. Nevertheless that is not the case, chronic L-DOPA treatment only produces a partial recovery of D1-like dopamine receptors [125], whereas increases even more the biological response to their activation, producing a very high level of GABA release in the striato-nigral terminals than occurred only with dopamine denervation in hemiparkinsonian rats [125, 128-129]. An analysis of D1 receptor expression in striatum in L-DOPA treated rats indicates that D1-like receptors activity does not go back to healthy conditions in LID [126]. During L-DOPA treatment the expression of early genes like c-fos, c-jun and zif 268 is increased more than observed in dopaminergic denervation [55]. Furthermore the effect was mimetized [122] and synergized by D1 dopamine receptor agonists [130]. This suggested that the DA converted by L-DOPA treatment, activates D1 dopamine receptors producing high gene expression and translation, causing an overstimulation of the direct pathway [119]. The high activity of D1 dopamine receptors is also supported by the high expression of substance P and dynorphin both markers of direct pathway neurons [55].
The abnormal activation of the direct pathway with increased GABA release in SNr (related with the activation of the movement) could be occurring during LID as we mention before. The changes in GABA transmission is supported by studies in which has been shown altered metabolic activity measured by 2-deoxyglucose during LID in striato-nigral terminals [131] but also the increased expression of the enzymes responsible of synthesize GABA [132]. The mechanism underlying the increased GABA release in the striato-nigral neurons during LID has been studied by several groups of investigation [125, 128, 132-133] and some hypothesis has been proposed.
First was postulated that the increased GAD65 and GAD67 expression observed in denervation and L-DOPA treatment, induces an enhanced synthesis of GABA, which is available for the release [132, 134]. However the fact that GABA contents in SNr is not altered by denervation [135] indicates that the synthesis of GABA is not a simple cause-effect relationship.
Then, studies of D1 dopamine receptors signaling in the striato-nigral terminals turned to be the most studied and strong hypothesis. Since the level of expression of D1 dopamine receptors was contradictory and the down-regulation does not explain the hyperactivity of direct pathway, their signal transduction pathways had been dissected. Cai and coworkers (2002) [123] showed an increased coupling between D1 dopamine receptors and Gαolf proteins in hemiparkinsonian rats, but the level of protein expression of Gαolf remained unchanged. In contrast studies in postmortem patients with PD showed increased expression of Gαolf proteins [136] and the effect was also observed in hemiparkinsonian rats, interesting the effect was reverted by chronic but not acute L-DOPA treatment [134], which was also demonstrated in either mild or severe dyskinetic rats after chronic L-DOPA treatment [52]. Recent studies have shown a persistent increase in Gαolf expression in dyskinetic mice [59] however the reason for this discrepancy is unknown and requires more study.
In next steps downstream the activation of D1 receptors induces the activity of adenylyl cyclase isoform V by coupling of Gαolf protein, which in turn induces the production of a second messenger cAMP in striato-nigral neurons and PKA activation, supersensitivity of D1 receptors could be in these proteins. Since cAMP modulates firing rate and GABA release in striatum and SNr [113-114] and stimulates the protein kinase activated by cAMP (PKA) which in turn can produce several effects that are related with GABA release, a higher expression/or activity of adenylyl cyclase, PKA and DARPP-32 signaling was related with LID [54]. Consequent with the activation of D1 receptors Ras-mTOR-ERK induced altered mRNA translation was found in the nucleus striatum [57-58, 67, 120, 137]. However other studies have been suggested that ERK hypersensitivity is not related with cAMP/PKA signaling and this is a condition is needed for the development of LID, whereas hypersensitivity of cAMP/PKA has a permissive role [59]. Recent studies suggested that Shp-2 phosphatase is the link between D1 receptor activation and ERK, and that is persistent activated in LID [60]. Probably ERK supersentivity is related with control of the expression of proteins related with cAMP/PKA pathway supersensitivity. The activation of cAMP/PKA is the mechanism that conduces to the increased GABA release in the striato-nigral terminals of the direct pathway of basal ganglia since GABA release is highly sensitive to cAMP (Fig. 3) [114, 125] and the increased activity through the direct pathway is a necessary condition to produce the involuntary movements.
Rangel-Barajas and coworkers (2011) [52] have shown that a persistent increase in activity and expression of adenylyl cyclase V/VI occurs in LID animals without changes in activity of PKA of striato-nigral terminals. This change on the adenylyl cyclase V/VI is correlated with an increased GABA release in SNr in severe dyskinetic rats and did not happened in mild dyskinesia. It was also suggested an increased phosphorylation of DARPP-32 in Thr34 found in denervation and LID, this change cannot been associated exclusively with higher GABA release since not all GABA released in striatum by D1 receptor stimulation is related with DARPP-32, inferred from DARPP-32 know-out mice studies [138] and it’s likely that the increased activity of adenylyl cyclase V could mediate the phosphorylation and therefore activation of DARPP-32 via PKA [139]. Thus a higher expression/activity of adenylyl cyclase seems to have a central role in the LID. Probably several beneficial effects that helps in experimental therapies to control LID can be related with antagonistic actions on adenylyl cyclase for example, 5HT1A receptor activation, which modulates negatively AC by Gαi proteins reducing LID [96, 140], CB1 receptor also coupled to Gαi proteins decreased LID and PKA activation [141] and finally mGlu4 receptors modify also LID [142]. According with a recent study showed by single exon sequencing, that the only gene codifying for adenylyl cyclase V was mutated in a familiar form of dyskinesia [143]. Further
In summary LID could represent an exaggerated supersitivity of D1 receptor response to the denervation induced by L-DOPA treatment leading to a pulsatile and high GABA release on striato-nigral terminals through the sensitization of adenylyl cyclase activity.
The D3 dopamine receptors are expressed mostly in limbic system, islands of Calleja, olfactory bulb, and the pituitary intermediate lobe, with a low but significant expression in basal ganglia structures [147]. The amino acid sequence homology for the helical transmembrane spanning (TMS) segments of the D2 and D3 dopamine receptor subtypes was found to be 75-80%. Since the TMS regions are involved in the construction of the orthosteric-binding site, the pharmacologic profiles of D2 and D3 receptors are very similar [148-150]. Probably that is the reason why in PD the role of D3 dopamine receptors were poorly studied. The pharmacological approach to treat PD besides L-DOPA was because D2-like dopamine agonist showed effectiveness to treat bradykinesia [151]. In the past two decades with advanced pharmacological and molecular tools, the role of D3 dopamine receptors became a potential field of study in PD and LID animal models.
