Chapter 1: "Permanent Maxillary and Mandibular Incisors"\n
Chapter 2: "The Permanent Maxillary and Mandibular Premolar Teeth"\n
Chapter 3: "Dental Anatomical Features and Caries: A Relationship to be Investigated"\n
Chapter 4: "Anatomy Applied to Block Anaesthesia"\n
Chapter 5: "Treatment Considerations for Missing Teeth"\n
Chapter 6: "Anatomical and Functional Restoration of the Compromised Occlusion: From Theory to Materials"\n
Chapter 7: "Evaluation of the Anatomy of the Lower First Premolar"\n
Chapter 8: "A Comparative Study of the Validity and Reproducibility of Mesiodistal Tooth Size and Dental Arch with the iTero Intraoral Scanner and the Traditional Method"\n
Chapter 9: "Identification of Lower Central Incisors"\n
The book is aimed toward dentists and can also be well used in education and research.',isbn:"978-1-78923-511-1",printIsbn:"978-1-78923-510-4",pdfIsbn:"978-1-83881-247-8",doi:"10.5772/65542",price:119,priceEur:129,priceUsd:155,slug:"dental-anatomy",numberOfPages:204,isOpenForSubmission:!1,isInWos:null,hash:"445cd419d97f339f2b6514c742e6b050",bookSignature:"Bağdagül Helvacioğlu Kivanç",publishedDate:"August 1st 2018",coverURL:"https://cdn.intechopen.com/books/images_new/5814.jpg",numberOfDownloads:7270,numberOfWosCitations:0,numberOfCrossrefCitations:1,numberOfDimensionsCitations:3,hasAltmetrics:0,numberOfTotalCitations:4,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 4th 2016",dateEndSecondStepPublish:"October 25th 2016",dateEndThirdStepPublish:"July 16th 2017",dateEndFourthStepPublish:"August 16th 2017",dateEndFifthStepPublish:"October 16th 2017",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,editors:[{id:"178570",title:"Dr.",name:"Bağdagül",middleName:null,surname:"Helvacıoğlu Kıvanç",slug:"bagdagul-helvacioglu-kivanc",fullName:"Bağdagül Helvacıoğlu Kıvanç",profilePictureURL:"https://mts.intechopen.com/storage/users/178570/images/7646_n.jpg",biography:"Bağdagül Helvacıoğlu Kıvanç is a dentist, a teacher, a researcher and a scientist in the field of Endodontics. She was born in Zonguldak, Turkey, on February 14, 1974; she is married and has two children. She graduated in 1997 from the Ankara University, Faculty of Dentistry, Ankara, Turkey. She aquired her PhD in 2004 from the Gazi University, Faculty of Dentistry, Department of Endodontics, Ankara, Turkey, and she is still an associate professor at the same department. She has published numerous articles and a book chapter in the areas of Operative Dentistry, Esthetic Dentistry and Endodontics. She is a member of Turkish Endodontic Society and European Endodontic Society.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Gazi University",institutionURL:null,country:{name:"Turkey"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"174",title:"Dentistry",slug:"dentistry"}],chapters:[{id:"56461",title:"Permanent Maxillary and Mandibular Incisors",doi:"10.5772/intechopen.69542",slug:"permanent-maxillary-and-mandibular-incisors",totalDownloads:1484,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Mohammed E. Grawish, Lamyaa M. Grawish and Hala M. 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\r\n\tThis book "Crystallization" aims to bring together several fields of research whose points in common is the phenomenon of crystallization. In this book, we will try to explain this phenomenon as well as the industrial techniques used for the implementation. We welcome topics on the crystallization of organic materials, polymers and macromolecules such as proteins. The techniques used for crystal growth, the methods of synthesis of single crystals, polycrystalline powder and thin film. The phenomenon of twin poses a problem during the resolution of structures. The explanation of this phenomenon can help researchers to solve their structures. The phenomenon of polymorphism interests several researchers, the description of the phenomenon of crystallization can give an explanation on the obtaining of a phase and not another. Phase indexing and prediction of growth faces is a field closely related to the crystallization and very useful for studying surface phenomena.
",isbn:"978-1-83969-317-5",printIsbn:"978-1-83969-316-8",pdfIsbn:"978-1-83969-318-2",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"3478d05926950f475f4ad2825d340963",bookSignature:"Dr. Youssef Ben Smida and Dr. Riadh Marzouki",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10504.jpg",keywords:"Crystallization, Germination, Growth, Twin, Polymorphism, Proteins, Cell Growth, Protein Engineering, Polymer Nucleation, Crystallization Kinetics, Growth Kinetics, Evaporative Crystallization",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 13th 2020",dateEndSecondStepPublish:"December 11th 2020",dateEndThirdStepPublish:"February 9th 2021",dateEndFourthStepPublish:"April 30th 2021",dateEndFifthStepPublish:"June 29th 2021",remainingDaysToSecondStep:"a month",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Junior Researcher in crystallography, electrochemistry of solids, and theoretical calculation methods (DFT and MD) within a Research Center, member of the Tunisian Chemical Society, and Tunisian Association of crystallography.",coeditorOneBiosketch:"Assistant Professor of crystallography, worked on phosphate and arsenate at the king Khaled university, member of the Tunisian Chemical Society and Tunisian Association of crystallography, a reviewer in several journals, editor of book, and authors of several papers.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"311698",title:"Dr.",name:"Youssef",middleName:null,surname:"Ben Smida",slug:"youssef-ben-smida",fullName:"Youssef Ben Smida",profilePictureURL:"https://mts.intechopen.com/storage/users/311698/images/system/311698.jpg",biography:"Dr Youssef Ben Smida had obtained his PhD in chemistry from the Faculty of Sciences of Tunis, University of Tunis ElManar, in June 2015. He worked on the synthesis of new single crystals and the determination of their crystal structures by using the single crystal X-ray diffraction technique. Dr Ben Smida worked for one year as contract researcher at the faculty of sciences of Tunis in the university year 2015-2016. Since June 2017, he was recruited as Assistant Professor in the National Center of Researcher in Materials Science, technopark Borj Cedria, Soliman Tunisie. He works in the following fields: Crystallography, Solid State Electrochemistry, Theoretical methods (DFT and MD) and photuminescence.",institutionString:"University of Carthage",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Carthage",institutionURL:null,country:{name:"Tunisia"}}}],coeditorOne:{id:"290142",title:"Dr.",name:"Riadh",middleName:null,surname:"Marzouki",slug:"riadh-marzouki",fullName:"Riadh Marzouki",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bUyIWQA0/Profile_Picture_1598339436253",biography:"King Khalid University Assistant Professor of Inorganic Chemistry in King Khalid University (KSA) & University of Sfax (Tunisia) Researcher in Crystallography and Materials Laboratory: Department of Chemistry, Faculty of Sciences of Tunis, Tunisia (Since 2009). Till now: 31 publications in Crystallography area (single crystal and polycrystalline powder) and 2 Open Lectures; 10 communications (5 oral); 7 Projects (financed by King Khalid University, KSA) Ph.D. thesis (2013): Crystallography and materials chemistry Area Research Interests: 1. Crystallography: Synthesis, Crystal structure determination, Charge Distribution, Bond Valence Sum calculations,2. Densification, control of the microstructure of ceramics, 3. Electrical conductivity studies (microstructure, structure and substitution effects), 4. Ion pathways simulation using BVS and BVSE models",institutionString:"King Khalid University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"King Khalid University",institutionURL:null,country:{name:"Saudi Arabia"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"8",title:"Chemistry",slug:"chemistry"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"247865",firstName:"Jasna",lastName:"Bozic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/247865/images/7225_n.jpg",email:"jasna.b@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3621",title:"Silver Nanoparticles",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"silver-nanoparticles",bookSignature:"David Pozo Perez",coverURL:"https://cdn.intechopen.com/books/images_new/3621.jpg",editedByType:"Edited by",editors:[{id:"6667",title:"Dr.",name:"David",surname:"Pozo",slug:"david-pozo",fullName:"David Pozo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"22890",title:"1980-2011: Parkinson's Disease and Advance in Stem Cell Research",doi:"10.5772/19150",slug:"1980-2011-parkinson-s-disease-and-advance-in-stem-cell-research",body:'Replenishing the depleted striatal dopamine stores with its immediate precursor, L-3,4-dihydroxyphenylalanine (l-DOPA), to mimic dopamine-mediated neurotransmission still represents the gold standard for treating Parkinson’s disease (PD). This pharmacological therapy offers immediate and effective symptomatic relief, especially at the early stages of the disease; it has, however, no influence on underlying neurodegenerative processes (Dass et al., 2006) that continue to evolve with time and are paralleled by a gradual loss of drug efficacy. As the disease progresses, steady adaptation, mostly continuous increase, of dopaminergic drug dosage is necessary, thereby favoring the emergence of considerable side effects, such as dyskinesia and psychiatric disturbances. The development of new treatments, or combination of treatments, able to relief motor symptoms and also delay or even halt the loss of dopaminergic neurons, has been and remains a fundamental issue for the development of innovative clinical strategies in PD. Transplantation of dopamine-secreting cells directly providing dopamine in the striatum, in particular, has been considered an adequate substitute to pharmacotherapy. However, although efficacy of this approach has now been asserted in numerous pre-clinical studies utilizing animal models of PD, positive outcomes in clinical trials involving PD patients have been very variable and rather modest, and have been plagued by graft-induced dyskinesias. New sources for cell replacement and particularly stem cells (including induced patient-derived cells) may now provide advantages for future clinical therapies (Wakeman et al., 2011).
This chapter will briefly introduce rodent and nonhuman primate PD-like models commonly used in pre-clinical studies, which represent a fundamental platform for the pre-clinical evaluation of innovative interventions. We will then evidence the progresses accomplished since the first intracerebral transplantation of fetal neural tissue in PD patients describing the subsequent novel discoveries for the application of stem cell to pre-clinical PD models, and give an overview of ongoing cell-based therapeutic strategies. Thereafter, multiple issues connected to stem transplantation to efficiently contrast adverse effects of increased age will be reviewed including decrease of apoptosis related to tissue degeneration, requirement of correct graft integration in the host vascular and neural circuits, reduction of diffuse inflammatory response/oxidative stress and correct release of key growth factors. In addition we will discuss the emergence of novel biotechnologies that will, most likely, help unravel the complex interrelationship between transplanted stem cells and the host environment and will favor the development of novel therapeutic procedures readily applicable in PD patients.
Animal models represent a fundamental step in the attempt to elucidate gene-environment interactions and to define pathogenic mechanisms involved in the aetiology and progression of the neurodegenerative diseases. Most of the current knowledge on pathophysiology of PD originates from studies conducted on animal models of the disease, since animals and humans share several anatomical features (as shown in Figure 1). In addition, they represent the first essential pre-clinical platform for the evaluation of any targeted therapeutic intervention. Notably, subsequent clinical trials in small human cohorts remain essential for the development of efficient therapies able also to alleviate disability related non-motor symptoms (Meissner et al., 2011) which are currently underestimated in animal models (Dunnett and Lelos, 2010).
Anatomical comparison between mouse and human brainsThe comparison between rodent (A) and human brain (B) enlightens their anatomical similarities and physiology. The connections between striatum, SNc, and cerebral cortex in the human brain are indicated by dotted black lines and may correlate the simultaneous degeneration of these areas during disease onset and progression. Moreover, dopaminergic innervations of the striatum/SVZ (black dotted lines) could also explain reduction of adult brain neurogenesis both in PD patients and animal models.
