Clinical stages of Spigelian hernia.
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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"8067",leadTitle:null,fullTitle:"Molecular Docking and Molecular Dynamics",title:"Molecular Docking and Molecular Dynamics",subtitle:null,reviewType:"peer-reviewed",abstract:"This book clearly explains the principles of in silico tools of molecular docking and molecular dynamics. It provides examples of algorithms and procedures proposed by different software programs for visualizing and identifying potential interactions in complexes of biochemical interest. The book is structured in six chapters, each of which discusses different molecular simulation methodologies and provides concrete examples of complexes interactions. In each chapter authors give an overview of the treated subject, a description of the methodologies used, and a discussion of the results. The authors describe computational ways to achieve a rational design of bioactive compounds with various therapeutic applications, including antitumoral agents, antitubercular drugs, nonsteroidal anti-inflammatory drugs, and radiopharmaceuticals.",isbn:"978-1-78984-092-6",printIsbn:"978-1-78984-091-9",pdfIsbn:"978-1-78985-262-2",doi:"10.5772/intechopen.77898",price:100,priceEur:109,priceUsd:129,slug:"molecular-docking-and-molecular-dynamics",numberOfPages:100,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"1d45bbc09e3ad00be279eea0df45abcc",bookSignature:"Amalia Stefaniu",publishedDate:"December 18th 2019",coverURL:"https://cdn.intechopen.com/books/images_new/8067.jpg",numberOfDownloads:6329,numberOfWosCitations:8,numberOfCrossrefCitations:7,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:12,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:27,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 12th 2018",dateEndSecondStepPublish:"November 5th 2018",dateEndThirdStepPublish:"January 4th 2019",dateEndFourthStepPublish:"March 25th 2019",dateEndFifthStepPublish:"May 24th 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"213696",title:"Dr.",name:"Amalia",middleName:null,surname:"Stefaniu",slug:"amalia-stefaniu",fullName:"Amalia Stefaniu",profilePictureURL:"https://mts.intechopen.com/storage/users/213696/images/system/213696.jpg",biography:"Amalia Stefaniu has a background in chemical engineering, acquiring her Bachelor’s degree at Politehnica University of Bucharest, Faculty of Engineering in Foreign Languages. She followed postgraduate academic studies with Drugs and Cosmetics specialization and she obtained a Masters degree in Biotechnologies and food safety. She completed her PhD in Exact Sciences - Chemistry Domain in 2011 at the University Politehnica of Bucharest, Faculty of Applied Chemistry and Materials Science, Department of Inorganic Chemistry, Physical Chemistry and Electrochemistry. She joined the National Institute for Chemical Pharmaceutical Research and Development, Bucharest in 2001, where she worked first as Chemical Research Engineer in the Pharmaceutical Biotechnologies domain. Her current position is Senior Research Scientist. Her research focuses on properties prediction, mathematical modeling, molecular docking, and therapeutic compounds design.",institutionString:"National Institute for Chemical - Pharmaceutical Research and Development",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"2",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1195",title:"Drug Discovery",slug:"pharmacology-toxicology-and-pharmaceutical-science-pharmacology-drug-discovery"}],chapters:[{id:"65421",title:"Introductory Chapter: Molecular Docking and Molecular Dynamics Techniques to Achieve Rational Drug Design",doi:"10.5772/intechopen.84200",slug:"introductory-chapter-molecular-docking-and-molecular-dynamics-techniques-to-achieve-rational-drug-de",totalDownloads:1261,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:null,signatures:"Amalia Stefaniu",downloadPdfUrl:"/chapter/pdf-download/65421",previewPdfUrl:"/chapter/pdf-preview/65421",authors:[{id:"213696",title:"Dr.",name:"Amalia",surname:"Stefaniu",slug:"amalia-stefaniu",fullName:"Amalia Stefaniu"}],corrections:null},{id:"65870",title:"Binding of Chlorinated Phenylacrylonitriles to the Aryl Hydrocarbon Receptor: Computational Docking and Molecular Dynamics Simulations",doi:"10.5772/intechopen.84818",slug:"binding-of-chlorinated-phenylacrylonitriles-to-the-aryl-hydrocarbon-receptor-computational-docking-a",totalDownloads:853,totalCrossrefCites:3,totalDimensionsCites:4,hasAltmetrics:0,abstract:"The development of ligands capable of binding to the aryl hydrocarbon receptor (AhR) and hijacking its signaling pathway is of potential use for the design of novel agents against breast cancer. To guide the synthesis of new compounds and characterize their binding to the AhR, we employed homology modeling, ligand docking, and molecular dynamics simulations. As there is currently no crystallographic information available for the structure of the AhR’s ligand-binding PAS-B domain, a homology model was developed. The location of the binding site was identified by scanning the model for concave areas and comparing them to known ligand-binding sites in proteins related to the AhR, such as the CLOCK:BMAL1 transcriptional activator complex and the hypoxia-inducible factor-2α (HIF-2α). Docking of several chlorinated phenylacrylonitriles was performed with the modeling suite MOE, identifying π-π stacking, hydrophobic, and van der Waals interactions as the driving forces for binding, an observation consistent with the hydrophobic nature of the site. Molecular dynamics simulations with one of the compounds for 100 ns verified the overall stability of a docking-predicted pose and revealed the presence of interacting water molecules in the vicinity of the ligand. Given the buried location of the ligand in the core of the receptor, this observation was somewhat unexpected, but it explained a slight shift of the ligand pose seen during the simulation.",signatures:"Stefan Paula, Jennifer R. Baker, Xiao Zhu and Adam McCluskey",downloadPdfUrl:"/chapter/pdf-download/65870",previewPdfUrl:"/chapter/pdf-preview/65870",authors:[null],corrections:null},{id:"66926",title:"In Silico Drug Design and Molecular Docking Studies of Some Quinolone Compound",doi:"10.5772/intechopen.85970",slug:"-em-in-silico-em-drug-design-and-molecular-docking-studies-of-some-quinolone-compound",totalDownloads:1432,totalCrossrefCites:2,totalDimensionsCites:3,hasAltmetrics:1,abstract:"Quinolones are an important class of heterocyclic compounds that possess interesting biological activities like antimicrobial, antitubercular, and antitumor. The objective of this study is to evaluate in silico the antitumoral and antimycobacterial activity of some quinolone derivatives by using CLC Drug Discovery Workbench Software. Docking studies were carried out for all ligands, and the docking scores were compared with the scores of standard drugs, topotecan and levofloxacin. The docking studies have been carried out to predict the most possible type of interaction, the binding affinities, and the orientations of the docked ligands at the active site of the target protein.",signatures:"Lucia Pintilie and Amalia Stefaniu",downloadPdfUrl:"/chapter/pdf-download/66926",previewPdfUrl:"/chapter/pdf-preview/66926",authors:[{id:"213696",title:"Dr.",name:"Amalia",surname:"Stefaniu",slug:"amalia-stefaniu",fullName:"Amalia Stefaniu"},{id:"94504",title:"Dr.",name:"Lucia",surname:"Pintilie",slug:"lucia-pintilie",fullName:"Lucia Pintilie"}],corrections:null},{id:"66756",title:"Virtual Screening of Sesquiterpenoid Pogostemon herba as Predicted Cyclooxygenase Inhibitor",doi:"10.5772/intechopen.85319",slug:"virtual-screening-of-sesquiterpenoid-pogostemon-herba-as-predicted-cyclooxygenase-inhibitor",totalDownloads:935,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"To analyze the structural features that dictate the selectivity of the two isoforms of the cyclooxygenase (COX), the three-dimensional structure of COX-1/COX-2 was assessed by means of binding energy calculation by way of virtual molecular dynamic simulations using ligand sesquiterpenoid Pogostemon herba. This study was conducted to investigate the molecular interaction between ligand alpha-bulnesene (CID94275), alpha-guaiene (CID197152), seychellene (CID519743), and alpha-patchouli alcohol isomers (CID442384, CID521903, CID6432585, CID3080622, CID10955174, and CID56928117) to COX-1 and COX-2. Molecular docking tools proposed by Hex 8.0 were employed in this research. Discovery Studio Client 3.5 software tool and virtual molecular dynamic 1.9.1 software were also used to visualize the molecular interactions identified in this research. In order to calculate the binding energy of the molecular dynamic interaction, AMBER12 software was utilized. Results of the analysis on all sesquiterpenoid indicate that those compounds were the inhibitors of COX-1 and COX-2. Overall, the binding energy calculations (using PBSA Model Solvent) of alpha-patchouli alcohol (CID521903) and seychellene (CID519743) have been identified as the candidates of non-selective inhibitor; alpha-bulnesene (CID94275), alpha-guaiene (CID107152), and alpha-patchouli alcohol isomers (CID6432585, CID3080622, CID10955174, CID56928117) have been suggested as the candidates for a selective COX-1 inhibitor; whereas alpha-patchouli alcohol (CID442384) was the candidate for a selective COX-2 inhibitor.",signatures:"Sentot Joko Raharjo",downloadPdfUrl:"/chapter/pdf-download/66756",previewPdfUrl:"/chapter/pdf-preview/66756",authors:[null],corrections:null},{id:"65166",title:"Protein-Protein Docking Using Map Objects",doi:"10.5772/intechopen.83543",slug:"protein-protein-docking-using-map-objects",totalDownloads:815,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Protein-protein