With very good agreement is known that during denervation, the D2-like dopamine receptors are up-regulated in pallido-nigral neurons of the basal ganglia [20], then it was unclear whether or not the D3 dopamine receptors subtype was participating in the supersentitivity by dopamine denervation, however their low expression in striatum made focus the attention in D2 dopamine receptors [152]. It was pointed out that in the basal ganglia, the segregation of the expression of D1-like and D2-like dopamine receptors in the direct and indirect pathways respectively was not precisely accurate, but a relative low abundance of D3 receptors were expressed also in the direct pathway [23]. Probably disease conditions enhance their expression, according with that; recently it has been shown that D3 dopamine receptors are up-regulated in caudo-putamen and SNc in Lewy Body disease and Parkinson disease Dementia [153].
Bordet and coworkers (1997)[7] showed that mRNA codifying to D3 dopamine receptors remains unchanged during dopamine denervation, but the L-DOPA treatment induces a remarkable increase in dynorphin positive striatal neurons, which project to the SNr where D3 dopamine receptors normally has moderate expression. Interesting the binding for D3 dopamine receptors was decreased in hemiparkinsonian rats [148,154] but up-regulated when animals were treated with L-DOPA [7]. Since then, the ectopic over-expression of D3 dopamine receptors has been related with L-DOPA induced behavioral sensitization in hemiparkinsonian rats [119], and several studies support the idea that D3 dopamine receptors can attenuate the LID by normalizing their function [8, 11, 120]. However the location of D3 receptor sensitized by L-Dopa treatment is not clear. On the other hand D3 dopamine receptors interact with proteins and/or form heterodimers with other receptors that can change signal pathways and responses, e.g. D2/D3, D1/D3 heterodimers [14-16]. Recently it has been shown that the up-regulation of D2 dopamine receptors in denervated striatum is probably mediated by D3 receptors through Ca2+ channels [155]. All these finding together shown that several changes in D3 receptor expression and function can be related with Parkinson Disease and L-DOPA treatment.
D3 receptors are members of the D2-like receptors are coupled to Gαi proteins [106]. It has been shown classical Gαi responses mediated by these receptors: inhibition of adenylyl cyclase, blockade of Ca2+ channels, open of K+ channels etc [106]. However interaction with D1 receptors produces an antagonistic and synergistic response [14, 156]; that depends of the nuclei studied. In the antagonist interactions, D3 receptors prevent D1 receptor stimulatory effects by the inhibition of adenylyl cyclase stimulated by D1 receptor, an interaction explained by cross-talk inhibition the AC activity. In the synergistic interaction D3 receptors potentiates D1 effects, and this interaction seems to be more complex and explained in terms of heterodimerization, where D3 receptor induces an increased sensitivity of D1 receptor for dopamine, potentiating cAMP formation and stabilizing them in the membrane (Fig. 3) [15-16]. This synergistic interaction occurs at the striato-nigral pathway and it’s regulated by CAMKIIα during neural activity [13-14].
D3 receptors have been associated with different elements of the basal ganglia. The mRNA codifying for D3 receptors have been shown in dopaminergic neurons [147], subthalamo-nigral neurons [30] and striato-nigral neurons [23]. In dopaminergic neurons D3 receptors controls the firing rate and dopamine release [157] and has neurotrophic effects [158]; probably the decreased expression in D3 receptors observed in dopaminergic denervation [148, 154] occurs by the degeneration of the dopaminergic neurons. Several studies have pointed out the importance of these receptors in nigral neurogenesis [158], neuro-protection and repair in PD [160] and other cognitive conditions related to PD [153].
Synergistic and antagonistic interaction between D1 and D3 dopamine receptors in the striato-nigral neurons. Glu, glutamate; DA, dopamine; GPe, external globus pallidus; Sth, subthalamic nucleus, SNr, substantia nigra pars reticulata, GPi, internal globus pallidus; ACV, adenylyl cyclase V; PKA, protein kinase activated by cAMP.
In subthalamo-nigral neurons D3 receptors are probably controlling the firing rate and glutamate release that have been attributed to members of the D2-like receptor family [31-32]. Since during denervation subthalamic neurons shown high activity rates and contribute to hypomotility, the D2-like agonist used in the control of Parkinson disease like pramipexole or ropirinole are able to decrease neuronal firing or glutamate release leading a clinical improve of symptoms. Interesting these D3-preferring agonists decrease the dyskinesia.
As we mention D3 receptors interact with D1 receptors at striato-nigral neurons. The synergistic interaction has been shown in striatum [15-16] and substantia nigra on nerve terminals [14]. In the interaction D3 receptors increases D1 receptor affinity for dopamine, increasing cAMP formation and GABA release in striato-nigral terminals, this effect is very important since the higher release of GABA seems to mediate LID. Co-precipitation in native tissue and studies using transferred energy like FRET and BRET in heterologous expression system indicate that the heterodimerization is the cause for the observed effects [13-16].
The D1/D3 dopamine receptors interaction is important in dopaminergic denervation and L-DOPA treatment? The expression of D3 receptors in the striato-nigral and subthalamo-nigral neurons leads the speculation that D3 receptors are involved in the motor control by potentiation of GABA release stimulated by D1 receptors and inhibition of glutamate release leading to a decreased activity of the output neurons and increased activation of motor cortex. These effects are expected occur by the administration of L-DOPA and explain their powerful therapeutic effect; however the role of D3 receptors in subthalamo nigral and D1/D3 interaction at striato-nigral neurons during denervation and L-DOPA treatment is unknown. However behavioral experiments suggested that D3 dopamine receptor agonists potentiate the D1 receptor-induced rotation in hemiparkinsonian rats only after L-DOPA treatment [161] suggesting that the D1/D3 interaction persist.
Chronic L-DOPA therapy sensitizes D3 receptor expression, which has been related with LID development and the therapeutic management was experimentally evaluated. Two current opinions are in literature, one proposed that the normalizing D3 function decreases LID with partial agonists [8, 12], another one propose that antagonist also are able to do that [10-11] while other suggested that antagonist does not modify LID [9].