PD models have been classically based on the administration of neurotoxins able to replicate some of the pathological and phenotypic features of the human disease both in rodents and primates. Toxins can be given systemically or intra-cerebrally, depending on the type of toxin used and animal specie involved, and mimic the selective degeneration of nigrostriatal neurons characteristic of the human disorder.
The classical systemic model is based on the injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that selectively affects dopaminergic neurons and first recognized in the mid-1980’s as the cause of marked parkinsonism in young drug users of Northern California (Langston et al., 1983). MPTP crosses the blood brain barrier and is transformed in its active metabolite, 1-methyl-4-phenylpyridinium ion (MPP+) that is then actively taken up by dopaminergic neurons of the substantia nigra pars compacta (SNc). Systemic administration of MPTP to nonhuman primates induces a parkinsonian phenotype closely resembling the human pathology. MPTP-treated monkeys have an excellent anti-symptomatic response to dopaminergic drug treatment and develop motor complications linked to long term L-DOPA therapy (Kim et al., 2009). Concordantly, several pharmacological drugs currently applied to treated PD patients (i.e. dopamine agonists, amantadine, etc..) have been developed in this MPTP model (Fox et al., 2006). Alternative cell replacement strategies using various cell sources have been successfully performed indicating the technical feasibility of the model for future studies (Redmond et al., 2010; Serra et al., 2008). The large related costs and the difficulty to reliably standardize acute toxin administration to replicate most of the underlying mechanisms of a chronic progressive disorder form still represent major drawbacks and limit the use of this PD model in large scale studies (Fox and Brotchie, 2010). MPTP can also be systemically administered to mice but not rat, which are resistant, and several different experimental paradigms have been developed and used over time.
The prototypical intracerebral model is based on the local injection of 6-hydroxydopamine (6-OHDA) and was the first PD animal model ever generated (Ungerstedt, 1968). Six-OHDA is a hydroxylated analogue of dopamine and, similarly to MPTP, is actively taken up by dopaminergic neurons. The neurotoxin can be injected in the SNc, or into the medial forebrain bundle (mfb) that conveys efferent fibers from the nigral cell bodies to the striatum (as shown in Figure 1) and causes massive and rapid anterograde degeneration of the nigrostriatal pathway. This procedure induces large nigral cell loss and striatal dopamine depletion (90-100%). The neurotoxin can also be injected into the striatum; in this case rapid damage to striatal dopaminergic terminals is observed followed by a progressive loss of SNc neurons (50-70% neuronal loss), which are secondarily affected through a “dying back” mechanism. This procedure has a slower time course compared to the intra-mfb injection and provides a progressive model of nigrostriatal degeneration, more similar to the gradual evolution of the neurodegenerative process of human PD. Importantly, injection of 6-OHDA is commonly carried out unilaterally, with the contralateral hemisphere serving as control, because of the high mortality rate associated with bilateral injection. The rat 6-OHDA model is commonly used in neuroprotective studies, both involving administration of novel pharmaceutical compounds or cell transplantation because it is i) cost-effective, ii) highly reproducible and iii) opened to articulate behavioural analyses (Redmond et al., 2010; Serra et al., 2008).
Numerous transgenic mouse models, that reproduce monogenic mutations observed in familiar forms of PD, have also been developed over the years. These models have not been discussed in this chapter as they typically display very low degree or even no nigrostriatal degeneration (for review see (Dawson et al., 2010)) and are not commonly used in stem cell transplantation experiments.
In 1987, the first clinical trials involving transplantation of human fetal mesencephalic tissues or xenotransplantation of fetal pig neural cells in humans were performed with the clear scope of replacing dopaminergic neurons lost during PD progression. Since then and overall, contradictory results have been observed, even among patient groups treated within the same centers (Bjorklund et al., 2003). Along with the observed poor graft survival (around 10%; (Hagell and Brundin, 2001), a substantial subset of patients (15-56%) developed dyskinesias (Freed et al., 2001; Hagell and Brundin, 2001; Olanow et al., 2003), while the presence of Lewy bodies in long-term implants, recently reported, suggests the possibility of a host-to-graft disease propagation (Kordower et al., 2008; Li et al., 2008; Mendez et al., 2008). Functional improvements, represented by reduction of symptoms (30%–40% improvement of the unified Parkinson’s disease rating scale, motor score in the drug-free phase) have been clearly observed (Hagell and Brundin, 2001) even in the long term (Mendez et al., 2008; Piccini et al., 1999). Positive outcomes were dampened by enhanced microglial activation and disruption of blood brain barrier linked to surgical procedures (Olanow et al., 2003). Failures were also related to the scarcity, as well as heterogeneous composition of the donor tissue itself (Carlsson et al., 2009; Freed et al., 2001). Nonetheless, these first trials supported the feasibility of transplantation procedures as an alternative therapeutic approach in PD (Brundin et al., 2010; Olanow et al., 2003). Moreover, these first trials have enlightened critical parameters mandatory for successful tranplantations including: a) purity of cell preparation; b) correct localization of the graft in the host brain c) preference for reduced age of donor/host cells (whenever possible), d) limited extension of brain injury at the time of transplantation (early pathological phases), and e) appropriate time of grafting (in relation to disease onset) to maximize survival of endogenous dopaminergic neurons (Lindvall and Kokaia, 2009). Altogether, these observations have encouraged the search for alternative cell sources that need to be efficient, safe, and ethically acceptable (additional details on this debated/controversial topic can be found in (Kimmelman et al., 2009)).
The scientific progresses in biological and cellular technologies have allowed a better conception of the mechanisms involved in cell development, and in particular of factors/conditions ruling Stem Cells (SCs) proliferation and differentiation. Essentially, SCs are undifferentiated multipotent cells capable of both self-renewal and generation of several differentiated functional cell types to preserve tissue homeostasis throughout the entire life span of an organism. Multiple properties of SCs, including their the ability to potentially generate an unlimited number of dopaminergic neurons under physiological conditions, make them attractive candidates for regenerative therapy (Dass et al., 2006).
Therefore, SCs have been increasingly recognized as a valuable replacement and/or supporting tool for PD wherein a well-characterized cell type is mainly affected. Cell therapy may be performed using either autologous (ideal from an immunologic perspective) or allogeneic tissue-specific differentiated cells. Transplantation of healthy SCs that have been collected, expanded and eventually pre-differentiated in vitro have been originally proposed as a feasible appealing neural-replacement strategy. To date, several fetal and adult SC lineages have been directly differentiated into multiple cellular types, including neural cells and dopaminergic phenotypes. These naïve SCs, or their induced neuronal progeny, have been successfully transplanted in animal models of PD granting significant behavioral improvements. Ideally, however, new therapies should not only aim at replenishing the depleted dopamine store, but should also allow rescue of neuronal terminals and soma both in striatum and SNc.
Innovative therapeutic strategy should also take advantage and enhance the plastic property of the adult Central Nervous System (CNS) to regenerate affected brain areas through the activation of endogenous neurogenesis following cell transplantation. To reach these targets, other known intrinsic properties of SCs have already been exploited. Indeed, the potential of SCs to restore injured tissues is not only related to their direct differentiation but also to their capacity to produce and release trophic factors that may in turn inhibit apoptosis, promote angiogenesis and even direct stimulation of host regeneration (Lindvall and Kokaia, 2009;\n\t\t\t\tLindvall and Kokaia, 2010). Neuroprotection can also be enhanced by transplanting SCs engineered to express either tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine synthesis, or neurotrophic factors, such as glial cell-line derived neurotrophic factor (GDNF), the most potent survival factor for degenerating dopaminergic neurons. Grafting of engineered SCs in this case provides a substantial reservoir allowing the unlimited supply of the required substance without the requirement of invasive injection pumps, as detailed below. Several SC types have already been transplanted in PD animal models yielding interesting but variable results (Wakeman et al., 2011).
SCs can be efficiently derived from early stage embryos (pluripotent SCs with unlimited potential to differentiate) or from committed resident tissues (multipotent SCs with restricted potential to differentiate). Interestingly almost all organs arising from endodermal, mesodermal and ectodermal germ layers can originate both fetal and adult SCs (i.e. amniotic/cord blood and tissue derived SCs). Regardless of their origin SCs could physiologically repair damaged tissues after intense injuries also promoting angiogenesis and neurogenesis processes, essential for CNS development and regeneration (Lindvall and Kokaia, 2010).
Embryonic Stem cells (ES) are derived from the inner cell mass of pre-implantation embryos and are a source of pluripotent cells, as they are able to differentiate into all adult cell types. Once established, the pluripotent ES cells can be maintained under defined culture conditions, but can also be induced to terminally differentiate into a specific lineage (Bibikova et al., 2008). ES cells may potentially give rise to an infinite number of dopaminergic neurons that may be subsequently transplanted in depleted brain areas either in animal models of PD or even in patients (Lindvall and Kokaia, 2009). A particular emphasis has been posted on the validation of reliable methods for differentiation of ES cells towards midbrain dopaminergic neurons with a high survival index following transplantation (Hwang et al., 2010). Several protocols, characterized by presence of different feeder cell layers (i.e. bone marrow stromal cells, (Perrier et al., 2004) or astrocytes (Roy et al., 2006)) coupled to morphogen/growth factor exposition, have been developed. Transplantation of these in vitro-differentiated cells has produced variable results and often gave rise to tissue overgrowth with formation of neuroepithelial tumors, probably linked to the presence of residual immature cells in the original grafts. To overcome uncontrolled proliferation within transplants, cell-sorting protocols have been applied to specifically isolate pure populations of ES-derived dopaminergic neurons. These procedures, however, selectively impaired neuron survival indicating that fundamental factors were lost in the negative fraction (Friling et al., 2009).
Recently, epigenetic manipulation to force dopaminergic gene expression has been also exploited (Andersson et al., 2006). Following transplantation in parkinsonian rats, these differentiated cells integrated in the brain of the animals and significantly improved PD-related behavioral stereotypies (Yang et al., 2010). Application of this methodology to clinical practice, however, remains unrealistic until well-standardized, tumor-free samples will be available. Additional protocols for induction of dopaminergic phenotypes in ES cells have been recently developed (Chambers et al., 2009; Cooper et al., 2010), but functional efficacy of these cells has not been tested in PD animal models yet. Moreover, their use is still limited by our scarce knowledge of the development and specification of midbrain dopaminergic neurons (Pruszak and Isacson, 2009). Altogether, all experimental studies performed so far, demonstrate that ES-derived dopaminergic neurons are still unable to efficiently survive in and innervate lesioned brain areas in animal models of PD without inducing the formation of tumors (Arenas, 2010). In addition, ES cells frequently carry aberrant chromosome content in relation to growth advantage (Meisner and Johnson, 2008). Finally, the therapeutic application of ES cells will necessarily require both animal cell- and serum-free conditions (Klimanskaya et al., 2005), still substantially limiting their standardized application in clinic (Gruen and Grabel, 2006).