docking is a molecular modeling strategy to predict biomolecular complexes and assemblies. Traditional protein-protein docking is performed at atomic resolution, which relies on X-ray and NMR experiments to provide structural information. When dealing with biomolecular assemblies of millions of atoms, atomic description of molecular objects becomes very computational inefficient. This article describes a development work that introduces map objects to molecular modeling studies to efficiently derive complex structures through map-map conformational search. This method has been implemented into CHARMM as the EMAP command and into AMBER in its SANDER program. This development enables molecular modeling and simulation to manipulate map objects, including map input, output, comparison, docking, etc. Through map objects, users can efficiently construct complex structures through protein-protein docking as well as from electron microscopy maps according to low map energies. Using a T-cell receptor (TCR) variable domain and acetylcholine binding protein (AChBP) as example systems, we showed the application to model an energetic optimized complex structure according to a complex map. The map objects serve as a bridge between high-resolution atomic structures and low-resolution image data.",signatures:"Xiongwu Wu and Bernard R. Brooks",downloadPdfUrl:"/chapter/pdf-download/65166",previewPdfUrl:"/chapter/pdf-preview/65166",authors:[{id:"104593",title:"Dr.",name:"Xiongwu",surname:"Wu",slug:"xiongwu-wu",fullName:"Xiongwu Wu"},{id:"111719",title:"Dr.",name:"Bernard",surname:"Brooks",slug:"bernard-brooks",fullName:"Bernard Brooks"}],corrections:null},{id:"66152",title:"Computational Study of Radiopharmaceuticals",doi:"10.5772/intechopen.85140",slug:"computational-study-of-radiopharmaceuticals",totalDownloads:1033,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Radiopharmaceuticals contain radionuclides and pharmaceuticals. Research on radiopharmaceuticals has been increasing in recent years by increasing the importance of early diagnosis in diseases. It is generally accepted that investigation and development of new radiopharmaceuticals are time and resource consuming. Computational methods have provided exciting contributions to pharmaceutical research and development. The need for designing new radiopharmaceutical drugs enhances the importance of computational programs. At this point, the structure, chemical, physical and physicochemical properties of molecules should be predicted/evaluated by using computational methods. While these methods obtain useful estimates, they make it easier for researchers and clinicians to make the right choices. Also, by providing accurate and effective results, they contribute to reduce the cost of research and can be used to simulate complex biochemical situations before research helping us to avoid harmful effects of drugs. In this study, authors emphasis about radiopharmaceuticals and the computational tools related to the development of new radiopharmaceuticals.",signatures:"Emine Selin Demir, Emre Ozgenc, Meliha Ekinci, Evren Atlihan Gundogdu, Derya İlem Özdemir and Makbule Asikoglu",downloadPdfUrl:"/chapter/pdf-download/66152",previewPdfUrl:"/chapter/pdf-preview/66152",authors:[null],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"9236",title:"Cheminformatics and its Applications",subtitle:null,isOpenForSubmission:!1,hash:"3fed97d1719b8a321190c86985494a34",slug:"cheminformatics-and-its-applications",bookSignature:"Amalia Stefaniu, Azhar Rasul and Ghulam Hussain",coverURL:"https://cdn.intechopen.com/books/images_new/9236.jpg",editedByType:"Edited by",editors:[{id:"213696",title:"Dr.",name:"Amalia",surname:"Stefaniu",slug:"amalia-stefaniu",fullName:"Amalia Stefaniu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"671",title:"Drug Discovery and Development",subtitle:"Present and Future",isOpenForSubmission:!1,hash:"74072e600a9fb54b8257355a7954399e",slug:"drug-discovery-and-development-present-and-future",bookSignature:"Izet M. 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This chapter reviews literature regarding the role of Reg, a family of small C-type lectins, with a focus on the endocrine pancreas and introduces novel findings generated in our laboratory on the role of Reg as autoantigen in T1DM. It is not intended as a comprehensive literature review, but rather discusses a selection of articles in more detail in order to illustrate aspects that are important for the understanding of this protein family. In the author’s view the scientific challenge consists in the development of a theory of Reg action that unifies seemingly disparate roles played by members of this family and provides the field of Reg research with a defined framework allowing unification of the many, to date, unconnected observations. Thus, although we focus on Reg and the endocrine pancreas, we also discuss findings obtained in other Reg research areas that appear to have little connection with the endocrine pancreas and T1DM. We choose this approach because we consider that the effects of Reg in the endocrine pancreas need to be understood in the context of a broader view of this protein family. The reader may easily find a large volume of additional literature on the effects of Reg referenced in the presented reports.
\n\t\tTo act as a guide though the confusing nomenclature of this protein family we have prepared a phenogramm of the family incorporating Reg proteins from 5 different species (Fig. 1). In the text - as in the phenogramm- we use ‘Reg’, followed by a roman numeral designating the subfamily and a Greek letter that designates the member within the subfamily. Alternative names are used for those members where no Reg nomenclature exists and are otherwise indicated in brackets behind the standard name. ‘Reg’ is used without further classification when referring to the entire family. Reg stands for ‘regenerating islet-derived’, a name, which is not ideal since many Reg proteins are not or not solely associated with islet regeneration but function in different tissues and under quite diverse physiological conditions, as will be discussed in more detail later. In fact the first members of this family were described as a component of pancreatic stones in chronic pancreatitis or as constituent of normal pancreatic juice involved in the control of calcium carbonate crystal growth (Keim, Rohr et al. 1984, Multigner, De Caro et al. 1983, Sarles, Dagorn et al. 1990). Hence the names PAP or PSP (pancreatitis associated protein or pancreatic stone protein) or lithostathine remain in use for some of these proteins. Additional designations include ‘pancreatic thread protein’ (PTP), a name given to a bovine
\n\t\t\tPhenogramm of human (h), mouse (m), rat(r), hamster (ham), and bovine (b) Reg family members. ‘Reg’ followed by roman numerals and Greek letters was chosen as standard protein name whenever this nomenclature was found in the protein data bank. Otherwise the alternative names were used. These are indicated in brackets for members, which are found under both the standard and the alternative name in the data banks. Protein data bank accession numbers are given after each member. Abbreviations: Reg=regenerating islet-derived; INGAP=islet neogenesis associated protein; PTP=pancreatic thread protein; PAP=pancreatitis associated protein; HIP=hepatocellular carcinoma/intestine/pancreas; PSP=pancreatic stone protein
Alignment of human, mouse, rat and hamster Reg family members. Features of Reg discussed in this review are highlighted. Blue background (mRegI): signal peptide; dark green background: prosegment (bactericidal effect/fibril formation. The arginine residue at the end of the prosegment is part of tryptic cleavage site); light blue background (mRegII): N-terminal fragment (acceleration of T1DM, activation of autoaggressive T-cells in NOD mice); lime green background: C-terminal fragment (delay of T1DM, T regulatory cells in NOD mice); light green letters: EPN motif (carbohydrate binding); gray background: loop 1 and loop 2 (carbohydrate binding); dark green letters: INGAP peptide (islet neogenesis/regeneration); blue letters denote the 6 cysteine residues that form the Reg C-type lectin domain.
pancreatic protein that precipitates at neutral pH in the form of double helical threads and was subsequently identified as a member of the Reg family (Gross, Brauer et al. 1985) and ‘HIP’ (for hepatocellular carcinoma, intestine, pancreas) – a name assigned to a human family member after Lasserre at al. found that it was overexpressed in a proportion of the hepatocellular carcinoma samples they had investigated (Lasserre, Christa et al. 1992). The designation ‘Reg’ was introduced because rat RegI (lithostathine) was rediscovered in a cDNA library constructed from
Although ‘Reg’ may not be an ideal designation the family is structurally well defined and a given protein sequence can unequivocally be assigned to it. To qualify as a member of the family a protein has to fulfill only one structural requirement; it must consist of a single C-type lectin domain of the type found in the first discovered Reg member, without additional attached domains. Any newly discovered protein was assigned to the family if it fulfilled this requirement and was assigned to a subfamily by primary sequence comparison with already existing Reg family members. This classification method resulted in the depicted phenogramm in which the three major subfamilies RegI and II, RegIII and RegIV each arise from a separate root. To illustrate the features of individual Reg members discussed in this review a primary sequence alignment is also shown (Fig. 2).