The mechanisms through D3 dopamine receptors selective compounds can help to LID is still unclear, but recent studies have suggested that it could be due to a modulation of D1 dopamine receptors or direct actions on D3 receptors. Albarran and coworkers [162] reported that activation of D3 receptors in hemiparkinsonian dyskinetic rats prevents the D1 dopamine receptor stimulation of GABA release at striato-nigral terminals and the effect is mediated by an antagonist interaction between the receptors explained by a cross-talk as previously described [156]. This change in the D1/D3 relationship observed in dyskinesia with respect normal conditions could explain why D3 receptor agonist prevents dyskinesia in L-DOPA treatment models, antagonizing adenylyl cyclase stimulated by D1 receptors and in consequence GABA release. This observation also suggested that the maintenance of the dyskinesia is due to the sensitization of the D1 receptor signaling pathway in the direct pathway that has been related with the LIDs [52]. If the heterodimeric interaction between D1 and D3 receptor is modified by L-DOPA remains unclear and more studies are needed to clarify it. The effect of antagonist in LID need to be also clarified since current basal ganglia models does not predict the effect observed, also the wide expression of D3 receptors in other brain areas can contribute to the observed effect. However all the studies suggest that the use of D3 receptors ligands on LID is promising.
The D1 dopamine receptors supersensitivity in striato-nigral neurons are closely related with LID with a central role of adenylyl cyclase, co-expression of D3 receptors with D1 receptors and the modifications of their interaction during experimental Parkinson and LID suggested a promissory therapeutical alternative in the management of motor disabilities related with L-DOPA administration.
The work was supported by a grant (152326) from CONACyT (México) to BF.
Since the introduction of the latest version of the Diagnostic and Statistical Manual (DSM-5; [1]), Post-Traumatic Stress Disorder or PTSD takes a central position among stress-related disorders. This distressing and demoralizing disorder is triggered by exposure to a life-threatening or terrifying event, experienced in person or witnessed indirectly. The symptoms needed for a diagnosis are summarized as involuntary re-experiencing the adverse event(s), efforts to avoid such intrusive memories, negative cognitions or mood alterations, and increased arousal [1]. Although PTSD is precipitated by exposure to a severe life event, it is not clear why some people develop PTSD after potentially traumatic events (PTEs), while others do not. Several risk factors have been found, such as prior exposure to (and the number of types of) traumatic events [2], neuroticism, lack of social support or being female [3].
Although the percentage of older adults meeting full diagnostic criteria for this disorder appears to be lower than in younger adults [3, 4], PTSD among them often presents a serious condition [5] with high comorbidity rates [6] and showing a chronic, fluctuating course [7]. As older adults present the fastest-growing segment in the world population, evidence-based treatment approaches are required to address the needs of trauma-affected older populations. After all, PTE’s can occur during all stages of life. Moreover, since populations of older adults not only grow in size, but also in life expectancy, trauma-related psychotherapy in later life can be followed by many more years to live.
In older adults, however, the symptoms are often misunderstood as depression, anxiety, somatic illness or memory problems due to aging. Consequently, PTSD has been described as a ‘hidden variable’ in the lives of older adults suffering from such a confusing array of symptoms [8]. Psychotherapy for older PTSD patients has been found to encounter several more barriers. To start with, long-standing stereotypes regarding older adults’ capacity to change present a broadly generalized example of agism (age-related discrimination). Due to Freud’s assumptions on psychoanalysis [9], advancing age was long considered a disadvantage in psychotherapy. Furthermore, low recognition of PTSD in primary care [5, 10], the reluctance of older adults to accept services of mental health professionals to deal with their problems [11] and insufficient empirical data [12] play a role. Taken together, in an age of a growing population of older adults, those suffering from PTSD risk receiving less-than-optimally efficacious treatment, which may be considered a research gap as well as a clinical problem challenging both researchers and clinicians.
Regarding trauma-related psychotherapy in later life, recent case studies reported encouraging results [13, 14, 15]. Trauma-focused exposure seemed to be well tolerated without adverse effects on comorbid cardiac conditions [16]. Some small controlled studies yielded preliminary positive treatment results for PTSD [17, 18, 19], although the small sample sizes did not allow for definitively bridging the research gaps. More robust studies [20, 21] suggested that (variants of) Trauma-Focused Cognitive Behavioral Therapy (TF CBT) can be safely and effectively used with older adult PTSD patients [22]. It must be realized, however, that the generalizability of those conclusions may be limited by the fact that most research has been conducted in Western countries, predominantly among Holocaust survivors or aging male military veterans. In addition, most studies are poorly reflective of the demographic context, as they do not include sufficient participants over the age of 74 [23].
To strengthen the existing evidence, a set of three studies (including a randomized controlled trial or RCT) was conducted, comparing treatment effects for PTSD of two psychotherapeutic interventions in treatment-seeking older adults with PTSD in the Netherlands [24], an exploratory analysis of self-reported symptoms and resilience measures in the same sample [25], and qualitative analysis of cognitions and emotions [26]. A global summary of these studies and their findings will allow for discussing current developments in the field of treating trauma-related disorders in later life.
Participants enrolled in the RCT and the explorative analysis were recruited from two Dutch mental health centres (Centre’45/Arq and Sinai Centre), which specialized in treating trauma-related disturbances. To capture important age-related challenges and losses in terms of emotional attachment, physical independence and socio-economic setbacks [11], treatment-seeking, community-dwelling out-patients with PTSD aged 55 years and over were accepted for this trial. Participants were enrolled between April 2013 and April 2016. Exclusion criteria involved not meeting full PTSD-IV criteria, changes in psychotropic medication during the study, severe cognitive impairment, high suicide risk, psychosis or bipolar disorder, current substance use disorder and concurrent psychosocial treatment during the study. Half of the sample consisted of native Dutch participants, the other half of resettled refugees from various countries, mainly from the Middle-East. The 33 civilian trauma survivors reported traumatic events including persecution, political, domestic and sexual violence, including childhood abuse. These events took place throughout the life course. The participants’ age ranged from 55 to 81 years; a mean age being 63.81 years, SD = 6.8 years; as for the gender distribution, 75% were men. All participants had encountered multiple adverse events. A total of 36.4% of the participants reported childhood trauma, implying Adverse Childhood Events (ACEs) between age 5 to 12; 30.3% reported sexual trauma. The majority (60.6%) of the participants suffered not only from PTSD (DSM-IV; 2000), but additionally from comorbid depression symptoms.
In the first two studies, treatment effects from two well-known psychological interventions were compared: Narrative Exposure Therapy or NET [27] and Present-Centered Therapy or PCT [28].
In NET, TF CBT is embedded in an autobiography, offering a lifespan time-frame for imaginal exposure. Following the introductory session, the therapist and patient collaboratively create a timeline of the patient’s life; subsequently elaborating this timeline in the next sessions. The final session allows the patient to receive the documented narration and focus on the future. This short-term treatment approach, which can be disseminated among local para-professional staff, is considered an innovative modification of TF CBT for vulnerable populations in low-resource regions. NET was extensively investigated in various populations of refugees and displaced persons in war- and disaster-affected areas, but also refugees and asylum seekers living in Western countries, demonstrating medium to large effect sizes and low dropout rates [29]. Some of those trials had investigated non-refugees, such as former political prisoners in Romania [17] or Chinese earthquake survivors [30, 31]. The lifespan perspective of NET suggests that this intervention shows high suitability for the population targeted in this trial.