Recently, induced Pluripotent SCs (iPS) have been derived from primary fibroblast cultures obtained from cutaneous biopsies of patients affected by neurodegenerative diseases (Kriks and Studer, 2009; Lindvall and Kokaia, 2009). This complex reprogramming sequence was performed by exogenous expression of specific transcription factors that allowed a cellular switch from an epigenome of reduced potency to one of pluripotency (Kiskinis and Eggan, 2010). The resulting iPS cells could then be differentiated into autologous, patient-specific non-mitotic cells, such dopaminergic neurons and glial cells, normally present only in the CNS, and generally only available post-mortem.
iPS cells present several advantages when compare to ES cells: 1) their possible autologous derivation (Park et al., 2008b), 2) the consequent lack of mandatory immunosuppressant therapy following transplantation, and 3) the absence of ethical concerns related to embryo disruption (Arenas, 2010). These derived and/or differentiated cells can be used as donor cells in transplantation paradigms and represent a valuable tool to dissect intrinsic pathological mechanisms or test new pharmacological approaches in samples not readily available from live patients (Abeliovich and Doege, 2009; Gunaseeli et al., 2011; Xu et al., 2010a). However, the use of oncogenes or retrovirus in the current iPS cell establishment protocol raises considerable safety concerns (Pasi et al., 2011). Indeed, iPS progenies show high propensity to form teratomas considerably restricting their potential use in cell therapy (Miura et al., 2009). Heterogeneity of iPS cell composition with variable levels of transgene expression overtime suggests a prudent approach for iPS application to clinical trials (Kiskinis and Eggan, 2010). Recently, alternative protocols that allow direct fibroblast reprogramming towards neurons without generation of pluripotent cells have been developed (Vierbuchen et al., 2010). An additional notable potential risk of autologous therapeutic reprogramming is linked to the possibility that unknown genetic factors, involved in the patient’s disease, could also potentially lead to disease-related alterations of the transplanted cells in the long term (Hwang et al., 2010). Transplantation of committed neural cells selected from differentiated PD patient-derived iPS cells has been tested in a lesional rodent model of PD with some overall beneficial effects. Transplanted cells integrated into the striatum of parkinsonian rats and improved behavioral deficits for up to 8 weeks, although no noticeable dopaminergic innervation from grafted cells to the surrounding striatum was observed (Wernig et al., 2008). Recently, Hargus et al, showed that iPS–derived dopaminergic neurons can be implanted and survive, without signs of neurodegeneration or tumor formation, both in healthy and 6-OHDA lesioned rats (Hargus et al., 2010). Although the grafted cells sent proper projections to close and remote target areas, acquisition of the appropriate regional identity is still argued. A significant behavioral improvement related to high survival of the transplanted dopaminergic neurons was also reported in simple, but not in complex motor functions, that rely on functional connections between grafted and host cells. Therefore, whether these preliminary results can be successfully translated into human clinical studies still awaits more experimental data (Hanna et al., 2010). Additional long-term studies will be necessary to recreate the correct pathophysiological conditions before validation of this model as an alternative cell-based therapy in PD (Kiskinis and Eggan, 2010). It has been hypothesized that an effective therapeutic effect following transplantation requires the survival of at least 105 electrophysiologically active dopaminergic cells, appropriately contacting and reinnnervating striatum, without tumor formation (Arenas, 2010). Nevertheless, iPS cells could still be exploited for drug screening or as disease model to unravel pathological cascades in PD (Xu et al., 2010a). An important draw back in the clinical application of iPS cells also resides in the elevated production costs of personalized iPS. The establishment of centralized iPS cell bank(s) has been proposed to insure that fibroblast-derived dopaminergic neurons for transplantation are obtained following the Good Manufacturing Practice (GMP) guidelines for clinical trial materials.
An innovative cellular approach is based on patient-derived neural stem cells (NSC) obtained from biopsies of their olfactory mucosa biopsies. This procedure allows the derivation of large quantities of NSC that can be grown in vitro as floating differentiable neurospheres. The cells bear significant pathological, disease-specific alterations in gene and protein expression, as well as cell function, such as dysregulated mitochondrial function, oxidative stress and xenobiotic metabolism (Matigian et al., 2010). Direct exploitation of these patient-derived neural cells will help obtain new insights in specific candidate genes and cell pathways for future studies of brain disease. These SCs could partially overcome the lack of appropriate animal models, faithfully recapitulating all of the clinical and pathological phenotypes of the disease, to study the mechanisms underlying PD as well as to develop translational drug development (Schule et al., 2009). In addition, these cells have a considerable advantage over ES and iPS cells, as they do not require reprogramming, and represent an important tool, with a considerable translational impact to all complex diseases. Moreover, biopsies easily obtained from neural tissues could supply new biomarkers for monitoring disease progression in PD patients. Development of such biomarkers represents a necessary step for the accomplishment essential for quality research and clinical trials (Lebouvier Thibaud et al., 2010). Derivation of patient NSC encompasses all the specific gene-environment interactions which appear fundamental along ageing process in sporadic neurological as well as psychiatric disorders (Matigian et al., 2010). Patient derived SCs are particularly intriguing for their potential in cell therapy and regenerative medicine: they may provide novel insights for the development of therapeutic strategies, aiming to contrast the neurodegenerative processes of PD. The discovery of the specific molecules involved in these biological events could also shed light on new pharmacological disease-modifying treatments and novel potential targets, readily applicable to patients (Schule et al., 2009).
Anyway, a cautionary approach is required, since this invasive methodology still requires development of standardized, validated protocols able to reach a structure (olfactory mucosa) not accessible to routine biopsies (Parkkinen et al., 2009)].
Multipotent SCs have been identified within specific niches in most adult tissues including bone marrow, muscle, brain, heart and liver. Adult SCs that comprise fetal, amniotic, umbilical cord blood, placental, as well as tissue derived SCs (i.e. hematopoietic, neural, mesenchymal, skin SCs) are less abundant and proliferative, and possess limited potential to differentiate compared to ES cells. A key added value of adult SCs, however, is their potential use in autologous therapies, in which cells can be harvested and used within the same patient, thus avoiding the ethical concerns and risks linked to ES cells (Fricker-Gates and Gates, 2010). The ideal procedure involves isolation of SCs from tissues and their preservation in standardized stocks at centralized unit banks for long term storage and subsequent transplantation into patients upon request (Arenas, 2010) (see Figure 2). In this section we will summarize the actual state of the art and deadlocks regarding three main SC lineages: hematopoietic (HSC), mesenchymal (MSC) and neural (NSC).
Bone marrow resident HSC and MSC constitute two important cell sources for pre-clinical transplantation. HSC can be easily derived from autologous/allogeneic bone marrow or peripheral blood, and are routinely used in transplantation procedures for the treatment of several immuno-deficient/autoimmune diseases, as well as hematopoietic disorders, to reconstitute peripheral cell lineages (i.e. leukocytes, erythrocytes, etc). Recently, transplantation of HSC, engineered to release TH, has been reported to produce significant therapeutic effects in PD rats (Zhang et al., 2008).
A large body of data on the application of MSC in cell therapy can be found in literature; MSC are non-hematopoietic, multipotent cells which arise from the stromal structures of the bone marrow and are preserved in adults (Picinich et al., 2007). MSC can generate mature endothelial cells and several mesenchymal cell lineages including osteoblasts, chondrocytes, adipocytes and myoblasts (Liu et al., 2009). Several publications report efficient and multi-disciplinary protocols for their differentiation, in vitro, towards dopaminergic neurons (Heinrich et al., 2009; Kitada and Dezawa, 2009) even including the use of lentiviral vectors to induce TH expression (Barzilay et al., 2009). Positive outcomes in acute hypoxic-ischemic damages have been obtained utilizing MSC isolated from several stem sources, such as human placenta and amniotic fluid, either naïve (Cipriani et al., 2007) or following neural differentiation (Park et al., 2011). Positive results, such as stability and physiology of the correct phenotype in vitro (Thomas et al., 2011) and in vivo after transplantation of MSC in animal models of PD (Shetty et al., 2009), as well as in PD patients (Venkataramana et al., 2010) have been reported. The long-term fate of grafted cells is still, however, matter of debate (Schwarz and Storch, 2010; Schwarz and Schwarz, 2011) and application of cell therapy to a chronic degenerative disease like PD appears rather complex. Successful outcomes of transplantation can be influenced by multiple factors largely dependent on the source and type of SCs adopted. For example, it has been reported that neural differentiation of MSC is required before intrastriatal transplantation in PD rats to observe a graft-dependent improvement of motor deficits (Levy et al., 2008). Transplantation of naïve human umbilical vein-derived dopaminergic-like cell in a rat model of PD did not improve motor dysfunction, and required administration of a neurotrophin, nerve growth factor, to induce substantial recovery (Li et al., 2010a). Lineage negative cells from umbilical cord blood efficiently gave rise to neuronal cells and oligodendrocytes in vitro (Chua et al., 2009) while lineage specific (cKit+) amniotic-derived SCs fail to acquire a dopaminergic phenotype after epigenetic stimuli both in vitro and in an animal model of PD (Donaldson et al., 2009). Concordantly, upon neuronal induction bone marrow-derived MSC down-regulate markers of other lineages, but fail to differentiate into functional neurons (Thomas et al., 2011). The functional positive effects exerted by transplanted MSC in PD animal models, are still controversial on the basis of technical criticisms, strength of trial design or inconsistent experimental approaches (Meyer et al., 2010). MSC have a significant protective effect against dopaminergic cell loss both in vitro and in vivo (Park et al., 2008a), but whether this results from true dopaminergic neuron replacement and how the cells actually induced functional improvement are still far from being clarified (White, 2011). Thus, before MSC can be considered a reliable source for clinical replacement of dopaminergic cells, their ability to transdifferentiate terminally towards a neuronal lineage needs to be resolved and their mechanism of action following transplantation needs to be elucidated (Schwarz and Storch, 2010).
Another promising source of SC is represented by NSC, that can be derived from various source including the subventricular zone (SVZ), ES, umbilical cord blood, MSC, fetal brain as well as spinal cord, and grown in suspension as floating clusters (neurospheres) (Meyer et al., 2010). NSC can restore functions lost during ageing, and both migrate towards and repair neurological damages, exerting positive influence on the surrounding cells, including dysfunctional neurons (Ourednik et al., 2002). Autologous transplantation of in vitro-expanded cortical and subcortical tissue samples, obtained from a PD patient during a neurosurgical procedure, produced long lasting motor improvements (Lévesque et al., 2009). Interestingly, fetal and adult NSC possess comparable intrinsic therapeutic potential in terms of cell survival, integration and functional outcomes in a rat model of PD (Muraoka et al., 2008). However, albeit feasible, harvesting samples from patient remains an invasive procedure and is difficult to translate into a routine therapy. NSC do not give rise to dopaminergic neurons under physiological conditions, but several protocols have been optimized for their forced differentiation towards this lineage. Mimicking the procedures for dopaminergic differentiation from ES cells, a group has reported the differentiation of immature NSC into forebrain, but not midbrain (area A9), dopaminergic cells (Papanikolaou et al., 2008), while forced expression of Nurr1, a transcriptional factor specific for midbrain dopamine neuron development, induced dopaminergic neuron phenotype in NSC isolated both from SVZ and the white matter (Shim et al., 2007). The appearance of specific neuronal subtypes is not solely a direct consequence of external cues or the expression of neurotrophins but likely depends on the integrated temporal sequence of multiple factors that finally results in the correct neuronal phenotype. Regionalization and specification of the midbrain territory rely on a defined pattern of transcription factor expression and secretion of soluble molecules within the neuroectoderm in physiological conditions. This pattern is a composite process difficult to correctly recapitulate in vitro and has been only partially unraveled (Fricker-Gates and Gates, 2010). Interestingly, transplantation of NSC derived from MSC, using a complex protocol based on TH transfection and culture in media for differentiation, in 6-OHDA lesioned rats has been recently reported. Cell grafting induced significant behavioral improvements that were associated with partial preservation of dopamine content (Zou et al., 2010). A similar approach was applied to MPTP-lesioned parkinsonian rhesus monkeys; transplantation of TH- transfected bone marrow cells in the caudate nucleus and SNc improved both PD-related alterations in glucose metabolism and dopamine transport with an overall recovery of behavioral symptoms (Xu et al., 2010b). Similarly, allogeneic NSC modified to stably express and release the neurotrophic factor Neurotrophin-3 (NT-3), displayed enhanced dopaminergic neuron differentiation as well as migration distance, and induced the reinnervation in the neural circuitry coupled to functional recovery upon transplantation in 6-OHDA-treated rats (Gu et al., 2009). Recently, Murrell and colleagues proposed that dopaminergic neurons may be generated directly from adult olfactory SC of PD patients, similarly to Matigian et al (Matigian et al., 2010): in this paper the authors further demonstrated that differentiation of neural progenitor cells in dopaminergic-like neurons was able to correct behavioral asymmetry in the rat model of PD (Murrell et al., 2008).