\n\t\tMost studies that have investigated the role of Reg proteins have restricted themselves to one particular Reg member. Their basic approach
INGAP is noteworthy from another aspect. The discoverers of this Reg member report in their initial publication that they were able to achieve duct cell proliferation not only by exposure to full length INGAP but also with a pentadecapeptide corresponding to amino acids 104–118 (Fig.2). The investigators seem to have derived this peptide without any hypothesis based on a possible effector mechanism of INGAP/Reg or any kind of peptide screening approach. We learn that ”We included this region of the deduced protein because it differs from another related family of genes known to affect islet regeneration, Reg/PSP, in that it has a unique insertion of five amino acids and it precedes a potential N-glycosylation site situated at position 126, hence, a core of potential biological activity”. Although the discovery of this peptide might have been taken as a peculiarity in the Reg field it has resulted in a string of subsequent investigations all showing some positive effect of a peptide with this sequence and corresponding peptides from other Reg members on diabetes and/or ductal cell proliferation. The findings finally led to a trial in humans, which again demonstrated positive effects in type 1 as well as in type 2 diabetic patients (Dungan, Buse et al. 2009, Levetan, Upham et al. 2008, Pittenger, Taylor-Fishwick et al. 2007, Rosenberg, Lipsett et al. 2004).
\n\t\t\tWe have detailed the INGAP studies because they illustrate some important problems affecting the Reg field especially concerning diabetes/islet regeneration. No unequivocal effector mechanisms have been defined for this family and therefore it is not known if and how the differences between family members might manifest themselves clinically. It is not clear what process of ‘islet regeneration’ is preferentially impacted by Reg. Do all Reg members act as -cell mitogens? Can all Reg members induce islet neogenesis and are all Reg members equally able to protect -cells from apoptosis? Since these questions have not been answered we are left with a collection of observations lacking a basis (or a precise theory) from which they can be explained. As a consequence, it is difficult to generate testable hypotheses that would, for example, predict which cells should proliferate upon Reg stimulation and which should not, or that would allow improvement of the INGAP peptide sequence to produce a peptide with better mitogenic/anti inflammatory/anti-apoptotic/islet neogenesis-inducing properties.
\n\t\t\tStudies using overexpression or knockout mouse models to demonstrate Reg effects will be briefly considered here. As mentioned above there is no theory available that would predict which of the Reg members would be most promising for these studies and investigators have therefore tried different Reg candidates in these test systems. The first member to be tested in knockout experiments was RegI and this was also the first to be overexpressed in pancreatic islets under an insulin promoter (Unno, Nata et al. 2002). Overall, the results from these studies supported the observations obtained on exogenous administration of Reg. RegI ko mice had morphologically normal pancreatic islets and were euglycemic. However islets isolated from these mice incorporated less radioactive thymidine than islets from non-transgenic mice. Furthermore, stimulation with aurothioglucose, a method of inducing hyperplastic islets, failed to increase islet size in RegI ko mice to the same extent as it did in non transgenic mice, again supporting a mitogenic effect. A group that reported results on a knockout of RegIII found that the mice were more sensitive to caerulein-induced pancreatitis but the report did not mention any deleterious effect of this genotype on islet size, insulin or glucose levels, suggesting that there may have been no difference between knockout mice and normal littermates (Gironella, Folch-Puy et al. 2007). Expression of transgenic mRegI under the insulin promoter in -cells did not affect the size or morphology of islets compared to non-transgenic mice. However, when mRegI transgenic mice were crossed onto NOD mice the incidence of T1DM in the NOD RegI transgenic mice was significantly reduced compared to normal NOD mice (Unno, Nata et al. 2002). Subsequent mouse models tested the effects of transgenic expression of hamINGAP and mRegIII targeted to islets via an insulin promoter (Chang, Weaver et al. 2010, Xiong, Wang et al. 2011). These studies found enhanced glucose tolerance, partial protection from streptozotocin (STZ)-induced diabetes and alterations in gene expression profiles when compared to non-transgenic mice. Overexpression of mRegII targeted to the exocrine pancreas with an elastase-1 promoter failed to provide protection from streptozotocin-induced diabetes (Li, Wang et al. 2010), whereas hamINGAP targeted to the exocrine pancreas with the same promoter did confer resistance to STZ-induced diabetes and increased the -cell mass (expressed as insulin positive cells and the total pancreatic insulin/protein ratio) as well as the number of smaller islets compared to non transgenic littermates (Taylor-Fishwick, Bowman et al. 2006). The findings obtained from the two transgenic models with exocrine targeting of mRegII or hamINGAP were interpreted to indicate that different Reg members could have different effects. None of the more recent transgenic Reg models has so far been crossed onto the NOD background to study the impact of Reg overexpression in a T1DM model. The general conclusion from these studies is that Reg-induced effects appear to be pleiotropic probably impacting at least the three known processes mentioned above that contribute to ‘islet regeneration’.
\n\t\t\tIn our discussion of the effects induced by Reg, as derived from the presented findings, we place emphasis on a feature that was not observed in mice treated with exogenous Reg or in Reg transgenic mice. It is noteworthy that in the studies presented above euglycemia was maintained in the treated mice, hypoglycemia or excessive serum insulin levels were not observed and increases in islet mass were limited. This implies that the effects of exogenous (or transgenic) Reg as -cell mitogen or stimulator of islet neogenesis did not lead to an expansion of the islet mass beyond what is physiologically normal. This feature is especially apparent in the transgenic models, where Reg is expressed from a constitutive promoter leading to sustained Reg overexpression from an early time-point. In this situation it is tempting to argue that the absence of documented effects in these studies suggests that the Reg proteins do not have any effects under normal physiological conditions. However, a different argument can be presented. The findings might indicate that the effects of Reg on ‘islet regeneration’ are tightly regulated and do not exceed the limits imposed by the target system, be it -cells/islets or ductal precursor cells. In other words, when normal and transgenic mice are compared under normal, non-experimental conditions clinical differences are not found because the effect of the additional experimentally provided Reg input remains marginal. If this situation were expressed in the form of a hypothetical Reg effect curve where the X-axis represents the concentration and the Y-axis the effect, addition of exogenous or transgenic Reg would occur close to or at the point where the curve levels off i.e. adding more Reg at this stage would only have a marginal effect. In this model the system is kept close to the point of saturation due to the presence of endogenous Reg members and additionally due to the overlapping effect range of the various Reg members where one member can compensate at least to some extent for the loss of others. Thus knockout or overexpression of one Reg member shows little effect under normal conditions because the reduction/increase in the overall Reg concentration is small compared to the basal concentration that is provided by endogenous Reg members and keeps the system close to saturation. According to this interpretation it is possible that the effects of Reg are extremely important in the generation and maintenance of islet mass under normal conditions with an entire family of closely-related Reg members with overlapping functions rather than a single protein being necessary as a fail-safe mechanism to protect this function in a system that has to be kept at or close to saturation. Consequently this view would predict that, in order to better reveal the effects of Reg, a pronounced reduction in the Reg concentration by knocking out more than one and possibly all Reg members would be necessary.
\n\t\t\tReg expression in human and murine islets. RegI, RegI and RegIII (HIP/PAP) are expressed in human endocrine pancreas whereas RegII and RegIII are expressed in murine islets. (scale bar =50µm)
Such a multimember knockout model would be within the current technical capabilities because in the mouse all Reg family members except RegIV are located on one contiguous 75kb stretch of DNA (Kobayashi, Akiyama et al. 2000), and could therefore be knocked out as a whole. In such a model the effects of exogenous administration of Reg even under normal conditions might be quite spectacular or absolutely necessary for the survival of the animals with this genotype. Although this prediction might be considered a little extreme there are a few observations, which might support it. As we and others have shown, individual Reg family members seldom appear on their own. Wherever one family member is expressed others are likely to be found as well (see Fig. 3). Most importantly, the individual Reg members all contain the Reg C-type lectin domain, which is a strong indication that some of their functions may overlap and therefore generate redundancy. In terms of the hypothetical Reg effects graph mentioned above this means that the X-axis Reg concentration is unlikely to be derived from one single Reg member but is rather a result of the cumulative concentrations of all Reg members present at this site.