As for PCT, in a trauma-informed context, the focus is explicitly
The first two studies involved two conditions (NET vs. PCT) and three assessment timepoints (pre-treatment, post-treatment and at 4 months follow-up). Participants were randomly assigned to 11 sessions of NET or 11 sessions of PCT; each session covering 90 minutes.
In study 1 [24], the variables of interest were symptom severity and the symptom clusters (re-experience, avoidance and hyper-arousal) of PTSD (DSM-IV; [32]), using the well-validated Clinician-Administered PTSD Scale (CAPS; [33]). In addition to calculating group means, an individual clinically significant change [34] was rated.
In study 2, capturing the impact of PTSD in patients’ daily life, exploratory analyses of self-reported symptoms and several measures of resilience were conducted [25]. This approach allowed patients to report self-reported distress from PTSD (using HTQ; [35]), depression symptoms (BDI-II; [36]), subjective general distress (BSI; [37]), self-efficacy [38], quality of life [39] and finally post-traumatic growth [40].
To enhance the external validity of this research project, inter-session intervals were adapted to patients’ preferences and possibilities (weekly or once in 2 weeks). The resulting variation in treatment duration was addressed by advanced statistical analyses, using a (multilevel) piecewise mixed-effects growth model [41] to determine weekly change rates in the outcomes across time (therapy vs. follow-up) and conditions (NET- versus PCT-groups).
Finally, to explore post-traumatic cognitive processing during the treatment process, qualitative patient-reported outcomes were collected in study 3 [26]. This study consisted of the qualitative analysis of trauma narratives and individual interview responses in a subsample of four Dutch participants from the NET condition. All four participants reported multiple ACEs. Qualitative data analyses were conducted by using MAXQDA text software [42].
For all studies, methodological quality was addressed by trial registration, approval from the medical ethical committee (Leiden University), conducting a power analysis before starting the studies, randomization, blinding of assessors, protocol adherence, checks of treatment adherence and interrater reliability, and use of independent assessors.
In study 1, both NET and PCT were found to be safe and efficacious psychological treatments for older adults suffering from PTSD. Both interventions demonstrated low dropout rates. Markedly, none of the participants in either condition left treatment prematurely because of intolerable stress increase. During treatment, PCT showed a steeper decline than NET for CAPS-scores (all PTSD symptom clusters). In the NET-group, a more gradual symptom decline was observed. This divergence resulted in a significant superiority at post-treatment (Cohen’s
RCT outcomes of CAPS-total [
The mean severity of PTSD symptoms in both groups decreased from severe at the mean timepoint pre-treatment to moderate at the mean follow-up. In addition to focusing on group means, an individual clinically significant change [34] was rated. On the individual level, 71% of NET completers achieved a clinically significant improvement, compared to 50% of the PCT completers.
In study 2, regarding self-rated PTSD, depression symptoms and perceived general distress, both groups (NET and PCT) showed equal, medium to large, within-group effects as well [25]. Whereas resilience (defined in terms of self-efficacy, quality of life, and personal growth) did not significantly improve in either group, it was not compromised, thereby confirming the treatment effects of both interventions.
In study 3, the question was addressed how the benefits of treatment by NET can be understood from a patients’ perspective. Posttraumatic changes in thoughts and meanings are supposed to play an important role in recovering from PTSD [44, 45]. To explore cognitive processing during treatment, qualitative patient-reported outcomes were collected by analyzing autobiographic documents and interview responses. Would a cognitive and developmental framework clarify those outcomes? Would aging adults be able to change long-standing posttraumatic feelings and cognitions during treatment? In a sub-sample of NET-participants, the latter question could be answered with a convincing “Yes”. The participants involved reported gradual, meaningful changes in self-awareness and self-esteem [24]. “
Pulling together the strings from the presented studies, the short-term treatment effects of the PCT-group exceeded those in the NET-group. Nevertheless, this superiority was lost at follow-up. The within-group treatment effects in the NET-group were found to extend beyond PTSD, drawing depression symptoms and general distress into the scope of recovering from PTSD. Resilience, quantitatively measured, did not show significant responses for either group. In other words, compared with NET, the PCT-group showed significantly stronger short-term reductions in PTSD pathology (study 1), whereas this group did not show significantly improved resilience, neither comparatively, nor longitudinally (Study 2). The qualitative analysis, however, showed gradual cognitive and emotional changes on a personal level, reflecting the processing of adverse events and regaining self-esteem and initiative.
Taken together, the main findings of these studies suggest that both trauma exposure (NET) and a trauma-informed present-centred approach (PCT) are safe and effective interventions for older adults and that posttraumatic recovery in later life extends beyond clinician-rated PTSD symptoms, including mood and subjectively perceived distress as well. Moreover, older adults can change long-standing beliefs, even after long-past childhood trauma.
To reflect the impact of PTSD symptoms on daily life, the presented studies were characterized by a broad approach to the subject of treating trauma-related disorders in later life. Consequently, PTSD, comorbid depression and several measures of resilience were included in the analyses. An additional strength is the multimethod approach of this research project. The studies used advanced and variable methods of analysis. A third strength is the controlled comparison of treatment response in two innovative psychotherapeutic interventions for PTSD in a sample of older adults. The interventions had contrasting treatment approaches: imaginal exposure (focusing on the past) versus a focus on problem-solving in the present. The resulting response patterns may provide a useful tool for clinicians to discuss treatment preferences with their patients. The equal efficacy at follow-up might be an important attribution to ongoing discussions concerning the necessity of exposure in trauma treatment [46]. The clinical meaningfulness of the results was increased by the inclusion of a heterogeneous sample of civilians, including both native Dutch civilians and refugees. In addition, the participants were allowed to determine session intervals in accordance with their preferences and possibilities. Advanced statistical analyses addressed the resulting variability of inter-assessment intervals. Within a clinical environment, methodological rigor was addressed by randomization, protocol adherence, checks of treatment adherence and interrater reliability, and the use of independent assessors.