Albeit these overall positive data, additional long term trials on the safety, efficacy, as well as further understanding of the biological mechanisms activated by graft procedures still need to be accomplished. So far, real functional integration between ectopically grafted SC-derived dopaminergic neurons in the denervated striatum has been demonstrated only in organotypic cultures of wild type mouse striatum (Tonnesen et al., 2011). Therefore, studies aimed at the characterization of the molecular basis of the integration in/differentiation of (genetically modified) NSC, and their progeny, within the dopaminergic network deserve further extensive development. Finally, the invasive intracerebral procedure required for the isolation of NSC as a possible SC source in the treatment of neurodegenerative diseases still remains a major draw back for their clinical application.
It is also important to notice that all the three SC lineages (HSC, MSC and NSC) can be obtained from bank-stored umbilical cord blood and amniotic/placenta cells, while only HSC and MSC can be easily isolated from autologous peripheral blood, thus amplifying the potential SC pool for clinical or experimental settings without ethical concerns (Figure 2).
Recent discoveries regarding the role of the immune system in brain damage coupled to the development of new technologies to manipulate the immune response make immunotherapies an attractive target to treat neurological diseases (Tansey and Goldberg, 2010). In the past decade, neuroinflammation has emerged as an important substrate for PD (Brochard et al., 2009). Several epidemiologic studies have reported an inverse correlation between the chronic assumption of non-steroidal anti-inflammatory drugs and the risk of developing PD (Chen et al., 2003). Unrestrained widespread neuroinflammation emerges during the early phases of the neurodegenerative process both in PD patients and in animal models of the disease (Whitton, 2010) and significant evidence demonstrates that neuroinflammatory processes participate in PD pathophysiology. Gliosis and lymphocyte infiltration associated with production of soluble factors – potentially protective or toxic - are consistently reported in parkinsonian animals and PD patients (McGeer et al., 1988; McGeer and McGeer, 2004; McGeer and McGeer, 2008) Most studies in animal models of PD have demonstrated that efficient neuroprotective strategies that decrease nigrostriatal degeneration also consistently reduce associated neuroinflammatory processes, and vice-versa, underlying the fundamental link between neuroinflammation and neurodegeneration. Recent data have also supported the idea that a reduction in the levels of anti-inflammatory factors itself can further enhance vulnerability of dopaminergic neurons to apoptosis in a neurodegenerative environment (Barnum and Tansey, 2010; Lu et al., 2010; Maguire-Zeiss and Federoff, 2010). Furthermore, it has been recently suggested that pro-inflammatory cytokines exert a negative impact on neuronal differentiation, while anti-inflammatory cytokines facilitate neurogenesis (Mathieu et al., 2010) and neuronal migration towards appropriate targets (Das and Basu, 2008). These data clearly indicate that pro- and anti-inflammatory responses must be strictly balanced to prevent the potential detrimental effects of prolonged or unregulated inflammation on vulnerable neuronal populations (Lee and Park, 2009). It has been shown that outcome of the transplantation of ES-derived TH-positive cells in an MPTP mouse model of PD is strictly dependent on the concomitant administration immunosuppressive treatment (Toriumi et al., 2009) that significantly improved survival and integration of grafted SC overtime.
Noteworthy, inflammation, which has long been considered as thoroughly disastrous for brain repair, is now known to produce some positive effects on stem/progenitor cell recruitment/survival by growth factor signalling and the secretion of chemoattractant cytokines (Cayre et al., 2009; Mathieu et al., 2010). Conversely, inflammatory mediators, such as nitric oxide (NO) and reactive oxygen species (ROS), can contribute to neurodegeneration by triggering aberrant protein modifications with consequent misfolding and loss of function (Vicente Miranda and Outeiro, 2010). Application of MSC, a particular SC lineage described above (section 4.4), that knowingly possess significant inherent immunomodulatory properties, opens new perspective for cell transplantation in PD. MSC can interactively act on their environment through the local/distal release of trophic factors, as well as on the activation of immune response by means of cell contact-dependent mechanism and modulation of noxious inflammatory components (Lee and Park, 2009). MSC were proven to effectively protect dopaminergic neurons from lipopolysaccharide (LPS)-induced neurotoxicity, both in vitro and in vivo, via anti-inflammatory mechanisms involving the modulation of microglial activation (Kim et al., 2009). Microglia, in turn are responsible for the correct phagocytic clearance following injury, thus facilitating the reorganization of neuronal circuits and triggering repair (Neumann et al., 2009). Notably, aside from immunomodulation, the complex network of biological mechanisms activated by MSC transplantation includes their homing to the SNc, substitution of dopaminergic neurons, modulation of apoptosis and modification of ubiquitin-proteasome function. Concordantly, at the moment, MSC constitute the most attractive and autologous candidate disease modifying strategy for PD and other neurodegenerative disorders (Karussis et al., 2008).
The nigrostriatal network is highly organized and finely regulated in relation to specific functions and circumstances. As a consequence, restoring lost dopaminergic neurons does not necessarily coincide with correct reconstruction the pathway (Obeso et al., 2008). Partial maintenance of neuron survival and function in the SNc within the neurodegenerative environment, following transplantation of SCs could, per se, potentially translate in significant therapeutic outcomes. Substantial neuroprotective effects against dopaminergic depletion have been observed, for example, after transplantations of naïve, undifferentiated SCs such as adult adipose-derived adult stromal cells (McCoy et al., 2008), human NSC (Yasuhara et al., 2006) or human MSC (Blandini et al., 2010) in 6-OHDA lesioned rats. Similarly, neuroprotection was evident following grafting of human MSC in an animal model of progressive parkinsonism (Park et al., 2010; Park et al., 2008a). In an interesting approach, transplantation of genetically engineered NSC, in animal models of brain tumor or injury, could served as incessant sources of secreted therapeutic agents (neuroprotective or tumoricidal) playing the role of biological minipumps (Chen et al., 2007). This procedure could readily be applicable to neurodegenerative diseases, including PD. As already described for neuroinflammation, the complex interactions between grafted SCs and endogenous surrounding cells can reciprocally influence outcome of transplantation both through direct interconnections (adherent junctions) or long distance mediations (release of soluble factors) (Boucherie and Hermans, 2009). In Amyotrophic Lateral Sclerosis for example, non-neuronal neighboring cells, including astrocytes, can drastically enhance neuronal survival (Nagai et al., 2007). Concordantly, in PD, glial cells play a critical role in homeostatic mechanisms that promote neuronal survival through release of an array of pro- and anti-inflammatory cytokines, anti-oxidants and neurotrophic factors within the microenvironment of the brain (L\' Episcopo et al., 2010). Interestingly, grafting of MSC differentiated towards astrocyte-like phenotypes resulted in relevant improvements of motor impairment in 6-OHDA lesioned rats in the absence of dopaminergic differentiation (Bahat-Stroomza et al., 2009). Similarly, naïve MSC transplanted in the striatum of 6-OHDA lesioned animals acquired a glial-like phenotype and significantly reduced the toxin-induced neurodegeneration (Blandini et al., 2010).
Recent innovative approaches also include the use viral vectors to induce selected SC to produce/release specific neurotrophins possibly active in repairing/rescuing the degenerating nigrostriatal system. New protocols for efficient transduction of MSC allowing enhanced delivery of GDNF have been developed. Transplantation of the transduced cells in experimental PD resulted in the preservation of striatal TH immunoreactivity around the graft (Moloney et al., 2010). Similarly, GDNF- and Brain Derived Neurotrophic Factor (BDNF)-secreting MSC transplanted in 6-OHDA lesion rats improved behavioral deficits, typically detected in these animals (Sadan et al., 2009). Human neural progenitor cells that had been genetically modified to release GDNF, readily survived without tumor formation, following the intrastriatal transplantation into the brain of aged monkeys (Behrstock et al., 2006). A comparative study with non human primate has evidenced that the striato-nigral axon-transport is also compromised in advanced PD patient potentially limiting the regular retrograde transport of factors towards affected neuronal bodies in the SNc (Bartus et al., 2011). These therapeutic strategies may, therefore, be applicable mainly to patients at an early stage of the disease when part of the nigrostriatal network is still spared and may be rescued. Different clinical approaches may be required as disease proceeds with the wide loss of dopaminergic neurons (Rascol, 2009).
Donor cells, to physiologically repair damaged neural circuitry using SC transplantation, must be able to survive in sufficient number, to differentiate into the appropriate cell type and to adequately support the host brain environment. To optimize functional recovery and minimize side effects, grafted SCs should be able to functionally integrate in and be regulated by the host brain. Outcome of transplantation may be directly affected by time of grafting and cell number (Darsalia et al., 2011). Correlation between cell amount and therapeutic effects has, for example, been demonstrated for naive MSC that dose-dependently and regionally sustained the survival of striatal/nigral dopaminergic terminals and enhanced neurogenesis, following intrastriatal transplantation in parkinsonian rats (Blandini et al., 2010; Cova et al., 2010). Among the pathogenetic mechanisms involved in PD a role of reduced neurogenesis has been suggested (Geraerts et al., 2007). The SVZ, one of the two neurogenic zones region located in the lateral wall of the ventricles that maintains the largest pool of proliferating cells in the mature mammalian CNS, receives organized projections from the SNc. These efferent projections can influence precursor cell proliferation in both adult animal (Baker et al., 2004; O\'Keeffe et al., 2009a) and primate models (Freundlieb et al., 2006), probably through dopamine-induced release of Epidermal Growth Factor in the SVZ (O\'Keeffe et al., 2009b). Dopaminergic denervation within SVZ causes a reduced rate of neural precursor mitosis and abridged neuronal maturation in the long term, a phenomenon common among PD patients (Hoglinger et al., 2004) and toxin-induced animal models of PD (Aponso et al., 2008; He et al., 2006; He et al., 2008; Winner et al., 2009; Winner et al., 2006).
Schematic flow chart for cell therapy in PDA clinical approach to PD therapy will require 1) SC isolation (possible from different sources) 2) their expansion in vitro 3) direct or delayed transplantation through alternative or multiple administration routes. Independently from SC type and injection site, the therapeutic outcomes will depend upon donor and host ages, extension of the neuronal degeneration and graft size. The possible reparative mechanisms exerted by SC transplantation comprise neuronal replacement, neuroprotection of residual dopaminergic neurons and stimulation of endogenous neurogenesis, which may variably contribute to observed behavioral and physiological improvements. In PD cell therapy all the manipulations involving SCs should be conducted following the GMP guidelines in the absence of serum or other animal components.