\n\t\tThe potentially pleiotropic effects of Reg emphasize the importance of defining if, where, when, and how the Reg members bind. A receptor for Reg, which are secreted proteins, might act as focal point for Reg action and might enable us to place the events taking place upon receptor binding and the subtype specific characteristics of the Reg family within a theoretical framework. There has only been one investigation that specifically set out to isolate an islet Reg receptor (Kobayashi, Akiyama et al. 2000). In this study an expression library of rat pancreatic islets was probed with rRegI. This led to the isolation of a cDNA that had significant sequence homology to those “of multiple exostoses (EXT) family genes especially to human EXT-like gene 3 (EXTL3)/ EXT-related gene 1 (EXTR1) (over 97% amino acid identity), indicating that the cDNA encodes a rat homolog to human EXTL3/EXTR1”. EXTL genes are homologs of the EXT genes, which have been linked to hereditary multiple exostoses (HME), a rare medical condition in which multiple bony spurs or lumps (also know as exostoses or osteochondromas) develop on the bones of a child. However, EXTL genes are not linked to HME. EXT1 and 2 are thought to form Golgi-located hetero-oligomeric complexes and EXTL 1 and 3 contain a putative transmembrane domain with a short (31 amino acid for EXTL3 cytoplasmic domain) (Busse, Feta et al. 2007). All EXT family members are glycosyltransferases, which are involved in the biosynthesis of heparan sulfate and its analog heparin. EXT1 and 2 are essential for chain polymerization of heparan sulfate whereas EXTL3 most likely is involved in both chain initiation as well as elongation of heparan sulfate (Kim, Kitagawa et al. 2001). Heparan sulfate is a glycosaminoglycan found abundantly on the surface of most cells and in the extracellular space as proteoglycan. Heparan sulfate (HS) proteoglycans are involved in a wide range of biological processes such as cell adhesion, morphogenesis, cytokine effects and regulation of growth factors (Bernfield, Gotte et al. 1999). Regulation of HS proteoglycan biosynthesis would therefore be a good starting point to explain the pleiotropism of the Reg effects. However, the effects of Reg binding to EXTL3 are not known. Does this disrupt or enhance HS proteoglycan biosynthesis? How and where on the EXTL3 molecule does Reg bind and do different Reg members have different affinities? We do know that PANC-1 cells when incubated with a human version of the INGAP pentadecapeptide mentioned above respond with an accelerated translocation of the EXTL3 protein to the nuclear subcellular fraction (Levetan, Upham et al. 2008). Unfortunately, in this study, no alanine scans (mutated peptides each of which has an alanine replacing the naturally occurring residue at a different position in the sequence) or truncation or comparison studies with corresponding pentadecapeptides from other Reg members were performed. It is also known that islets contain HS (proteoglycans) and that heparinase treatment of isolated islets reduces their glucose responsiveness (glucose stimulated insulin secretion, GSIS). Furthermore islets of mice with a -cell specific ablation of EXTL3 obtained with a rat insulin 2 promoter-Cre/loxP-system had reduced GSIS, a reduced number of insulin positive cells and, until the age of four weeks, fewer cells positive for the proliferating cell nuclear antigen. These mice also responded to glucose challenge with increased blood glucose levels and their plasma insulin levels were reduced. These findings demonstrate that -cell specific EXTL3 knockout can affect the regulation of postnatal islet maturation via ablation or reduction or alteration of HS proteoglycan biosynthesis (Takahashi, Noguchi et al. 2009).
\n\t\t\tThese encouraging data might lead to the formation of a basis from which the effects of Reg could be explained. However, large gaps in our knowledge remain. It is not clear if Reg binding to EXTL3 changes HS proteoglycan synthesis and if so how. Even if Reg binding to EXTL3 were to cause an alteration in HS proteoglycan synthesis it is not clear if this would be sufficient to explain the effects seen in the models with transgenic expression or exogenous administration of Reg. There is therefore room for consideration of other potential Reg receptors. The methodology used in the experiments that discovered EXTL3 as Reg receptor involved screening of an islet cDNA library expressed in bacteria with rRegI. However proteins in a bacterial expression system are not subject to the same glycosylation that is introduced in a eukaryotic cell. Due to these limitations the screening assay could not detect Reg binding to carbohydrate structures found on glycoproteins or proteoglycans in eukaryotic cells. Reg-carbohydrate interaction however is an area that should definitely be covered by a search for potential Reg receptors because the family-defining structural feature of the Reg proteins is the C-type lectin domain. Lectins are proteins that bind to carbohydrate structures and C-type lectins do this better in the presence of calcium ions or their binding to carbohydrates is dependent on the presence of these cations. Surprisingly, despite the presence of a canonical C-type lectin fold, Reg-carbohydrate binding in the context of islet regeneration has so far not received any attention at all. A reason for this may possibly be that Reg proteins lack conserved amino acid residues that support Ca2+-dependent carbohydrate binding in other C-type lectins (Drickamer 1999). However this in no way rules out the possibility that Reg proteins recognize carbohydrate epitopes. To uncover what is known about this property of Reg it is necessary to leave the area of islet regeneration and explore other fields of Reg research.
\n\t\tResearchers studying the Reg family of proteins often work with a test system that involves the application of an artificial noxious stimulus thought to mimic a naturally occurring stress event. In a screen performed after application of the stimulus overexpression of one or more Reg members is observed. This was the case with the study that described the discovery of rRegI in regenerating pancreas and of INGAP. Recently a group of scientists investigating how gut microbial flora is maintained and controlled performed a study that compared gut epithelial cells from germ-free mice with those of mice that had been reconstituted with an intestinal microflora from conventional mice. They write ”…To gain new insights into how intestinal surfaces cope with microbial challenges, we used DNA microarrays to identify Paneth cell antimicrobial factors whose expression is altered by bacteria. [….] The results of our screen revealed 149 transcripts whose expression was changed 2- to 45-fold by microbial colonization. One of the most prominent responses uncovered by our analysis was a 31-fold increase in the abundance of RegIII transcripts in Paneth cells from conventionalized as compared with germ-free mice”. Subsequently this group demonstrated that mRegIII and hRegIII were bactericidal for Gram-positive bacteria. The bactericidal effect could be fully blocked by addition of chitotetraose (GlcNAc4) and somewhat attenuated by the addition of soluble peptidoglycan fragments, chitobiose (GlcNAc2), or N-acetylglucosamine. Interestingly, this assay revealed clear differences in susceptibility to glycan blocking between the mRegIII and hRegIII. Precipitation experiments and binding studies revealed that both mRegIII and hRegIII had affinity for peptidoglycans as well as mannan and chitin (Cash, Whitham et al. 2006). In a subsequent publication this group demonstrated that a short N-terminal peptide controlled the antibacterial activity of mRegIII and hRegIII. This peptide spans the region between the end of the leader sequence and a canonical trypsin cleavage site that is conserved in all but the RegIV subfamily where the conserved arginine residue is followed by a proline thus blocking tryptic cleavage (see Fig. 2). The group found that removal of the prosegment by tryptic cleavage drastically increased the antibacterial properties of the two Reg members. They also showed that removal of the prosegment did not interfere with peptidoglycan binding, which is essential for the antibacterial effects and suggest that the prosegment exerts its blocking activity via a mechanism different from interference with Reg-peptidoglycan binding. The authors propose that this regulatory mechanism has evolved to give the host control over antibacterial activity and that the activation of Reg by cleavage of the small inhibitor peptide likely occurs in the lumen of the gut by two trypsin isozymes, which are expressed in gut epithelial cells (Mukherjee, Partch et al. 2009). It should be added that, as mentioned before, some Reg members are secreted by the exocrine pancreas under normal physiological conditions and this might therefore be another site of activation of Reg for release of antibacterial effects. A third publication of this group reports on the molecular basis for peptidoglycan recognition by mRegIII and hRegIII. In this study the researchers used solution nuclear magnetic resonance to identify residues of hRegII involved in peptidoglycan binding. The three-dimensional structure of Reg is the C-type lectin fold containing a characteristic ‘long loop’ structure. In this long loop two subdomains can be distinguished which the scientists have designated loop 1 and loop 2. In other C-type lectins the loop 2 is involved in Ca2+-dependent carbohydrate binding via specific amino acid residues (the EPN motif, Fig. 2). However the corresponding residues in hRegIII (HIP/PAP) are not found in loop 2 but in loop 1 and, as the authors of the study show, participate in carbohydrate binding. Also missing in hRegIII are two conserved residues in the 4 strand of the C-type lectin fold, which are necessary for carbohydrate binding in other C-type lectins. Thus although these Reg family members lack the canonical C-type lectin carbohydrate binding motifs they are nevertheless lectins. Interestingly, based on the presence of the EPN motif in loop 1 scientists were able to predict that mRegIII should bind peptidoglycans whereas mRegIII, which lacks this motif should not. They were then able to confirm this prediction experimentally (Lehotzky, Partch et al. 2010). What conclusions can be derived from this? First, it should be appreciated that a C-type lectin domain can apparently bind carbohydrates via more than one mechanism. The domain functions as a three-dimensional scaffold within which changes affecting fine specificity are possible, allowing generation of diversity in carbohydrate binding. It is therefore quite conceivable that other Reg members also possess these properties despite lacking many or all of the residues that constitute the canonical C-type lectin carbohydrate binding motifs. These findings additionally give rise to new questions. All Reg members (except RegIV) contain the trypsin cleavage site, necessary for removal of the blocking peptide from hRegIII and mRegIII. Would this mean that all Reg members are potentially bactericides or only those containing the EPN motif in loop 1? This would make RegIII a bactericidal protein, while, as mentioned above, also protecting islets from STZ-induced diabetes when overexpressed (Xiong, Wang et al. 2011). What is the actual bactericidal mechanism of such Reg proteins? In studies on mRegIII Mukherjee, et al. discovered that carbohydrate binding per se is insufficient to explain this effect. Removal by tryptic cleavage of the short N-terminal blocking peptide does not interfere with carbohydrate binding yet drastically increases the bactericidal effect of the two investigated RegIII members (hRegIII and mRegIII). Is there a Reg effect that can manifest itself as bactericidal in the gut but as protective in pancreatic -cells? Or can Reg proteins act in different ways depending on whether they are ‘trypsin-activated’ or not? It should also be noted that RegIV, which has a blocked tryptic cleavage site and can therefore not undergo the unblocking process leading to an active bactericidal Reg member and has a deleted EPN motif nevertheless does bind carbohydrates (Ho, Lou et al. 2010). Perhaps the carbohydrate-binding step is common to all Reg members, with effector mechanisms diverging downstream of this event.