Some limitations merit attention as well. The participants’ mean age does not allow for generalizing the research findings to old age (over age 74). By using the 55 years limit, however, clinically important transitions could be captured and enough participants could be recruited to reach a sufficiently powered sample for the RCT on PTSD. Nevertheless, the study sample was small and mainly representative for the so-called young-old (ages 55 to 75), as distinguished [47] from the old-old (75 and over). In addition, out of fear of high dropout and concurrent influences in the follow-up interval, a short follow-up interval was chosen. In future research, a longer follow-up interval is strongly advisable. Therefore, the research findings from these studies have to be interpreted with caution. They can contribute, however, to ongoing discussions in the field of treating trauma-related disorders in later life, focusing on current issues and controversies, lessons learnt and future research. These topics will receive more attention in the following paragraphs.
Reflecting the heterogeneity and etiological complexity of mental health in old age [48], a broad range of measures and a multimethod approach was selected in the presented studies. About late adulthood and young-old age, several questions were addressed. To begin with: Would advancing age matter in terms of treatment response? Meta-analytic findings on NET [29] did not support this hypothesis. Furthermore, in a recent study including 2578 adults – aged from 18 to 80 years [49], the single factor limiting treatment response in all outcomes was found to be the number of traumatic events, confirming the established dose-response correlation of higher trauma exposure and elevated PTSD symptom severity [2, 50]. Taken together, advancing age does not matter in terms of treatment response. In terms of etiological complexity and of biographical and historical context, however, age is highly influential, requiring historical sensitivity and detailed curiosity from therapists.
Like all exposure-based treatments, NET addresses the way patients cognitively cope with past events. The treatment strategies of NET have been described as re-organizing memories and restoring narrative continuity and coherence [27]. In the RCT comparing NET and PCT, present-centred therapy (PCT) served as an active comparator. PCT focuses on the present: coping with concurrent stressors, maladaptive interaction patterns and learning solution-focused techniques [9]. In addition to this contrast, there are similarities as well. Both ‘dealing with the past’ and ‘coping with present stressors’ refer to (cognitive and emotional) coping with either distressing memories and meanings or maladaptive behavior patterns. Similar considerations might be valid regarding other comparisons, such as Prolonged Exposure versus Relaxation training [51]. The conclusion might be that engaging in such a process in a therapeutic relationship allows for changing both kinds of coping. Patient-reported outcomes suggested a gradual shift in cognitions and emotions, not quite resulting in the complete extinction of old feelings, but expanding the patients’ experiential repertory.
Since treatment changes in NET and PCT are found to be more similar than assumed, their direct comparison calls for close attention. The results of the RCT show that both approaches are safe and effective. Unexpectedly, at follow-up, NET and PCT show equal efficacy. Apparently, in this population dealing with the past and coping with the present show equal importance. Remarkably, change in terms of PTSD symptoms took place at a different pace per intervention. The gradual symptom decrease in the NET-group can be understood as an effect of the taxing exposure in NET. In contrast to the response pattern of PCT, the symptom decline in NET continued after treatment. This difference might be related to different learning strategies in both interventions. It could be suggested that increased coherence and habituation are more internalizing processes than problem-solving techniques, leading to more sustainable treatment results. The continuous symptom decrease in the NET-group tantalizingly suggests a further decline beyond the follow-up interval used and calls for a replication of the comparison with a longer follow-up interval. Meta-analytic findings regarding persisting within-treatment effects in NET justify such suggestions [29].
Clinically, the importance of patient preferences for this population is illustrated. Some patients did not accept randomization, because they needed to tell their stories and did not accept any uncertainty about the possibility to do so. Following patient preferences can enhance treatment motivation, without, on the other hand, blindly following avoidance-based wishes. Regarding treatment outcome, in patients with chronic PTSD and comorbid depression, treatment matching was found to improve treatment response [52]. Careful information and preparation of treatment choices are necessary to reach shared decisions. Regarding further research, the findings of the RCT call for replication in a larger sample, including older age groups, and a longer follow-up interval.
Both NET and PCT were found to be safe and efficacious treatments reducing PTSD symptoms in older adults suffering from PTSD. Compared with NET, the PCT-group showed significantly stronger short-term reductions in PTSD pathology, whereas this group did not show significantly improved resilience, neither comparatively, nor longitudinally. Nevertheless, the study findings suggest that posttraumatic recovery in later life extends beyond reductions in re-experiencing, avoiding and arousal symptoms, adding nuance to the current centrality of PTSD symptoms [53]. One might say that the current concept of PTSD in DSM-5 (including depression symptoms in the diagnostic criteria of PTSD), already reflects this nuance. These findings may inspire further research on resilience factors, both in individual and community contexts.
In addition to the described issues, several observations merit attention. Older adults suffering from PTSD report serious impairments in daily life. The presented studies show that patients who gain access to treatment can achieve a clinically significant treatment response. As for NET, the qualitative analysis showed that during and after treatment, renewed personal growth is found to be within reach for older adults, just as for younger patients. This renewed growth can be a sign of returning strength and vitality, notwithstanding residual symptoms. Even in later life, the taxing procedure of NET did not prevent significant symptom reductions, rendering credibility to interpreting treatment changes as results of cognitive and emotional reprocessing, without, however, ruling out the influence of the patient-therapist relationship.
Another observation refers to the age in terms of a remaining lifetime. Rapidly expanding life expectancies imply that improved quality of life after treatment offers new perspectives on potentially many more years of a satisfactory quality of life. This awareness may offset negative cognitions concerning the usefulness of treatment in later life. In these years, some patients hope for a new understanding between parents and children or grandchildren, potentially correcting existing intergenerational transmission of maladaptive interaction patterns [54]. In clinical practice, such intentions might call for careful preparation and timing, since self-disclosure of painful memories might evoke unexpected family dynamics. “
Psychological treatment for older adults has been characterized by several barriers: myths about older adults’ incapacity to change, low recognition of PTSD in primary care, the reluctance of older adults to use the services of mental health services for solving their problems and a limited body of evidence concerning trauma-focused treatment for older adults [12, 17, 21, 46]. Without addressing these barriers, older adults with PTSD will not gain access to treatment. By showing the potential of psychotherapy with older adult PTSD patients to achieve clinically meaningful results (both with NET and PCT), without compromising resiliency, the presented studies addressed the latter barrier.
Previously, age-specific modifications for standard treatments were proposed, such as increasing the structure of treatment, utilizing memory aids and simplifying materials [55]. These modifications mainly refer to form: i.e., the way in which treatment and its environmental conditions are personalized in response to patients’ individual needs. These adaptations do not appear to exceed adequate personalization of treatment in general. The present research does not call for conceptually changing current treatment protocols when treating older adults. Full information and careful psycho-education have been found to prepare senior participants sufficiently for their treatment, either including direct trauma exposure or focusing on current stressors. As for treatment duration, extension was not considered to be justified. In treatment modules of 11 sessions, at least half of the participants achieved clinically meaningful treatment changes for PTSD symptoms. When addressing specific symptoms, such as traumatic grief, trauma-related systemic problems or nightmares, alternative interventions may be considered, such as Brief Eclectic Psychotherapy for traumatic grief or BEP-TG [56], interpersonal therapy [52], or imaginary rehearsal therapy [57]. In case of persisting maladaptive cognitions, schema therapy – found to be safe and effective with older adults - might serve as a sequel treatment [58].