Release of growth factor by grafted SC may influence adult neurogenesis and up-regulate self renewal and/or differentiation of adult host cells both under physiological and pathological conditions. Pre-clinical data suggest that modulation of endogenous neurogenesis may represent an alternative ways to slow down neuronal cell loss and possibly regenerate affected brain areas by modulation of endogenous neurogenesis (Geraerts et al., 2007; Okano et al., 2007). Administration of several growth factors (i.e. Transforming Growth Factor-α, BDNF and Fibroblast Growth Factor) in striatum enhanced neuronal differentiation within SVZ with overall improvements in murine behavior (Chiocco et al., 2007). Moreover, in the SNc pharmacological activation of dopamine receptor D3 with a selective agonist -7-hydroxy-N,N-di-n-propyl-2aminotetralin- induced cell proliferation and maturation towards dopaminergic phenotype (Van Kampen and Eckman, 2006), thus suggesting the possible occurrence of adult neurogenesis in this region under the pathological conditions in PD (Arias-Carrion et al., 2009). Presence of neurogenesis in the SNc suggests that disease progression may rely on the loss of dopaminergic neurons as well as on the malfunctioning in their turnover. Possible efficacy of orthotopic dopaminergic neurogenesis in PD has been questioned for a long time (Hermann and Storch, 2008), but transplantation experiments have indicated that several SC types, including neural precursors (Arias-Carrion et al., 2006; Madhavan et al., 2009) and MSC (Cova et al., 2010), can significantly support endogenous neurogenesis during the degenerative process in animal models of PD (Hess and Borlongan, 2008). Neurogenesis has been confirmed in SVZ of human brains (Curtis et al., 2007), but its physiological role is still uncertain (Zhao et al., 2008). Similarly, the existence of an improved neuronal reconstruction in the basal ganglia of the human PD brain (Yoshimi et al., 2005) is still a matter of debate. The reasons for decreased neurogenesis observed with aging and in pathological states may be related to an intrinsic inability to respond to the proliferative stimulation in the neurogenic niche, a reduction in the number of proliferative SC number, or the presence of activated microglia and neuroinflammation (Russo et al., 2011). Therefore, unraveling the localization as well as the degree of neurogenesis rate in human brains, together with the discovery of the specific molecules involved in these biological events, could lead to the discovery of new pharmacological disease-modifying treatments and novel potential targets, readily applicable to PD patients (Lindvall and Kokaia, 2010). Finally, it appears realistic to combine the synergistic effects between exogenous and endogenous SC actions to obtain cues on potential mechanisms involved in the noxious effects of neurodegeneration in PD as possible targets for clinical therapy (see Figure 2) (Madhavan and Collier, 2010).
To date different SC types, as well as route of cell administration have shown efficacy in animal models. Two main routes have been generally used for SC delivery: intracerebral and intravascular. The first one is a stereotaxic transplantation of cells into the brain. Given, in PD, that brain damage principally occurs in both striatum (dopaminergic terminals) and SNc (neuronal soma), the best transplantation site, that would provide the most efficient and widest SC engraftment, is unknown. Nowadays, striatal administration of SCs is the most common approach for pre-clinical trials in PD (Blandini et al., 2010; Yasuhara et al., 2006; Zhu et al., 2009), although SC transplantation in mfb is also feasible (Gu et al., 2009). Gu and colleagues showed that double injection of NT-3 transfected NSC in mfb and ventral tegmental area of parkinsonian rats generates new TH positive cells in these areas with relevant behavioral and functional recovery (Gu et al., 2009).
Although the intracerebral route has provided a large panel of positive results in animal models and has allowed a better understanding of mechanisms underlying disease pathology, independently of the graft site, an outsized dilemma still resides in its invasive nature. To bypass this concern intravascular administration has also been undertaken. Intravenous administration of MSC after in 6-OHDA lesioned rats yields preservation of dopaminergic system and relevant behavioral improvements, although no transplanted SCs were observed in brain one month after injection (Wang et al., 2010). The intravenous administration route has obvious clinical advantages compared to intracerebral injection, yet evident efficient therapeutic benefits are fully dependent on the appropriate number of cells reaching the lesion sites. Concordantly, Wang et al have reported that the majority of SCs injected intravenously mostly dispersed in pulmonary tissue (Wang et al., 2010). This is in high contrast with the intracerebral route in which a large amount of cells are injected directly in or may easily migrate within the nearer lesion site. In 6-OHDA lesioned rats, the number of SCs still present at the site of injection, 4 weeks after transplantation, was proportional to the number of cells initially injected (Cova et al., 2010). Regardless of the delivery route adopted for transplantation, the biological mechanisms activated by SC graft rely both on cellular replacement and activation of the endogenous repair mechanisms coupled to neurorescue effects exerted on degenerating neurons (Lindvall and Kokaia, 2010). To date, no data from comparative studies between several administration routes (e.g., intrastriatal, intraventricular, and intravenous injections) of SC delivery in PD patients are available, although open labeled clinical trials with stereotaxic surgery have been already conducted (Venkataramana et al., 2010). An interesting clinical approach by multiple administration routes for the treatment of spinal cord injuries has just been developed. Such strategy induces noteworthy with improvements of the life quality for patients (Geffner et al., 2008) and could be very positively applied to chronic degenerative diseases such as PD.
Recently, an innovative alternative route for SC administration via a intranasal drop has been developed in an animal model of PD. MSC delivered into rat nostrils were found to migrate to lesion brain areas where they survived for at least 6 months (Danielyan et al., 2011). In these animals striatal dopamine levels were increased and motor functions improved up to 68% of values observed in control animals (Danielyan et al., 2011). This administration route appears safe and could potentially be repeated overtime in a given patients. The intranasal procedure could avoid problems related to surgical implantation of SCs, although the positive outcomes need to be further confirmed before any clinical applications.
Future therapeutic trials should also evaluate how the time point at which SC transplantation is performed, with respect to the cerebral insult, may influence efficacy of the procedure: earlier cell grafts may provide effective neuroprotection to degenerating neurons but the hostile environment may endanger their long-term survival by spreading disease hallmarks (Kordower et al., 2008; Li et al., 2008; Mendez et al., 2008). In principle, a time interval sufficient to allow in vitro expansion of autologous SCs, would obviously be desirable both from a practical and clinical perspective. On the other hand, transplantation at later disease stages, when cell loss is almost complete, will mainly aim at replacing lost dopaminergic neurons and will certainly be affected by the reduced expression of homing signals secreted in degenerative brain tissues. Conversely, transplantation at early stage will mostly rely on rescue and regeneration of surviving neurons. For CNS repair, transplantation of proliferating progenitors cells, whose fate is less predictable since they are more proliferative than neurons, would face difficulties in sorting from stray pluripotent SCs, in the absence of specific markers. A clear trial design will necessarily need to take in account all these different biological mechanisms and, most importantly, will require the development of the appropriate biomarkers (Rascol, 2009) to follow disease progression.
The choice of a specific SC type and its state of differentiation, as well as the amount of cells and route of administration will depend on the experimental endpoints, keeping in mind that each one faces inherent problems connected to local control of immune rejection, final differentiation towards dopaminergic neurons and cytokine release distally. For example transplantation of ES cells can lead to tumor formation and systemic injection of SCs may result in dispersion of the cells in non-target tissues. Circulating HSC could participate in the regeneration of peripheral tissues/organs, but only if a sufficient number of SCs is activated. Finally, as clearly pointed out by Irving Weissman, any future SC clinical application in neurodegenerative diseases will need to respect the four thresholds of clinical effectiveness: 1) cell homing to the diseased or injured tissue 2) effective engraftment, not just fusion with host cells 3) physiological effectiveness 4) permanence overtime (Weissman, 2000).
As mentioned above animal models of PD are fundamental tools to evaluate feasibility and potential of a given SC population. To date translation of results obtained in pre-clinical animal models of PD has been difficult. In particular, the effect and long-term survival of transplanted cells remains an open issue. The development of innovative imaging techniques, combined with the creation of reporter transgenic mice, has widen our understanding of some pathological mechanisms of the disease and allowed the identification of specific pharmacological targets (van Nuenen et al., 2009). Precise tracking of transplanted SCs through novel imaging techniques, as well as monitoring of engraftment efficiency directly in vivo allows the immediate correlation between beneficial effects and SC localization/amount (Lee et al., 2008). Genetic tags have and continue to help researchers and bioethicists to track transplanted cells overtime following their behavior and dispersion in tissues in animals. The simplest tag uses genetic recombination to introduce a fluorescent marker, such as green fluorescent protein, into a cell, but magnetic nanoparticles have also been proven to be helpful (Ferreira et al., 2008). Since cell therapy relies on SC involvement in physiological circuits their upshots could persist over a long time and should, therefore, be devoid of side effects. Homing, engraftment, cell fate, persistence and tumor formation of labeled SCs and their progeny needs to be carefully evaluated and could potentially be assessed using in vivo imaging. In complex neurodegenerative diseases, such as PD, grafted SCs or derived progenitor cells may protect residual neurons rather than replacing the degenerated ones. Therefore, tagged grafts could be easily characterized to determine if transplanted cells trigger endogenous mechanisms of repair or whether they directly replace lost cell populations. Successful application of magnetically-labeled mouse embryonic SCs to a rat model of PD coupled to the study of their diffusion up to 6 months post transplant has already demonstrated the feasibility and safety of this approach (Stroh et al., 2009). Imaging techniques are already used to study early and presymptomatic stages of PD (Wu et al., 2011) and effectively measures outcomes in clinical trials of neuroprotection demonstrate that it is a practical non invasive method extensible to all PD patients (Pavese et al., 2009). PET measurements of 6-(18F) fluorodopa (18F-FDOPA) uptake indicate nigrostriatal neuronal integrity and may provide a useful endophenotype for PD linkage studies (Kumakura and Cumming, 2009). Clinical benefits and graft viability of embryonic dopamine cell implantation have been followed by functional imaging for up to 4 years after graft in 33 patients, thus correlating motor improvements with increased 18F-FDOPA uptake (Ma et al., 2010).
Gaining more information about the pathology of the disease, the probable behavior of the grafted cells, as well as the reciprocal interconnections between the transplants and the host environment in animal models will be useful to predict possible complications and undesirable side effects readily translatable to future clinical trials for PD patients (Li et al., 2010b). Caution needs to be adapted since xenograft models of disease in animals may not accurately predict the same response in humans due to inherent differences. However, pre-clinical data will help improve patient selection for future clinical trials, assess restoration of brain connectivity, and monitor inflammatory processes in the continuous search of novel therapeutic targets (Politis and Piccini, 2010). Moreover, targeted delivery of SCs through alternative routes could be easily compared in animal models. Concordantly, one objective of modern neuroimaging is to identify markers for clinical diagnosis, monitor the disease progression, define the exact SC placement and analyze the impact of long-term drug/cell therapy through the direct spatio-temporal visualization of SCs as well as their effect on disease progression in patients, using non invasive techniques (Lee et al., 2008). A successful SC therapy requires extensive knowledge on SC properties, appropriate harvesting, manipulation and apt implantation, but also subsequent graft monitoring in the long time to verify the permanence of reparative mechanisms (Nikolic et al., 2009). On the basis of these data, it may be possible to properly select SC type, administration timing and delivery route for specific disease entities, anatomic areas, and physiologic circumstances to obtain reproducible experimental results for the creation of effective clinical protocols (Lindvall and Kokaia, 2010).