\n\t\t\t\tIn this context it is noteworthy that trypsin cleavage of Reg, which was discovered some years ago was reported to convert the previously soluble protein into a form that precipitates above pH6.5 and forms oligomeric fibrillar structures that combine into quadruple-helical filaments (QHF). It was also suggested that the small Reg prosegment inhibits formation of these fibrils. It was furthermore observed that rRegI is actually cleaved at the conserved trypsin site under conditions that rule out the presence of trypsin and other proteases thus suggesting that Reg may be subject to self-proteolysis at this site (Cerini, Peyrot et al. 1999) (Schiesser, Bimmler et al. 2001). Reg fibril formation may have profound consequences in degenerative processes in the central nervous system. These fibrils were found to be present in the pathological lesions of Alzheimer’s disease and hRegI was found to be overexpressed during very early stages of the disease before clinical signs appear (Duplan, Michel et al. 2001). Furthermore hRegI (lithostathine-1) deposits were also observed in the blood vessels and in focal and multicentric plaques in the cerebellum of patients with Creutzfeldt-Jacob disease (Laurine, Gregoire et al. 2003). The authors of these studies suggest that Reg fibrils might represent a common component of amyloid deposits and may be a component of the material that coats amyloid fibrils observed clinically. This raises the question as to whether Reg could play a role as a link between brain injury and the later onset of neurodegenerative diseases. If indeed this protein possesses the ability to undergo a process of self-proteolysis promoting the tendency to fibril formation then overexpression of Reg members in response to traumatic brain injury, which is well-documented as discussed below, might under certain circumstances contribute or even act as trigger for subsequent degenerative processes.
\n\t\t\t\tTo return to the bactericidal properties of Reg: fibril formation might actually be a process that contributes to its antibacterial effect. In such a scenario binding of Reg to bacterial carbohydrates would provide an anchorage and would be followed (or accompanied) by tryptic activation, which then leads to the formation of a Reg fibrillar coat on the surface of the bacteria. This coat could either inhibit bacterial movement or ‘plug’ channels in the bacterial cell wall or possibly cause perforation of the cell wall. A way to investigate this hypothesis would be to test if drugs that can dissociate Reg fibrils into individual protofilaments can actually reverse the bactericidal effect of Reg. Two remarks should end this section. The loop 1 of the C-type lectin domain that contains the EPN motif in mRegIII and hRegIII, described above, overlaps to a large extent with the peptide of INGAP reported to stimulate islet neogenesis (although there is no EPN motif in INGAP, see Fig. 2). Thus the intuition of the discoverer of this peptide was correct in so far as the loop 1 indeed corresponds to “a core of potential biological activity”. Although it should be added that a loop that has been cut at both ends no longer corresponds to a loop. These findings, together with the discovery by Christa et al. in 1994 that hRegIII (HIP/PAP) acted as a C-type lectin that bound to the disaccharide lactose (Christa, Felin et al. 1994) indicate that Reg proteins can bind carbohydrates despite the absence of the canonical binding motifs found to be essential for this task in other C-type lectins. This underlines the consideration that the rules governing carbohydrate binding in Reg C-type lectins are more complex than we currently understand.
\n\t\t\tInvolvement of the Reg family of proteins in nerve cell regeneration was observed while screening for genes overexpressed in an rat model that investigates motor neuron regeneration after crushing of the sciatic nerve. The authors write: “Within 24h of crushing the sciatic nerve, all motor neurons and a subpopulation of sensory neurons express high levels of rReg-2 (rRegIII/PAP-1) mRNA and protein. This again exemplifies the standard process of discovery for this family. The authors observed that migration of rReg-2 along growing motor and sensory axons occurs via orthograde transport and that rReg-2 acts as mitogen to Schwann cells, the cells that create the support on which neuronal regrowth can take place. Intraneural injection of an antiserum, which blocks rReg-2 greatly reduced regeneration of neurons. Interestingly, the authors found that recombinant rReg-2 alone had only a weak mitogenic effect on Schwann cells. However this effect could be enhanced by addition of forskolin, an activator of adenylate cyclase. It should be noted that the discovery of rRegI in a model of islet regeneration mentioned before involved the treatment of rats with nicotinamide, an inhibitor of 3’-5’ cAMP phosphodiesterase. Thus forskolin and nicotinamide both increase the intracellular levels of cAMP leading to an amplification of Reg-induced mitogenic effects. The authors mention that enhancement of the mitogenic effect by forskolin is also seen with other Schwann cell mitogens such as glial growth factors and platelet derived growth factor. There it is attributed to cAMP-induced increase in receptor expression for those factors. In an attempt to trace the signal that induced overexpression of rReg-2 the authors investigated the effects of peripheral axotomy on Reg-2 expression in the neonatal period when motor neurons are particularly sensitive to this intervention. The sensitivity to axotomy is ascribed to the interruption of retrograde transport of peripherally-derived neurotrophic factors. Indeed they found that the intervention greatly reduced constitutive Reg-2 expression levels compared with uninjured motor neurons. This finding indicated that Reg-2 expression in developing motor neurons was dependent on contact with peripheral targets, which act as source of neurotrophic factors. The authors argued that these factors might be leukemia inhibitory factor or ciliary neurotrophic factor (LIF/CNTF) because these proteins are related to the IL-6 family of cytokines and rReg-2 and other Reg gene family members have IL-6 responsive elements in their promoter region. They could show that targeted disruption of gp130, which is a common component of the receptors for IL-6, LIF, CNTF and CT-1 indeed abolished Reg expression in developing motor and sensory neurons of the mutant mice thus demonstrating that the expression of the mouse Reg protein(s) at this site is dependent on the cytokines of the LIF family acting through the LIF receptor (Livesey, O’Brian et al. 1997).