Future research calls for rigorous research methodology to be integrated in clinical-service provisions in ways that mutually improve both research and clinical practice [59]. Routinely assessing adverse childhood experiences by using the ACE (Adverse Childhood Events) Questionnaire (World Health Organization; WHO [60]) may support patients in better understanding their current health problems. Even if such experiences are initially denied, patients may hear the message that talking in therapy about such issues is acceptable. Since both age-related changes and PTSD symptoms can include attention and memory problems, cognitive functioning should be routinely assessed as well [61]. Extending routine assessments with cognitive and physiological measures (blood pressure or heart rate) could provide additional evidence on risks and outcomes of psychotherapy in older adults [22, 46]. Furthermore, directly comparing trauma-related psychotherapy with pharmacotherapy for older PTSD patients could improve treatment matching. Moreover, e-health applications for assessment and/or treatment (the timeline in NET or homework assignments in PCT) could bring interesting innovations and inspire yet further research. Summarizing, this field of research is still in its infancy and calls for expanding the scope of research. In particular, founding research sites outside Western countries and reaching new target populations will encourage researchers and clinicians in this fascinating field to move forward.
For senior PTSD patients, both Narrative Exposure Therapy and Present Centered Therapy show the potential to significantly reduce symptoms of PTSD and related problems, whereas resilience factors are not compromised by either treatment procedure, Furthermore, gradual changes in posttraumatic feelings and cognitions mirror increasing self-esteem and initiative, implying that older adults can change long-standing self-related beliefs, even after long-past childhood trauma. These findings allow for three conclusions. First, whereas PTSD may be described as a hidden variable in the lives of older adults, their strength and flexibility are shown to be hidden factors in their recovery process. Second, psychological treatment in later life may be meaningful for years to come. Third, pessimism concerning the treatment of older adults with trauma-related psychopathology is unfounded. By overcoming these ungrounded convictions, treating trauma-related disorders in later life is coming of age.
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These reactions occur through a regular radical chain causing growth of polymer by three steps, namely, initiation, propagation, and termination. To understand ionizing radiation-induced polymerization, the water radiolysis must be taken into consideration. This chapter explores the mechanism of water molecules radiolysis paying especial attention to the basic regularities of solvent radicals’ interaction with the polymer molecules for forming the crosslinked polymer. Water radiolysis is the main engine of the polymerization processes, especially the “free-radical polymerization.” The mechanisms of the free-radical polymerization and crosslinking will be discussed in detail later. Since different polymers respond differently to radiation, it is useful to quantify the response, namely in terms of crosslinking and chain scission. A parameter called the G-value is frequently used for this purpose. It represents the chemical yield of crosslinks, scissions and double bonds, etc. For the crosslinked polymer, the crosslinking density increases with increasing the radiation dose, this is reflected by the swelling degree of the polymer while being immersed in a compatible solvent. If crosslinking predominates, the crosslinking density increases and the extent of swelling decreases. If chain scission predominates, the opposite occurs. A further detailed discussion of these aspects is presented throughout this chapter.",book:{id:"6149",slug:"ionizing-radiation-effects-and-applications",title:"Ionizing Radiation Effects and Applications",fullTitle:"Ionizing Radiation Effects and Applications"},signatures:"Mohamed Mohamady Ghobashy",authors:[{id:"212371",title:"Dr.",name:"Mohamed",middleName:null,surname:"Mohamady Ghobashy",slug:"mohamed-mohamady-ghobashy",fullName:"Mohamed Mohamady Ghobashy"}]},{id:"53504",doi:"10.5772/66925",title:"Applications of Ionizing Radiation in Mutation Breeding",slug:"applications-of-ionizing-radiation-in-mutation-breeding",totalDownloads:3478,totalCrossrefCites:9,totalDimensionsCites:13,abstract:"As a predicted result of increasing population worldwide, improvements in the breeding strategies in agriculture are valued as mandatory. The natural resources are limited, and due to the natural disasters like sudden and severe abiotic stress factors, excessive floods, etc., the production capacities are changed per year. In contrast, the yield potential should be significantly increased to cope with this problem. Despite rich genetic diversity, manipulation of the cultivars through alternative techniques such as mutation breeding becomes important. Radiation is proven as an effective method as a unique method to increase the genetic variability of the species. Gamma radiation is the most preferred physical mutagen by plant breeders. Several mutant varieties have been successfully introduced into commercial production by this method. Combinational use of in vitro tissue culture and mutation breeding methods makes a significant contribution to improve new crops. Large populations and the target mutations can be easily screened and identified by new methods. Marker assisted selection and advanced techniques such as microarray, next generation sequencing methods to detect a specific mutant in a large population will help to the plant breeders to use ionizing radiation efficiently in breeding programs.",book:{id:"5451",slug:"new-insights-on-gamma-rays",title:"New Insights on Gamma Rays",fullTitle:"New Insights on Gamma Rays"},signatures:"Özge Çelik and Çimen Atak",authors:[{id:"147362",title:"Dr.",name:"Özge",middleName:null,surname:"Çelik",slug:"ozge-celik",fullName:"Özge Çelik"},{id:"147364",title:"Prof.",name:"Çimen",middleName:null,surname:"Atak",slug:"cimen-atak",fullName:"Çimen Atak"}]},{id:"32846",doi:"10.5772/36950",title:"Current Importance and Potential Use of Low Doses of Gamma Radiation in Forest Species",slug:"current-importance-and-potential-use-of-low-doses-of-gamma-radiation-in-forest-species",totalDownloads:5277,totalCrossrefCites:2,totalDimensionsCites:13,abstract:null,book:{id:"1590",slug:"gamma-radiation",title:"Gamma Radiation",fullTitle:"Gamma Radiation"},signatures:"L. G. Iglesias-Andreu, P. Octavio-Aguilar and J. Bello-Bello",authors:[{id:"110581",title:"Dr.",name:"Lourdes",middleName:null,surname:"Iglesias-Andreu",slug:"lourdes-iglesias-andreu",fullName:"Lourdes Iglesias-Andreu"}]},{id:"58410",doi:"10.5772/intechopen.72074",title:"Radiation-Induced Degradation of Organic Compounds and Radiation Technologies for Purification of Aqueous Systems",slug:"radiation-induced-degradation-of-organic-compounds-and-radiation-technologies-for-purification-of-aq",totalDownloads:1415,totalCrossrefCites:8,totalDimensionsCites:12,abstract:"Environmental application of radiation technologies is