Additionally, cell transplantation in animal is often performed before or contemporaneously to neurotoxin lesion. Further development of experimental models that more accurately recreate neurodegenerative conditions present in patients, in which treatment can only intervene when the degenerative process is overt and motor symptoms are manifest, is required. In particular, the creation of genetic animal models is becoming increasingly important to elucidate gene-environment interactions, define pathogenic mechanisms, and provide a platform for testing cell therapeutic interventions (Magen and Chesselet, 2010).
The development and validation of conventional pharmacological therapy for clinical use is a long process that usually requires at least a decade. Cell transplantation, which represents an advanced therapeutic strategy far more complex than any pharmaceutical compound, was introduced surprisingly early into the clinic. Although some positive effects have been observed in the pioneering clinical studies sufficient caution should be taken before this strategy can be “routinely” applied to PD patients in order to avoid complications that may set back the field. In particular, defining and validating a specific cell type that may be consistently used in transplantation procedures is still a milestone that needs to be achieved. Extensive interactions and communication between clinicians and pre-clinical scientists is mandatory to allow the constant fine-tuning of the design of therapeutic strategies for PD patients.
The technological progress has led to radical changes in the contemporary world. The system of international relations changed. The development of information and communication technologies (ICT) has affected all the areas of public life including the economy, politics, social issues, and culture, bringing them together in the framework of establishment of an information society.
\nBy the present time, the information society concept has been represented in a number of international documents among which are the Declaration of Principles entitled “Building the Information Society: a Global Challenge in the New Millennium” (hereinafter referred to as the 2003 Declaration) and the Plan of Action of the World Summit on the Information Society of December 12, 2003.
\nInformation society is a more general category as compared to the global information society. It can be established within a single state or at the regional or global levels. At the global level, it will be referred to as the global information society.
\nThe global information society can be defined as a system of international relations that are established in the sphere of operation of information systems, which are based on information and communication technologies, in which international information relations affect political, economic, social, and cultural relations. At the same time, the states participate in relations in the global information society as equal subjects of international information relations.
\nThe development of ICT is related to the effect on established branches and institutes of international law as well as to the regulation of new relations that arise as a result of ICT development.
\nThe most complicated problem is the effect of ICT on established branches and institutes of international law. The mechanism for the development of international law provisions is such that legal regulations tend to “fall behind” the level of ICT development.
\nCurrently, the spreading and use of ICT affect the interests of the entire international community; these technologies can potentially be used for purposes that are incompatible with the objectives of international stability and security and can have an adverse effect on the integrity of the infrastructure of the states, disturbing their security in the civil and military areas.
\nThe efforts of individual states are insufficient for ensuring international information security. First of all, the prohibition on the use of information weapons by states must be established in international law. Separate regulation is required for matters of information security of individuals (protection from defamation and privacy).
\nThe forming special principles of international information law include the principle of confidentiality and security in using ICT. Strengthening the trust framework, including information security and network security, authentication, privacy, and consumer protection, is a prerequisite for the development of the information society and for building confidence among users of ICTs. A global culture of cyber security needs to be promoted, developed, and implemented in cooperation with all stakeholders and international expert bodies. These efforts should be supported by increased international cooperation. Within this global culture of cyber security, it is important to enhance security and to ensure the protection of data and privacy while enhancing access and trade. In the 2003 Declaration, the term “cyber security” has a wider meaning that only protection from cybercrimes. In particular, the Declaration notes that the summit participants support activities of the United Nations to prevent the potential use of ICTs for purposes that are inconsistent with the objectives of maintaining international stability and security and may adversely affect the integrity of the infrastructure within states, to the detriment of their security.
\nThese regulations ensure the relation of the developing principle of international information law with the existing principles, namely, the principle that the exercise of freedom of opinion, expression, and information is an essential factor in strengthening peace and international security; the principle that the media should contribute to the strengthening of peace and international understanding and to the struggle against racism, apartheid, and incitement to war; and the principle of the need to publicize the denunciation of information, the spreading of which has caused damage to efforts of strengthening of peace and international understanding, the development of human rights, and the struggle against racism, apartheid, and incitement to war.
\nThe problems of information security of individuals and legal entities have been examined in fundamental research on the comparative law of information technologies by Bainbridge [1], Campbell [2], Rowland and Macdonald [3], Smedinghoff [4], and Black [5].
\nThe issue of privacy protection, primarily using national legal instruments, has been covered in particular chapters in the fundamental research on the law of information technologies by Bell and Ray [6], Reed [7], and Angel [8] and special research by Solove [9] and Nouwt, Berend, and Prins [10].
\nTechnical and organizational aspects of ensuring information security have been covered in the works of Egan and Mather [11], Hunter [12], and Volonino and Robinson [13].
\nThe matter of implementation of the concept of ensuring international information security has already been considered in research, although the concept itself has not been stipulated. Lloyd [14] considered the acts of the UN, the Council of Europe, OECD, and the Asia-Pacific Community when addressing the issues of privacy, primarily considering “soft law” acts. In a review of cybercrime problems, this author gives a brief overview of the Council of Europe Convention on Cybercrime, the OECD Guidelines for the Security of Information Systems, and the EU acts.
\nThe contents and significance of the Convention on Cybercrime of November 23, 2001, have been discussed in the studies by Lloyd [14], Murray [15], and Koops, Lips, Prins, and Schellekens [16]. But these studies did not cover the problems of using the experience of the Council of Europe at the global level.
\nWith regard to the 2001 Convention, Hopkins [17] has noted its excessive broadness and lack of clarity in its basic terms. For example, this Convention defines a computer system as any device or a group of interconnected or related devices, one or more of which, pursuant to a program, performs automatic processing of data. In such case, the term device will include children’s toys, Palm Pilots, and cable television devices. Therefore, the scope of the 2001 Convention extends from real computer crimes to interference in any devices where software is used.
\nThe concept of personal data in international acts has been criticized in the legal doctrine. In particular, Berčič and George [18] state that this definition is too broad because any information about a person can be regarded as personal data (e.g., information that an individual is wearing a red shirt). On the other hand, there arise practical complicacies with attributing certain data as personal data (e.g., social security identification numbers).
\nPolcak [19] has pointed out that in various European countries, there are complicacies with attributing IP addresses, personal telephone numbers, data entered anonymously when receiving services via the Internet, and data of deceased persons as personal data.
\nThe absence of unified list of personal data in the national legal systems is the reason of the imperfection of the international legal regulation. The efforts made in the area of harmonization have not been successful enough. This is confirmed by the attempts that are being made at the national level to create an own definition of personal data. In particular, a number of authors have named the Durant v. FSA case in British courts as an example. In this case, the Court of Appeals has defined personal data as information that affects the privacy of the data subject including their personal and family life and business or professional abilities [20].
\nIt should be noted that currently, proposals to make global international treaties primarily come from non-state actors. In August 2000, a group of researchers from Stanford University presented the Draft International Convention to Enhance Protection from Cyber Crime and Terrorism (the Stanford Project). Brown drafted a convention regulating the use of information systems in armed conflicts. On November 6, 2009, the International Conference of Data Protection and Privacy Commissioners adopted a resolution entitled “Standards of Privacy and Personal Data,” for which it established a work group to develop a draft global treaty and listed the criteria for the drafting of it. It is planned to submit the developed sections of the treaty to the UN. Thus, researchers and international forums are proposing specific projects, but no systemic work is carried out in the framework of the UN, International Telecommunication Union (ITU), or UNESCO.
\nAt the same time, there are no monographic researches of the general concept of international information security that would cover the regional and global levels and the problems of development of its legal basis.
\nThe present study, based on the analysis of international acts, reveals the content of the general concept of international information security that would cover the regional and global levels. “Soft law” acts are appropriate for the formulation of the general concept of international information security, but not for its implementation. Therefore, the author proposes a draft convention with the purpose of creating of global network of information security.
\nThe objective of the research is consideration of the international information security concept that has developed at the global and regional levels and formulation proposal for elaboration of legal instruments for its implementation in connection with the concept of the global information society. For this, the analysis of existing international information security system at the global and regional levels shall be made, a description and a generalization of the analysis results. For the analysis of existing international information security system, formal-logical, systemic-structural, and problematic-theoretical methods have been used. At the same time, comparative-legal method is used to analyze the provisions of information security at the global and regional levels.
\nIn order to solve the problems of international security that have arisen with the development of ICT, the UN General Assembly has adopted resolutions entitled “Developments in the field of information and communications in the context of international security” at each of its sessions since 1998. The main idea of these resolutions is that the significant progress, which has been achieved in the development and implementation of the latest information technologies and telecommunications, has caused negative consequences as well as positive ones. At the same time, the positive consequences, namely, new opportunities for the entire mankind, are obvious.
\nHowever, the UN General Assembly has expressed concern that new technologies and facilities that these technologies and means can potentially be used for purposes that are inconsistent with the objectives of maintaining international stability and security and may adversely affect the integrity of the infrastructure of states to the detriment of their security in both civil and military fields.
\nThe resolutions invite states to inform the UN Secretary-General on the following issues, namely, (1) general assessment of the problems of information security, (2) development of concepts relating to information security, and (3) development of international principles aimed at ensuring information security of global information and telecommunications systems and combating information terrorism and crime.
\nIt should be noted that there exist resolutions which confirm a certain progress in ensuring information security. They contain specific proposals for the development of an information security system that can be used for the draft of relevant international treaties. For example, the UN General Assembly adopted the Resolution No. 58/199 of December 23, 2003, on the creation of a global culture of cybersecurity and the protection of critical information structures, which defines elements for protection of critical information infrastructures, namely, (1) having emergency warning networks regarding cyber-vulnerabilities, threats, and incidents; (2) raising awareness to facilitate stakeholders’ understanding of the nature and extent of their critical information infrastructures and the role each must play in protecting them; (3) examining infrastructures and identifying interdependencies among them, thereby enhancing the protection of such infrastructures; and (4) promoting partnerships among stakeholders, both public and private, to share and analyze critical infrastructure information in order to prevent, investigate, and respond to damage to or attacks on such infrastructures, etc.
\nThe nature of the elements for protection of the most important information structures is such that they can be included in an international treaty if they are specified.
\nCurrently, an institutional mechanism for ensuring international information security has been established in the framework of the UN. States submit their assessments of the condition of information security on a regular basis, which are included in the reports of the Secretary-General and have contributed to a better understanding of the essence of problems of international information security and related concepts.
\nThe work of the Group of Governmental Experts on Developments in the Field of Information and Telecommunications in the Context of International Security and the resulting report (2015) have been quite effective. The Group concluded that international law and, in particular, the Charter of the United Nations are relevant and important for the maintenance of peace and stability and the development of an open, safe, stable, accessible, and peaceful information environment; that voluntary and non-binding standards, rules, and principles of responsible behavior of states in the use of information and communication technologies can mitigate the risk of violation of international peace, security, and stability; and that, subject to the unique features of the information and communication technologies, more standards can be developed over time.