\n\t\t\t\tThis study was expanded subsequently by another group of scientists who showed that CNTF-related cytokines could induce rReg-2 expression in cultured motor neurons, which in turn acts as an autocrine/paracrine neurotrophic factor for a subpopulation of motor neurons by stimulating a survival pathway involving phophatidylinositol-3-kinase, Akt kinase and NF-B. They also demonstrated that rReg-2 expression
Before leaving this area two additional studies on the effects of Reg in the nervous system should be mentioned. The first provides an example of the observation that Reg family members are seldom found alone while the second introduces yet another role for mRegIII, which has been identified as a potential bactericidal lectin, an islet regeneration factor and an inflammatory modulator in pancreatitis. The first study used a model that induces traumatic brain injury (TBI) by weight drop and then studied the expression of rat Reg members by quantitative real-time PCR and in situ hybridization in the cerebral cortex. This study reported a low level of rReg-2 (rRegIII/PAP-1) and of rRegIII (PAP-III) mRNA in normal animals. Upon surgery and TBI the mRNA levels of both rat Reg members increased dramatically. First rReg-2 mRNA increased 12hrs post TBI and remained elevated until day 5 post TBI. This was followed, at 24 hrs post TBI, by rRegIII mRNA with a sharper temporal peak persisting until day 3 post TBI. The mRNA level of rReg-2 was also somewhat elevated in the cortex contralateral to TBI and the sham-operated ipsilateral side (Ampo, Suzuki et al. 2009). Two points here are relevant. First, low levels of Reg mRNA are detected in normal cortex, and as mentioned above, more than one Reg member is expressed. As shown in Fig. 3 this also correlates to the situation in pancreatic islets and would suggest redundancy due to overlap in the effector mechanisms mediated by different Reg members and a role for these proteins not only in response to stress but also under normal physiological conditions.
\n\t\t\t\tThe second study described the generation of a mouse model in which the exons 2-5 of the gene encoding mRegIII had been deleted and replaced with a lacZ reporter selection cassette. These mice were phenotypically indistinguishable from wild-type or heterozygous littermates. Interestingly, the knockout mice exhibited marked elevation of expression of mRegIII suggesting that the Reg system is designed to contain redundancies where one Reg member to some extent compensates for loss of another. The authors of this study provide evidence that, as in the case of rReg-2, expression of mRegIII is restricted to certain neuronal populations and is also developmentally regulated. Peak RegIII expression was observed on postnatal day 4 and had disappeared from all areas of the brain and spinal cord by postnatal day11. mRegIII deletion did not affect the total number of motor neurons in the facial motor nucleus, suggesting that no neuronal cell death had resulted from the loss of mRegIII. As in the aforementioned knockout studies, it was the application of a noxious stimulus that clearly revealed the effect of the knockout. When the scientists severed the facial motor nerve at postnatal day 3.5 and applied either saline or CNTF to the cut end of the nerve, more CNTF-treated motor neurons survived in the wild-type mice than in the knockout mice where CNTF treatment showed no improvement in survival over saline (Tebar, Geranton et al. 2008). In the latter case, as in pancreatic islets, knockout of a single Reg member causes no or only mild effects under normal physiological conditions. Only when a noxious stimulus is applied do the effects of the knockout become visible. As described above we attribute this to the presence of compensatory effects induced by other Reg members leading to saturation of the system under normal conditions, hence our advocacy of a multimember Reg knockout model and experiments designed to demonstrate the redundancies predicted to exist within the Reg family.
\n\t\t\t\tThe neuronal role of Reg also extends to effects on macrophages. We previously mentioned publications that investigated the role of rReg-2 (rRegIII/rPAP-1) and of mRegIII in the neuronal context. As was to be expected more than one Reg member is involved in this process. rRegIII is not only overexpressed in the cerebral cortex in response to traumatic brain injury as briefly mentioned above but also in the Schwann cells upon nerve injury (Namikawa, Fukushima et al. 2005). Injuries to axons in the peripheral nervous system induce the degeneration of distal axons, a process, which is accompanied by cellular responses. Among these responses the most striking is the invasion of the degenerating nerve by macrophages. They clear debris consisting of myelin components that inhibits axonal growth and secrete a number of soluble factors that can stimulate axonal growth. The influx of macrophages is ascribed to attractants that are released from the Schwann cells, which have undergone dedifferentiation as a consequence of loss of axon-Schwann cell contact. A number of such attractants have been described and include LIF and the monocyte chemoattractant protein-1 (MCP-1). Using a two-chamber cell migration assay Namikawa et al. could show that rRegIII is equally effective as MCP-1 in promoting macrophage migration. The scientists produced a dose-response curve that showed an increase in the macrophage migration index at concentrations of rRegIII between 0.1 and 10ng/ml. Doses above 10ng/ml did not further increase this index but rather led to a decrease with the effect completely disappearing at 500ng/ml, therefore revealing an effective concentration range typical for cytokines and chemokines. The authors also demonstrated that rRegIII knock-down achieved with siRNA introduced into rat nerves by adenoviral gene transfer reduced the capacity of explanted nerve segments distal to the injury to attract macrophages (Namikawa, Okamoto et al. 2006). However, attraction is not the only effect on macrophages ascribed to Reg. rRegIII (PAP-2) is also able to modulate the inflammatory response in these cells. Viterbo et al. showed migration of macrophages to beads coated with rRegIII with subsequent agglutination. They also demonstrated that this Reg member binds to macrophages, but do not reveal whether this occurs via EXTL3 the islet Reg receptor, or via a different receptor. (We suggest that it occurs via carbohydrate binding). They then measured, by real-time PCR and ELISA, a range of cytokine responses in the macrophages during exposure to rRegIII. They reported upregulation of mRNAs for IL-1, IL-6, TNF and IL-1 most likely via the NF-B pathway (Viterbo, Bluth et al. 2008).
\n\t\t\t\tConsidering the roles of Reg introduced here the general conclusion may be drawn that Reg proteins are functionally placed well within the large family of endogenous lectins of which C-type lectins are a subgroup (Mascanfroni, Cerliani et al. 2011, Toscano, Ilarregui et al. 2007). These endogenous glycan-binding proteins have been implicated in a wide range of functions including first-line defense against pathogens (bactericidal effect of Reg) cell-trafficking (macrophage attraction of Reg), immune regulation (cytokine responses induced by Reg) neoplastic transformation (Reg expression in liver cancer). Reg is unique among the C-type lectin family in that it consists of a secreted lectin domain only. This feature makes its distribution wider than that of C-type lectins, which constitute part of receptors in the cell membrane. It is therefore possible that Reg can also act as a modulator of the interactions between lectins in receptors and their carbohydrate ligands (van Vliet, Garcia-Vallejo et al. 2008).