an important part of radiation processing. Radiation treatment of aqueous systems contaminated with organic compounds is a promising method of water and wastewater purification and corresponding technologies are being developed. In this chapter, the following aspects of radiation treatment process are considered: sources of contamination and major contaminants of water and wastewater; primary processes in aqueous systems initiated by ionizing radiation; principal ways of contaminant conversion as consequences of primary processes (complete mineralization of organic compounds, partial decomposition of organic molecules resulted in detoxification, decolorization, disinfection of polluted water, and improvement in biological degradation of contaminant, polymerization of monomers’ contaminants, oxidation-reduction processes, and coagulation of colloids); sources of ionizing radiation; and main equipment applied in radiation technologies of aqueous system purification.",book:{id:"6149",slug:"ionizing-radiation-effects-and-applications",title:"Ionizing Radiation Effects and Applications",fullTitle:"Ionizing Radiation Effects and Applications"},signatures:"Igor E. Makarov and Alexander V. Ponomarev",authors:[{id:"213652",title:"Dr.",name:"Igor",middleName:null,surname:"Makarov",slug:"igor-makarov",fullName:"Igor Makarov"},{id:"213657",title:"Dr.",name:"Alexander",middleName:null,surname:"Ponomarev",slug:"alexander-ponomarev",fullName:"Alexander Ponomarev"}]}],mostDownloadedChaptersLast30Days:[{id:"32842",title:"Sterilization by Gamma Irradiation",slug:"sterilization-by-gamma-irradiation",totalDownloads:74766,totalCrossrefCites:37,totalDimensionsCites:85,abstract:null,book:{id:"1590",slug:"gamma-radiation",title:"Gamma Radiation",fullTitle:"Gamma Radiation"},signatures:"Kátia Aparecida da Silva Aquino",authors:[{id:"102109",title:"Dr.",name:"Katia",middleName:"Aparecida Da S.",surname:"Aquino",slug:"katia-aquino",fullName:"Katia Aquino"}]},{id:"32837",title:"Environmental Gamma-Ray Observation in Deep Sea",slug:"environmental-gamma-ray-observation-in-deep-sea-",totalDownloads:2917,totalCrossrefCites:4,totalDimensionsCites:6,abstract:null,book:{id:"1590",slug:"gamma-radiation",title:"Gamma Radiation",fullTitle:"Gamma Radiation"},signatures:"Hidenori Kumagai, Ryoichi Iwase, Masataka Kinoshita, Hideaki Machiyama, Mutsuo Hattori and Masaharu Okano",authors:[{id:"108174",title:"Dr.",name:"Hidenori",middleName:null,surname:"Kumagai",slug:"hidenori-kumagai",fullName:"Hidenori Kumagai"},{id:"108237",title:"Dr.",name:"Masa",middleName:null,surname:"Kinoshita",slug:"masa-kinoshita",fullName:"Masa Kinoshita"},{id:"137650",title:"Dr.",name:"Ryoichi",middleName:null,surname:"Iwase",slug:"ryoichi-iwase",fullName:"Ryoichi Iwase"},{id:"137656",title:"Dr.",name:"Hideaki",middleName:null,surname:"Machiyama",slug:"hideaki-machiyama",fullName:"Hideaki Machiyama"},{id:"146918",title:"Dr.",name:"Mutsuo",middleName:null,surname:"Hattori",slug:"mutsuo-hattori",fullName:"Mutsuo Hattori"},{id:"146919",title:"Dr.",name:"Masaharu",middleName:null,surname:"Okano",slug:"masaharu-okano",fullName:"Masaharu Okano"}]},{id:"58998",title:"Ionizing Radiation-Induced Polymerization",slug:"ionizing-radiation-induced-polymerization",totalDownloads:1784,totalCrossrefCites:8,totalDimensionsCites:17,abstract:"Ionizing radiation can induce some kinds of reactions, other than polymerization, such as dimerization, oligomerization, curing, and grafting. These reactions occur through a regular radical chain causing growth of polymer by three steps, namely, initiation, propagation, and termination. To understand ionizing radiation-induced polymerization, the water radiolysis must be taken into consideration. This chapter explores the mechanism of water molecules radiolysis paying especial attention to the basic regularities of solvent radicals’ interaction with the polymer molecules for forming the crosslinked polymer. Water radiolysis is the main engine of the polymerization processes, especially the “free-radical polymerization.” The mechanisms of the free-radical polymerization and crosslinking will be discussed in detail later. Since different polymers respond differently to radiation, it is useful to quantify the response, namely in terms of crosslinking and chain scission. A parameter called the G-value is frequently used for this purpose. 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A further detailed discussion of these aspects is presented throughout this chapter.",book:{id:"6149",slug:"ionizing-radiation-effects-and-applications",title:"Ionizing Radiation Effects and Applications",fullTitle:"Ionizing Radiation Effects and Applications"},signatures:"Mohamed Mohamady Ghobashy",authors:[{id:"212371",title:"Dr.",name:"Mohamed",middleName:null,surname:"Mohamady Ghobashy",slug:"mohamed-mohamady-ghobashy",fullName:"Mohamed Mohamady Ghobashy"}]},{id:"53780",title:"Gamma-Ray Spectrometry and the Investigation of Environmental and Food Samples",slug:"gamma-ray-spectrometry-and-the-investigation-of-environmental-and-food-samples",totalDownloads:2501,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Gamma radiation consists of high‐energy photons and penetrates matter. This is an advantage for the detection of gamma rays, as gamma spectrometry does not need the elimination of the matrix. The disadvantage is the need of shielding to protect against this radiation. Gamma rays are everywhere: in the atmosphere; gamma nuclides are produced by radiation of the sun; in the Earth, the primordial radioactive nuclides thorium and uranium are sources for gamma and other radiation. The technical enrichment and use of radioisotopes led to the unscrupulously use of radioactive material and to the Cold War, with over 900 bomb tests from 1945 to 1990, combined with global fallout over the northern hemisphere. The friendly use of radiation in medicine and for the production of energy at nuclear power plants (NPPs) has caused further expositions with ionising radiation. This chapter describes in a practical manner the instrumentation for the detection of gamma radiation and some results of the use of these techniques in environmental and food investigations.",book:{id:"5451",slug:"new-insights-on-gamma-rays",title:"New Insights on Gamma Rays",fullTitle:"New Insights on Gamma Rays"},signatures:"Markus R. 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Some candidates of the GeV counterpart of gamma-ray bursts, observed by Tupi telescopes, are also presented.",book:{id:"5451",slug:"new-insights-on-gamma-rays",title:"New Insights on Gamma Rays",fullTitle:"New Insights on Gamma Rays"},signatures:"Carlos Navia and Marcel Nogueira de Oliveira",authors:[{id:"189908",title:"Dr.",name:"Carlos",middleName:null,surname:"Navia",slug:"carlos-navia",fullName:"Carlos Navia"},{id:"243084",title:"MSc.",name:"Marcel",middleName:null,surname:"De Oliveira",slug:"marcel-de-oliveira",fullName:"Marcel De Oliveira"}]}],onlineFirstChaptersFilter:{topicId:"227",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},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:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:106,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:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,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. 