\nIn addition, the EU, OAS, and Caribbean Community (CARICOM) have achieved certain results in the development of regional concepts of the improvement of information security. For example, on February 7, 2013, the Joint Communication to the European Parliament, the Council, the European Economic and Social Committee, and the Committee of the Regions entitled “Cybersecurity Strategy of the European Union: An Open, Safe and Secure Cyberspace” was adopted. The strategy contains principles for cyber security, strategic priorities, and actions. The principles of cybersecurity include the principle that the EU’s core values apply as much in the digital as in the physical world; protecting fundamental rights, freedom of expression, personal data and privacy; access for all; democratic and efficient multi-stakeholder governance; and a shared responsibility to ensure security.
\nIn order to support member states in their fight against cybercrime, OAS, through the Inter-American Committee Against Terrorism (CICTE) and the Cyber Security Program, is committed to developing and furthering the cyber security agenda in the Americas. Cooperating with a wide range of national and regional entities from the public and private sectors on both policy and technical issues, the OAS seeks to build and strengthen cyber security capacity in the member states through technical assistance and training, policy roundtables, crisis management exercises, and exchange of best practices related to information and communication technologies.
\nCARICOM Ministers with responsibility for information and communication technologies met on May 19, 2017, as efforts continue to move on the establishment of the CARICOM Single ICT Space. Several preparatory meetings of officials were held to advance work on the Integrated Work Plan for the Single ICT Space and the draft Terms of Reference for the CARICOM-US Joint Task Force. The Integrated Work Plan will set out the activities that need to be completed for the development of the Single ICT Space. The activities of the work plan will focus on areas such as conducting gap analyses, public awareness, specific telecommunications issues, legal and regulatory reform for cyber security, bringing technology to the people, resource mobilization, as well as forecasting for the CARICOM Digital Agenda 2025. The Single ICT space and the Region’s Digital Agenda 2025 will be constructed on the foundation of the Regional Digital Development Strategy (RDDS) which was approved in 2013 and will also have inputs from the Commission on the Economy and the Post-2015 Agenda.
\nThe concept of international information security is developing in the framework of soft law. International treaties in this field are quite scarce.
\nThe privacy problem has been represented in the international law. Currently, the privacy provision is contained in many international documents. Of particular importance is Article 12 of the 1948 Universal Declaration of Human Rights, which stipulates that no one shall be subjected to arbitrary interference with his privacy, family, home, or correspondence nor to attacks upon his honor and reputation. Everyone has the right to the protection of the law against such interference or attacks. States recognize noninterference in personal and family life as a fundamental human right. It should be noted that the 1948 Universal Declaration is a recommendatory act, but a number of its provisions represent the established international customs. At the same time, the right to protection of private life may be restricted, which makes it impossible to regard it as a right that is recognized unconditionally.
\nCurrently, the protection of privacy has a treaty origin. Provisions for protection of privacy are stipulated in Article 17 of the 1966 International Covenant on Civil and Political Rights, Article 8 of the 1950 European Convention for the Protection of Human Rights and Fundamental Freedoms, and Article 11 of the 1969 American Convention on Human Rights.
\nArticle 12 of the 1948 Universal Declaration of Human Rights has been incorporated into Article 17 of the 1966 International Covenant on Civil and Political Rights. Everyone has the right to the protection of the law against such interference or attacks. Similar provisions are stipulated by regional international treaties.
\nIt appears quite reasonable to abolish the unification of the concept of privacy and personal data as a component of privacy in international law. Privacy is an area where individual needs of a person to be left to himself/herself are revealed. Every individual will delineate the limits of his/her privacy to himself/herself. Contemporary international law is limited to the regulation of matters of collection, processing, storage, and transfer of personal data, which are not the only issues of privacy. It appears that the privacy provision in the International Covenant on Civil and Political Rights is quite generalized but does not require specification in the information age, as it enables any individual to protect privacy in every case when the individual so wishes.
\nThe problem of personal data protection in the framework of information security problems is perfectly reasonable to be considered. Information security is a category applicable to all subjects of information relations including states and non-state (legal entities, individuals, TNCs, nongovernmental organizations, etc.) ones. Information security of individuals is related to the respect of their privacy in the information sphere, protection from defamation, libel, insults, psychological pressure, information terrorism, etc. Therefore, the legal problems of privacy in the information sphere are a component of legal regulation of information security of the individual.
\nIf one tries to define the content of privacy in the information area, it will be different for every individual. In the information sphere, the range of data that a person tries to make inaccessible to the public is always different. For example, one person will not hide the fact that they are infected with HIV and may say it in an interview to a journalist, while another person will choose to not even tell close friends about it. Thus, the boundaries of privacy are always individual.
\nContemporary international law provides limited privacy protection because it cannot adapt to the needs of each individual due to the general nature of the provisions. At the same time, the current international acts do not contain a list of personal data but give a fairly wide definition of such data.
\nAn identical approach to the definition of personal data is characteristic of the OECD Guidelines governing the Protection of Privacy and Transborder Flows of Personal Data of September 23, 1980, and the 1981 Convention for the Protection of Individuals with regard to the Automatic Processing of Personal Data. In these documents, personal data are defined as any information relating to an identified or identifiable individual. Therefore, protected data include any information about an individual that can be identified. Such a broad range of protected information makes it possible to protect personal data in the situation of changing technologies that are used to collect and process data. In particular, protected data include PIN codes, logins, passwords, etc.
\nDespite the quite broad definition of personal data in international documents, the concept of personal data is somewhat narrower than privacy in the information area. Based on the provision of the Universal Declaration, the concept of privacy includes not just personal but also family secrets as well as the secret of correspondence. Personal data only relate to data about identified or identifiable individual. Certain provisions are applied only to individual, information on whom is stored in a particular system. For example, the 1981 Convention stipulates that any individual has the right to establish the existence of an automated personal data file, its main purposes, as well as the identity and habitual residence or principal place of business of the controller of the file; to obtain at reasonable intervals and without excessive delay or expense confirmation of whether personal data relating to him are stored in the automated data file as well as communication to him of such data in an intelligible form; to obtain, as the case may be, rectification or erasure of such data if these have been processed contrary to the provisions of domestic law giving effect to the basic principles set out in Articles 5 and 6 of this Convention; etc.
\nTherefore, the right to access, correct, and destroy personal data is recognized only for the person whose data have been collected. However, family secret is a different term. For example, one may conceal data about a disease of one’s child or husband or addictions of deceased relatives. In essence, while personal data relate to one person, family secret is kept in a certain family and affects its collective private interests. Disclosure of family secret can harm both individual and the family as a whole including family breakdown and ruined relationships.
\nThe existing special international acts that protect personal data in the course of their automated processing contribute to protection of not just personal but also family secrets. However, they offer no direct protection of family secrets.
\nAs for the confidentiality of correspondence, certain provisions for telecommunications are contained in the Convention of the International Telecommunication Union. Article 40 of the ITU Convention provides for the secrecy of telecommunication messages. Government telegrams and service telegrams may be expressed in secret language in all relations. Private telegrams in secret language may be admitted between all Member States with the exception of those which have previously notified, through the Secretary-General, that they do not admit this language for that category of correspondence. Member States which do not admit private telegrams in secret language originating in or destined for their own territory must let them pass in transit, except the Constitution. ITU does not have the power to regulate information on the Internet including measures for ensuring its confidentiality. At the regional level, a provision on the confidentiality of electronic communications is stipulated at the EU. The relevant provision is contained in the Directive 2002/58/EC of the European Parliament and of the Council of July 12, 2002, concerning the processing of personal data and the protection of privacy in the electronic communications sector.
\nThe most progressive in privacy protection is the EU experience. This integration organization has adopted the Regulation No. 2016/679 of the European Parliament and of the Council on the protection of natural persons with regard to the processing of personal data and on the free movement of such data, and repealing the Directive 95/46/EC (the General Data Protection Regulation) of April 27, 2016. This act is of direct effect and application in the EU Member States. A feature of the General Regulation is that any processing of personal data in the context of the activity of establishing a controller or data processing entity in the Union must be performed in accordance with the Regulation regardless of whether the data processing is affected within the Union. In order to ensure that individuals are not deprived of the protection provided by the Regulation, processing of personal data of data subjects located in the Union by a controller or data processing entity that have not been established in the Union must be governed by this Regulation if the data processing relates to the supply of goods or services to such data subjects regardless of payment. The Regulation establishes a certain legal regime for personal data processing including the conditions for their processing and requirements to their storage and transfer. The processing of personal data by public authorities, computer emergency response teams (CERTs), computer security incident response teams (CSIRTs), providers of electronic communication networks and services, and providers of security technologies and services is a legitimate interest of the relevant data controller to the extent that it is necessary and adequate as compared to the objectives of providing network and information security, i.e., the ability of the network or information system to resist (with a given level of confidence) accidental events and illegal or intentional acts that compromise the availability, authenticity, integrity, and confidentiality of stored or transferred personal data as well as the safety of the relevant services transferred via such networks and systems. Protection of privacy within the EU is also supported by the EU Court. In the Maximillian Schrems v. Data Protection Commissioner case (complaint No. C362/14), the transfer of personal data by Facebook in the USA was appealed against in the framework of the Principles of Privacy program. The EU Court concluded that the Commission had not stated in its Resolution that the USA had actually provided an adequate level of protection by virtue of their laws or international obligations. Therefore, without having to examine the content of the Principles of Privacy, Resolution 2000/520 did not comply with the EU acts in the field of privacy and is therefore invalid.
\nHowever, the EU experience takes account of the patterns of functioning of integration organizations and requires significant adaptation for use at the global level.
\nAt the regional level, two conventions have been adopted where computer crimes are regarded as crimes of international nature. These are the Convention on Cybercrime of November 23, 2001 (hereinafter referred to as the 2001 Convention) and the Commonwealth of Independent States Agreement on Cooperation in Combating Offenses related to Computer Information of June 1, 2001 (hereinafter referred to as the CIS Agreement).
\nThe basic ideas of these conventions are the definition of unified elements of computer crimes, which the states should include in their national law, and development of measures for combating such crimes.
\nThe CIS agreement has no definition of a computer system whatsoever, which results in an uncertainty with regard to the object of infringement.
\nBoth the 2001 Convention and the CIS Agreement contain definitions of computer data. However, the definition in the Agreement is more concise; namely, it is information stored in computer memory, on machine or other device, in a form that is accessible to perception or transfer via communication channels. This definition is incomplete.
\nThe 2001 Convention offers a broader concept; namely, computer data includes any representation of facts, information, or concepts in a form suitable for processing in a computer system, including a program suitable to cause a computer system to perform a function. As a result, the CIS Agreement does not cover any software that is inaccessible to human perception but causes computer systems to operate. Interference in such software is dangerous for the public. In this case, the broader approach in the 2001 Convention should be considered justified.
\nThe CIS Agreement contains an attempt to define computer crime, which cannot be regarded as successful. A crime in the field of computer information is described as a criminal offense, the object of infringement in which is computer information. This definition is different from the definition that has been accepted in the doctrine. It is not mentioned that computer information can be both the object and the means of an offense.
\nThe 2001 Convention contains a number of terms that are unknown to the CIS Agreement, namely, service provider and data flows. The need to use these terms is due to the fact that the 2001 Convention defines a broader range of measures for combating computer crime than the CIS Agreement.