\n\t\t\tReturning to the endocrine pancreas we now focus on studies performed in our laboratory that investigate the possibility that Reg might act as an autoantigen in T1DM. The insight that the pathogenesis of T1DM is driven by a disorder of the immune system has been well established by numerous animal experiments and clinical observations. That certain MHC alleles are associated with an increased risk of developing T1DM, that antibodies are present against -cell self antigens and that lymphocyte infiltrates are observed in the endocrine pancreas all point to the adaptive immune system, i.e. B- and T-cells, as necessary elements in the process leading to islet damage/destruction and thus insulin dependency. Although insulin has received much attention in the search for potential cellular targets of the autoimmune process it has become evident that it is not the only -cell component to which self-reactivity exists in T1DM. Our initial interest in the Reg proteins arose following our observation that one of its members, hRegIII, (HIP/PAP) was overexpressed in the remaining pancreatic islets of a patient who had died shortly after onset of the disease. This raised the question as to whether a vicious circle could become operational in a situation where a protein that becomes overexpressed as a result of the inflammatory process in the pancreatic islets, subsequently functions as an autoantigen (Gurr, Yavari et al. 2002). We therefore investigated if such a situation could occur during the pathogenesis of T1DM using the NOD mouse as model. We first defined Reg members present in mouse islets and found RegIII as well as RegII and, in more heavily infiltrated islets, also RegIII. RegIII expression was restricted to non -cells of the islets while RegII was found throughout the endocrine pancreas (Fig. 3). In the NOD model of T1DM autoantigens such as insulin and glutamic acid decarboxylase have been used as vaccine antigens to prevent or delay the onset of the disease. If a Reg member acted as autoantigen it might also have these properties and we therefore tested both RegII and RegIII as vaccines. While we could not prevent or even delay T1DM with RegIII we found a clear preventive effect with RegII vaccination. To ascertain that this effect was due to an immune-mediated process and not to the potential effects of Reg on islet regeneration we cleaved RegII into two fragments. The N-terminal fragment (NtfrII, residues 22-75) contained the first three cysteine residues of the Reg C-type lectin domain and the C-terminal fragment (CtfrII) contained the remainder of the protein (see Fig. 2). This, we argued, would inactivate possible direct effects of RegII on islet regeneration while retaining the function of Reg as autoantigen. On testing the two fragments we found that vaccination with the N-terminal fragment actually accelerated disease whereas vaccination with the C-terminal fragment delayed disease. This delay was more pronounced than that achieved with the full-length protein. In addition, it could be induced with late stage vaccinations, that is, delaying vaccination until shortly before onset of T1DM in NOD mice. We next demonstrated by adoptive transfer experiments that the clinical effects were mediated by T-cells. Both CD4+ and CD8+ T-cells from donors vaccinated with the N-terminal fragment could transfer disease to NOD-SCID mice - a strain that lacks B and T-cells and therefore does not develop T1DM. Similar experiments with T-cells obtained from donors vaccinated with CtfrII showed that CD4+ T-cells from these mice could delay the onset of T1DM induced by diabetogenic T-cells. Taken together these experiments clearly demonstrated that the clinical effects seen after RegII vaccination were in fact immune-mediated and not a result of a direct effect of RegII on islet regeneration. They also identified the N-terminal fragment of RegII as the part of the protein that contained T-cell epitope(s) able to activate autoreactive T-cells, whereas it appeared that vaccination with the C-terminal fragment had activated T-regulatory cells. We had thus established that RegII could act as an autoantigen in T1DM of NOD mice (Gurr, Shaw et al. 2007). Another group had demonstrated in the meantime that 24.9% of patients with T1DM, 14.9% of patients with type 2 diabetes and 2.7 % of control subjects had autoantibodies against RegI, thus confirming that Reg can also become a target of the autoimmune response in humans (Shervani, Takasawa et al. 2004). To add the second component of the vicious circle postulated above we had also shown that isolated human islets, when incubated with IL-6, secreted increased amounts of hRegIII (PAP/HIP). In a pancreatic islet under autoimmune attack this cytokine might be released by infiltrating macrophages leading to overexpression of Reg. Reg in turn then, since it acts as autoantigen, and as attractant for macrophages, as discussed above, enhances the inflammatory process thus leading to further overexpression and the operation of a vicious circle. However, we wanted to know if this process actually occurred
In order to establish a temporal profile of the I-Ag7 NtfrII peptide complexes we collected pancreatic lymph nodes of NOD mice at different ages, prepared single cell suspensions and exposed them to the antibody. After washing, bound phages were detached, bacteria were infected and a colony count was obtained. As a control we used a mutated version of the antibody D9, which had a deletion in its heavy chain and only marginally bound to NOD antigen-presenting cells pulsed with NtfrII. The numbers of T-cells in the pancreatic lymph
\n\t\t\tTemporal profile of I-Ag7 NtfrII peptide complexes (A) and spontaneous T-cell responses (B) in the pancreatic lymph nodes of NOD mice during the pathogenesis of T1DM. The y-axis in (A) displays the ratio of colony forming units (cfus) obtained with a binding antibody (D9) to colony forming units obtained with a mutated, non-binding antibody (D9mut); the y-axis in (B) displays the ratio (SI=stimulation index) of the number of spots obtained when cells of the pancreatic lymph nodes were incubated with NtfrII to the number of spots obtained when cells of the pancreatic lymph nodes were incubated without antigen (ELISPOT assay for IL-2). Both profiles show the same biphasic pattern but the T-cell pattern is shifted by two weeks i.e. the T-cell response in the pancreatic lymph nodes follows the temporal pattern of the I-Ag7 NtfrII peptide complexes.
nodes that responded to stimulation with NtfrII were also counted. On plotting both curves (NtfrII peptide I-Ag7 complexes and number of T-cells reactive for NtfrII) we observed that both curves had a biphasic profile and that the ‘T-cell’ curve followed the ‘complex’ curve with a delay of about two weeks (Fig. 4 A and B). This biphasic profile observed would clearly rule out the continuous operation of a vicious circle but suggests a temporary operation between 6 and 10 weeks of age. It also hints at the tight control of Reg expression. Reg does appear to become overexpressed in response to islet inflammation as manifested by the increase of I-Ag7 NtfrII peptide complexes in the pancreatic lymph nodes. However, beyond a certain degree (or duration) of the inflammatory process (at ages >8 weeks Fig. 4A) this response ceases and the islets appear to actually reduce Reg expression. The existence of such control mechanisms can also be inferred from the observation that Reg acts as a macrophage chemoattractant. In this case an additional vicious circle may be constructed, involving IL-6 released from macrophages, which leads to up-regulation of Reg and more influx of macrophages. However, as demonstrated by the discoverers of the chemoattractant properties of Reg, the dose response curves do not level off but the attractant effect disappears above a certain Reg concentration. These observations exemplify two main levels of control that must be considered for the understanding of Reg action. One of the control levels is represented by the limits, which the target system imposes on Reg action - chemoattractant effect on macrophages - and the other by the limits, which the source system imposes on Reg production or release – I-Ag7 NtfrII peptide complexes in pancreatic lymph nodes of NOD mice.
\n\t\tThe Reg family of proteins has been studied for over 25 years and today all mouse and human Reg members have been identified. However to date there is no unifying theory of Reg action and therefore the large body of work on the effects of Reg in different physiological systems remains a collection of unconnected observations. While it is important to accumulate more information on the role of individual Reg members, a framework needs to be developed within which this information can be placed and correlated. Such a unifying theory should be able to explain the seemingly very different effects induced by Reg such as, for example, Schwann or -cell mitogenesis and bactericidal effects. Currently no such theory exists but its basic components should involve carbohydrate binding based on the fact that the unifying structure of the Reg family is a C-type lectin fold. It should additionally encompass fibril formation and possibly EXTL3 binding as well as up-regulation of Reg under a wide range of noxious stimuli (cytokine-mediated or other). Extracellular matrix remodeling might also play a role. These components then need to be placed and understood within the framework of regulatory constraints imposed by the systems impacted by Reg as well as by those that generate Reg. In this review we have drawn attention to areas of Reg research that introduce and exemplify some of these components. Development of a theory of Reg action would require a change in experimental approach away from ‘what particular function is conveyed by a particular Reg member in a specific system?’ to comparative studies concerned with ‘what is common to all Reg members, how do they differ and what is the origin of these differences?’ implemented with consideration of the basic components of the theory as outlined above. Consequently we argue that a model in which not one particular member but an entire subfamily or all Reg members have been knocked out would greatly further the development of this unifying theory. Such models might allow the characterization of the effects of Reg under normal conditions by eliminating the ‘masking effects’ of the likely redundancies that occur within the family. How the genomic organization of the Reg family would facilitate generation of these models is mentioned above. We are confident that they would also reveal that Reg proteins are necessary for islet (re)generation.
\n\t\t\tAs far as the properties of Reg as autoantigen are concerned we are in the process of performing studies that evaluate if the antibodies specific for the Reg peptide MHC complexes generated in our laboratory may be useful as therapeutic agents for the treatment or prevention of T1DM. An important aim in the prevention and treatment of T1DM is the development of a specific immunotherapy, that is an intervention that targets and blocks/eliminates specifically self-reactive T-cells but does not affect T-cells, which are necessary for the normal functioning of the immune system. This aim can be achieved by intervening with the process that generates specificity in the immune system, namely the binding of the T-cell receptor to its antigen, which is the complex formed by the T-cell epitope and the presenting MHC. An antibody that recognizes this complex, such as D9 introduced here, might interfere with the activation of the self-reactive T-cell recognizing the same complex and could represent a potential means to achieve specific immune suppression. A variant of this approach is the active vaccination with the receptor of a self-reactive T-cell in order to generate an immune response that targets only T-cells with this receptor but not others. This approach is known as anti-idiotypic vaccination and has been tested with some success in models of other autoimmune diseases. Which of these approaches might actually be practicable and effective in the treatment of T1DM will be the focus of future studies in our laboratory.
\n\t\t\tA successful therapy for T1DM will likely have two main components; one designed to support or enhance islet protection/regeneration and the other to control the aberrant immune response. Although more widely studied autoantigens like insulin or glutamic acid decarboxylase might be more suitable for addressing the control of the aberrant immune response, Reg is unique in that it represents an islet component that can play a role in relation to both therapeutic main approaches through its impact on islet regeneration on the one hand and its role as autoantigen on the other hand.
\n\t\tThe work investigating the role of Reg as an autoantigen in T1DM was supported by funding from the Juvenile Diabetes Research Foundation (JDRF) and the American Diabetes Association (ADA). The author thanks Margaret Shaw and Yanxia Li for their efforts in carrying out the practical work. The author additionally thanks Professor Robert Sherwin for his overall support.