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Prior to his appointment at Stellenbosch University, he has been at the University of Pretoria, Department of Computer Science (1998-2018), where he was appointed as South Africa Research Chair in Artifical Intelligence (2007-2018), the head of the Department of Computer Science (2008-2017), and Director of the Institute for Big Data and Data Science (2017-2018). 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He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"23",title:"Computational Neuroscience",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",isOpenForSubmission:!0,editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",isOpenForSubmission:!0,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. Papakostas has received a diploma in Electrical and Computer Engineering in 1999 and the M.Sc. and Ph.D. degrees in Electrical and Computer Engineering in 2002 and 2007, respectively, from the Democritus University of Thrace (DUTH), Greece. Dr. Papakostas serves as a Tenured Full Professor at the Department of Computer Science, International Hellenic University, Greece. Dr. Papakostas has 10 years of experience in large-scale systems design as a senior software engineer and technical manager, and 20 years of research experience in the field of Artificial Intelligence. Currently, he is the Head of the “Visual Computing” division of HUman-MAchines INteraction Laboratory (HUMAIN-Lab) and the Director of the MPhil program “Advanced Technologies in Informatics and Computers” hosted by the Department of Computer Science, International Hellenic University. He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. He is a Senior Member of the IEEE Computer, the IEEE Computational Intelligence, and the IEEE Systems, Man, and Cybernetics Societies, and the Association of Computing Machinery (ACM). Finally, his main research interests include data science, computational intelligence, and their applications.",institutionString:null,institution:{name:"University of Córdoba",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"26",title:"Machine Learning and Data Mining",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",isOpenForSubmission:!0,editor:{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. 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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. 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She is now a lecturer at the University of Witwatersrand, South Africa, and a principal researcher at the Health Economics and Epidemiology Research Office (HE2RO), South Africa. Dr. Moolla holds a Ph.D. in Psychology with her research being focused on mental health and resilience. In her professional work capacity, her research has further expanded into the fields of early childhood development, mental health, the HIV and TB care cascades, as well as COVID. She is also a UNESCO-trained International Bioethics Facilitator.",institutionString:"University of the Witwatersrand",institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419588",title:"Ph.D.",name:"Sergio",middleName:"Alexandre",surname:"Gehrke",slug:"sergio-gehrke",fullName:"Sergio Gehrke",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038WgMKQA0/Profile_Picture_2022-06-02T11:44:20.jpg",biography:"Dr. Sergio Alexandre Gehrke is a doctorate holder in two fields. The first is a Ph.D. in Cellular and Molecular Biology from the Pontificia Catholic University, Porto Alegre, Brazil, in 2010 and the other is an International Ph.D. in Bioengineering from the Universidad Miguel Hernandez, Elche/Alicante, Spain, obtained in 2020. In 2018, he completed a postdoctoral fellowship in Materials Engineering in the NUCLEMAT of the Pontificia Catholic University, Porto Alegre, Brazil. He is currently the Director of the Postgraduate Program in Implantology of the Bioface/UCAM/PgO (Montevideo, Uruguay), Director of the Cathedra of Biotechnology of the Catholic University of Murcia (Murcia, Spain), an Extraordinary Full Professor of the Catholic University of Murcia (Murcia, Spain) as well as the Director of the private center of research Biotecnos – Technology and Science (Montevideo, Uruguay). Applied biomaterials, cellular and molecular biology, and dental implants are among his research interests. He has published several original papers in renowned journals. In addition, he is also a Collaborating Professor in several Postgraduate programs at different universities all over the world.",institutionString:null,institution:{name:"Universidad Católica San Antonio de Murcia",country:{name:"Spain"}}},{id:"342152",title:"Dr.",name:"Santo",middleName:null,surname:"Grace Umesh",slug:"santo-grace-umesh",fullName:"Santo Grace Umesh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/342152/images/16311_n.jpg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"333647",title:"Dr.",name:"Shreya",middleName:null,surname:"Kishore",slug:"shreya-kishore",fullName:"Shreya Kishore",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333647/images/14701_n.jpg",biography:"Dr. Shreya Kishore completed her Bachelor in Dental Surgery in Chettinad Dental College and Research Institute, Chennai, and her Master of Dental Surgery (Orthodontics) in Saveetha Dental College, Chennai. She is also Invisalign certified. She’s working as a Senior Lecturer in the Department of Orthodontics, SRM Dental College since November 2019. She is actively involved in teaching orthodontics to the undergraduates and the postgraduates. Her clinical research topics include new orthodontic brackets, fixed appliances and TADs. She’s published 4 articles in well renowned indexed journals and has a published patency of her own. Her private practice is currently limited to orthodontics and works as a consultant in various clinics.",institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"323731",title:"Prof.",name:"Deepak M.",middleName:"Macchindra",surname:"Vikhe",slug:"deepak-m.-vikhe",fullName:"Deepak M. Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Univeristy of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:null},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:null},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"355660",title:"Dr.",name:"Anitha",middleName:null,surname:"Mani",slug:"anitha-mani",fullName:"Anitha Mani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"355612",title:"Dr.",name:"Janani",middleName:null,surname:"Karthikeyan",slug:"janani-karthikeyan",fullName:"Janani Karthikeyan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334400",title:"Dr.",name:"Suvetha",middleName:null,surname:"Siva",slug:"suvetha-siva",fullName:"Suvetha Siva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}}]}},subseries:{item:{id:"15",type:"subseries",title:"Chemical Biology",keywords:"Phenolic Compounds, Essential Oils, Modification of Biomolecules, Glycobiology, Combinatorial Chemistry, Therapeutic peptides, Enzyme Inhibitors",scope:"Chemical biology spans the fields of chemistry and biology involving the application of biological and chemical molecules and techniques. In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. 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Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. 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