\nAs for standardized elements of computer crimes, they are different in the 2001 Convention and the CIS Agreement. Some crimes have the same title but different meanings. For example, the 2001 Convention and the CIS Agreement state that illegal access to information is a criminal offense. However, the CIS Agreement is very laconic. It regards illegal access to information that is protected by law as a criminal offense if such act has caused destruction, blocking, modification or copying of information, or disruption of the operation of computers, computer systems, or their networks. The 2001 Convention stipulates that illegal access to a computer system as a whole or a part of it is a crime by itself, without stating any extra qualifying features. Therefore, the 2001 Convention prosecutes any illegal access to computer systems, while the CIS Agreement is limited to access that has led to certain consequences.
\nThe 2001 Convention includes a number of crimes that are not covered by the CIS Agreement. These are illegal data interception, data and system interference, misuse of devices, computer-related forgery, computer-related fraud, and crimes related to child pornography. A special feature of the 2001 Convention is that it covers certain common crimes (forgery, fraud) which become much more dangerous because they are committed using computers.
\nTherefore, the CIS Agreement uses a narrower approach to the concept of computer crime. These are only the crimes that infringe on the security of computer systems, i.e., the protected object is computer systems as such. The 2001 Convention criminalizes a broader range of acts where computer systems can be the object of or the means for committing the offense. The approach to the definition of computer crime in the 2001 Convention is more correct.
\nThe existing contradictions in the content of international treaties on combating computer crime may result in difficulties for the states that are parties to both treaties. Basically, the provisions of the two treaties are mutually exclusive, which complicates their simultaneous application.
\nIt should be noted that the 2001 Convention contains references to a number of international treaties. The issues of the relationship between the 2001 Convention and the CIS Agreement shall be resolved with consideration of clause 2 of Article 39 of the 2001 Convention. If two or more parties have already concluded an agreement or treaty on the matters dealt within this Convention or have otherwise established their relations on such matters, or should they in future do so, they shall also be entitled to apply that agreement or treaty or to regulate those relations accordingly. However, where parties establish their relations in respect of the matters dealt within the Convention other than as regulated therein, they shall do so in a manner that is not inconsistent with the Convention’s objectives and principles.
\nTherefore, in the case if a state is a party to both of the abovementioned international treaties, the CIS Agreement will apply to the same matter.
\nArticle 13 of the CIS Agreement stipulates that this agreement does not affect the rights and obligations of the parties arising out of other international treaties to which they are parties. Therefore, it allows the application of the 2001 Convention.
\nThe existence of various regulations regarding their correlation in the considered international treaties suggests that their practical application may be complicated. For example, the states may experience difficulties in choosing the legal aid procedure. Such issues should be resolved by consultations between the states concerned.
\nHowever, in view of the harmonization nature of international treaties and the fact that the content of the 2001 Convention is broader, in the case if a state is a party to the two treaties at the same time, such state shall implement the 2001 Convention and, in the part where the provisions of the treaties are different, the CIS Agreement, as this is allowed by the 2001 Convention itself.
\nThe concept of developing a comprehensive system of international security is useful because of its systemic nature. This concept is not limited to military security issues but also covers economic, political, humanitarian, and information security. It should be noted that this concept needs to be clarified. Since it concerns the development of a comprehensive system of international security, it should cover the entire system of international relations. The concept of developing a comprehensive system of international security also applies to non-state international relations.
\nA comprehensive system of international security means a status where the interstate system is protected from the dangers that exist in contemporary world. It implies stable functioning of the system of international relations. Relations between subjects of the interstate system also include information relations. The system of such relations includes interstate and non-state relations.
\nInformation security should be considered in two aspects.
\nIf the systemic approach is applied, information security will act as a backbone element. It can be regarded as a status of the international relation system, which is described by stability and security from information weapons and threats.
\nIn addition, information security can be regarded as an ideal model. There are conceptual ideas what exactly information security should be like. It is regarded in the sociological (as a certain state of social relations), technical (compliance with standards and other technical requirements), and legal (compliance with prohibitions and restrictions on the spreading of data) aspects. Based on conceptual ideas, information security can be defined as a model for stable functioning of the information relation system.
\nThe comprehensive system of international security and information security has a certain sphere of intersection. Information security of the international system is a component of the comprehensive system of international security. However, international relations are more than just relations between subjects of international public law. The requirement of information security is equally applicable to international non-state and domestic relations.
\nWhen one uses the concept of international information security, one may define this concept based on the more general concept of information security. If one distinguishes between domestic and international information security, the first one relates to domestic information relations and the second one, to international information relations. In each of the systems of relations, information security has common features; namely, it serves as a backbone element and ensures a stable state of the system of information relations. Therefore, international information security is a status of the international information relation system, which is described by stability and security from information weapons and threats.
\nThe development of the concept of international information security has led to the appearance of terms in the legal doctrine that had not previously been known in the practice of states. Currently, researchers use terms such as information weapons, information terrorism or cyberterrorism, and information crime or cybercrime.
\nThe state of international legal regulation is such that these new terms have not been stipulated in treaties (save for computer crimes). However, a number of social phenomena evidence that these terms should be regarded as destabilizing factors for the system of international relations.
\nAs for information weapons, they can be described quite generally as any means of affecting the mass and individual consciousness, which can damage, distort, destroy, or conceal data. A special feature of information weapons is that they are not used in the military field alone. Information weapons can be used for committing computer crimes, hacker attacks causing property damage, etc. The use of information weapons has been known in international practice since the second half of the twentieth century. For example, it was used widely in the Palestinian-Israeli conflict.
\nWith the adoption of individual conventions on cybercrime, there appeared a trend in international law to prosecute the consequences of the use of information weapons rather than the weapons as such.
\nIt should be noted that the use of information weapons has various scales. For example, information terrorism can be regarded as one of the most dangerous use of information weapons.
\nInformation terrorism can be defined as using information weapons for undermining the constitutional order of other states or the international legal order and international relations in general.
\nCyberterrorism comprises both direct terrorist activities with the use of computers, networks and data in networks, and various supplementary operations including coordination, preparation, and organization of terrorist activities using networks and data in networks and spreading knowledge about terrorism and terrorists’ skills.
\nIndividual examples of cyberterrorism have been known from the second half of the twentieth century. In 1985, a radical leftist group in Japan attacked the united railway management network using computer systems. Fortunately, the computers of the railway had good protection, which could not be hacked.
\nThe 2001 Convention takes no account of the special features of cyberterrorism. It only takes account of “ordinary” crimes.
\nIn this paper, computer crime is understood in the broad sense as any crime committed by using computer networks, software, or individual computers.
\nHowever, in the international law, the term computer crime will always have a special meaning, which is not necessarily the same as the meaning of this term in the national law. Some crimes that are punishable under the laws of one state do not affect the interests of another state or the international community as a whole.
\nWhile international crimes are threatening for the international peace and security, crimes of an international nature are common crimes in combating which states cooperate.
\nInternational crimes can be committed using computers. Global computer networks enable propaganda of war, genocide, apartheid, and racial discrimination. Moreover, the use of computers for military technology can lead to electronic communications becoming a means of aggression.
\nIt should be noted that the existing international treaties on computer crime regard computer crimes primarily as crimes of an international nature. They define the elements of crimes that must be criminalized in national law as well as measures of international cooperation in combating such crimes.
\nThe development of legal foundations of the global information society is to a great extent spontaneous. In the framework of the institutional mechanism of cooperation between states, there is not enough systemic vision of what the legal regulation should be like to meet the development of the technological progress.
\nTherefore, the information society concept needs a corresponding integral concept of international legal regulation of information exchange relations in the information society.
\nSome objectives have existed for a long time and are related to a lack of regulation of certain problems (matters of combating computer crime, protection of privacy at the global level, etc.), while others have appeared relatively recently as a result of technological progress.
\nWhat are the objectives that should be addressed at the global level? When determining the range of objectives, one should consider that information technologies have become global and reveal the interdependence of the contemporary world. At the same time, there is the experience of regulation of electronic data exchange relations in the framework of the Council of Europe, which should be recognized as progressive and useful for the global level.
\nThe primary objective for the global level is solving the problems that have already been solved in the framework of the Council of Europe (combating computer crime, protection of personal data). The models of the Council of Europe have already been tested in practice, and in any case they have no significant alternative.
\nFor the prosecution of computer crimes and protection of privacy, the global network of international information security can be created under the Security Council of UN decision by adoption of the international treaty. The global network of international information security shall provide for search in computer networks performed in one state on request of another state, real-time collection of traffic data and real-time collection and interception of content data. Therefore, the general mechanism of legal aid shall be applied, but its content is special.
\nIn the global network of international information security, any state may request another state to order or otherwise obtain the expeditious preservation of data stored by means of a computer system, located within the territory of that other state.
\nThe global network of international information security stipulates 24–7 access, i.e., each state shall designate a contacting board available on a 24-hour, 7-day-a-week basis, in order to ensure the provision of immediate assistance for the purpose of investigations or proceedings concerning criminal offenses related to computer systems and data or for the collection of evidence in electronic form of a criminal offense. Basically, this procedure can take a few minutes.
\nThe global network of international information security can also provide the access for non-state actors in privacy violations and defamation cases.
\nOne state may get access to publicly available computer data, regardless of their geographical location, without permission of any other state. This primarily applies to data that are contained on the Internet. If a website has no access codes and the data on it can be accessible to everyone, it can be used by search, investigative, and judicial authorities. It is a general practice of access to data in open computer networks. There exists an international custom, according to which states do not put special restrictions on the spreading of publicly available data in computer networks. Special regulations are established for data, the spreading of which is prohibited or restricted. If any person may have access to information, it would be illogical to deny such access to law enforcement authorities.
\nIn addition, any state can access, through a computer system in its territory, stored computer data, if the state obtains the lawful and voluntary consent of the person or legal entity who has the lawful authority to disclose the data. In this case, the state body of one state must address the provider, which is located in another state, directly.
\nTherefore, the development of the institute of mutual legal assistance in criminal matters, which is affected by the struggle with computer crimes, is not just about introducing electronic communication technologies in traditional types of legal assistance and not just about specifying legal aid measures in relation to electronic communication technologies but also about radical change in the very content of this institute.
\nThe system of international information security is establishing at the moment. The international information security of the interstate system is a component of the comprehensive system of international security. At the same time, international information security is a stabilizing factor in the system of non-state international relations. However, a number of threats to international information security affect the field of both interstate and international non-state relations. In “soft law” acts, a unified concept of the development of a system of international information security has been elaborated at the global and regional levels. However, “soft law” acts are not suitable for its implementation. They can contribute to development of international customs, but that can take a considerable time. Therefore, global international treaties should be drafted.
\nThe 2001 Convention and the CIS Agreement have become the first international treaties that stipulate a system of measures for combating a specific type of crime in the field of information, namely, computer crimes. Formerly, information crimes had been covered in particular international treaties along with other crimes (such as propaganda of racial discrimination). The treaties considered have a very important role, as they have established the foundations of the jurisdiction of states for criminal cases on the Internet and the rules of international cooperation that ensure coordinated actions of states in combating computer crimes. Despite some shortcomings of the treaties, as a whole they provide for systems of interrelated international and national measures for combating computer crimes and can be the basis for drafting of a global international treaty.
\n"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges".
\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.
",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\\n\\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\\n\\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nOAI-PMH
\\n\\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\\n\\nLicense
\\n\\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\\n\\nPeer Review Policies
\\n\\nAll scientific works are Peer Reviewed prior to publishing. Read more
\\n\\nOA Publishing Fees
\\n\\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\\n\\nDigital Archiving Policy
\\n\\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n"}]'},components:[{type:"htmlEditorComponent",content:'The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
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