\n\t\tHernias penetrating the anterior abdominal wall are considered the ventral hernias, and the majority of these are formed by the inguinal, femoral and umbilical hernia. Rare varieties include the lumbar and Spigelian hernias. The Spigelian hernias, principally acquired, has an incidence ranging from 0.1–2% of all abdominal wall hernias [1, 2]. These hernias occur through a well-defined defect in the Spiegel’s fascia of the anterior abdominal wall adjacent to the semilunar line, which corresponds anatomically to the lateral edge of the rectus abdominis muscle. These hernias, therefore, are also known as the “spontaneous lateral ventral hernia” or “hernia of the semilunar line”. Commonly it occurs at the lower part of the abdomen, below the umbilicus where the posterior rectus sheath is deficient.
The semilunar line, originally named the “linea semilunaris spigelii” (the line of Spiegel), is named after the Flemish anatomist and surgeon, Adrian van der Spiegel (1578–1625) who first described the anatomical and surgical significance of well-known linea semilunaris [1]. He defined it as the line of transition between the muscle and aponeurosis of transversus abdominis muscle, extending from the ninth costal cartilage to the pubic tubercle with a lateral convexity sometimes easily described as the lateral border of the rectus sheath. Although, Spiegel first described the linea semilunaris, it was not until more than hundred years later the Spigelian hernia was first described clinically by another Flemish anatomist and surgeon Josef Thaddaei Klinkosh in the year 1764, setting forth the surgical significance of this line [3]. He described it as a ventral hernia developing at the site of linea spigelii, and distinctively coined the name Spigelian hernia.
The Spigelian line marks the transition from transverse abdominis muscle to aponeurosis. The part of this aponeurosis that lies lateral to the rectus abdominis muscle is called Spigelian fascia/aponeurosis. Hence Spigelian aponeurosis is limited medially by the lateral edge of the rectus muscle and laterally by the semilunar line. Thus, anatomically the Spigelian fascia is the medial part of the transversus aponeurosis between the lateral border of the rectus sheath and semilunar line and stretches from the tip of the 9th costal cartilage until the pubic tubercle. The Spigelian hernia can occur at any point through this fascia.
The crescentic shape and wide variability in the width of Spigelian aponeurosis craniocaudally predispose to the specific site of these hernia formations (Figure 1). The Spigelian line in the cranial part of the abdominal wall lies close to the rectus abdominis muscle, and hence the Spigelian aponeurosis is very narrow in this zone, due to the presence of more muscular three flat muscles of the abdominal wall attaching to the lateral border of the rectus sheath. Thereby the muscular fibres and aponeurosis of the external and internal oblique muscles overlap the narrow Spigelian aponeurosis. This is probably the main reason why these hernias are uncommonly found above the umbilicus. It is also seen that the fibres of the internal oblique and transverse abdominis muscle run at an angle to each other above the umbilicus thereby providing additional strength and preventing hernia formation. More commonly these hernias are located in an approximately 6 cm transverse imaginary zone extending from the interspinal line to 6 cm superior to it. The Spigelian fascia is widest here with the greatest abdominal circumference and highest intra-abdominal pressure. Due to its etiological significance, this belt is aptly known as the Spigelian hernia belt [4].
Schematic diagram showing the Spigelian fascia and Spigelian hernia belt.
The size of the hernia orifices usually ranges from 0.5 to 2 cm in diameter. It has a well-defined, firm edge and is round to oval in shape (Figure 2). This well-defined, fibrous, inelastic edge is believed to increase the risk of incarceration and leads to a condition akin to Richter’s hernia formation [5, 6, 7, 8, 9]. In the beginning, these hernias are usually limited to the Spigelian aponeurosis on the axial plane, but when their size increases, these can dissect the fibres of transverse abdominis muscles laterally as its medial extension is limited by the rectus muscle and sheath, and create a bigger defect in the anterior abdominal wall. Another probable reason for its lateral position is because that the external oblique aponeurosis covers the Spigelian aponeurosis in its whole length and creates a potential space between the muscle layers. This provides enough space for the herniated sac to expand and take the route of least resistance laterally and is thus palpable more lateral than the actual location of the hernia orifice. This usually conforms to a mushroom-shaped appearance of these hernias on palpation.
Schematic diagram showing herniation through the Spigelian hernia. Note the hernial sac is obscured under the external oblique aponeurosis.
In most patients, due to the presence of the tough external oblique aponeurosis, a small Spigelian hernia may go unnoticed. For the Spigelian hernia to be palpable clinically, it needs to penetrate both the transverse abdominis, internal oblique muscles and further glide in between the two oblique muscles. Further, the dissection of the internal oblique is determined by the fact whether the internal oblique muscle ventral to Spigelian aponeurosis is aponeurotic or muscular. In the event the hernial sac encounters an aponeurotic layer in its way, the hernia sac will tend to lie between the transversus abdominis and the internal oblique muscles. Although, the aponeurosis of the internal oblique muscle strengthens the Spigelian fascia, more often than not it is the internal oblique muscle belly rather than the aponeurosis that covers the Spigelian fascia, thereby reducing the reinforcement. In cases when the hernial sac grows and dissects the two innermost muscle layers, the hernia may become palpable clinically. Most commonly these are palpable below the level of the umbilicus as the fibres of the transversus abdominis and internal oblique muscles run parallel to each other in this area, thus reducing the resistance further. Above the umbilicus, these muscle fibres form a criss-cross configuration providing additional support and resistance and thereby decreasing the chance of a Spigelian hernia to be palpable but at the same time increasing the chance for incarceration.
It was usually believed that Spigelian hernias tend to occur through small defects in the transversus abdominis aponeurosis where it was penetrated by the perforating vessels and nerves [10, 11]. These were also thought to occur at the junction of the semilunar line and semicircular line of Douglas as the majority of cases were described below the umbilicus in the region of the line of Douglas. This observation was attributed to the fact that not only Spigelian fascia is broadest here but also the lack of posterior rectus sheath represents the inherent weakness of this zone, and also due to fibres of transversus aponeurosis that runs parallel to the internal oblique. This concept was first challenged by Webber et al., who demonstrated that approximately 45% of Spigelian hernias occurred above the arcuate line [12]. Interestingly, although most of these hernias can occur in the Spigelian hernia belt below the umbilicus for the aforementioned reasons [13, 14], the defect may still lie above the arcuate line. The hernia sac usually consists of the peritoneum, preperitoneal fat and occasionally transversalis fascia. The hernial content can be small bowel or omentum but can include any organ depending on its location. The size of the neck has been reported to vary from as small as 0.5 cm to as large as 6 cm [15].
These hernias can be congenital or acquired. Congenital cases develop through the weak areas in the aponeurosis of the abdominal muscles formed during their development in the mesenchyme of the somatopleure originating from the invading and fusing myotomes of the anterior abdominal wall and are usually associated with cryptorchidism [14, 16]. The congenital variety presents in the younger age, is usually small and mostly remains subclinical. Adult hernias are usually acquired. The perforating vessels were believed to create the area of weakness in the Spigelian fascia which was enhanced by herniation of preperitoneal fat, although this is now considered of minor importance [17]. Spigelian fascia is widest below the umbilicus and potentially weakest. Besides, the abdominal girth is wider below the umbilicus and in accordance with the Laplace’s law, wall tension will be greater. Furthermore, transversus abdominis and internal oblique muscles in the upper part of the abdomen extent medially into the posterior rectus sheath and strengths the Spigelian fascia. The natural progression of the disease ranges from younger patients usually presenting with a smaller fascial defect with preperitoneal tissue being the most common content. However, with increasing age, elderlies are vulnerable to the development of larger defects with peritoneal contents constituting the main sac content [18].
Besides the anatomical factors, hernia formation can be predisposed by stretching of the abdominal wall by factors that increase the intraabdominal pressure such as chronic cough, chronic obstructive pulmonary disease, obesity, ascites, pregnancy. It has also been described as a complication of chronic ambulatory peritoneal dialysis [19, 20].
Besides these, scarring from previous abdominal surgeries, paralysis of the anterior abdominal wall may weaken the Spigelian aponeurosis and create an area of weakness [21].
It has also been reported that the creation of pneumoperitoneum during laparoscopic surgeries can predispose to herniation through a pre-existing weakness in the Spigelian fascia [22].
The true prevalence of Spigelian hernia remains elusive as the majority of these cases are asymptomatic. A recent study showed that on ultrasonographic examination of 785 anterior abdominal wall hernias, only 1.4% of patients had Spigelian hernias indicating the rarity of the condition [23]. In another study, 2% of incidental Spigelian defect was identified during laparoscopic procedure further affirming the uniqueness of this hernia [24]. Spigelian hernias are slightly more common in females, occur mostly on the right side and usually affect people in their fourth to the seventh decades of life [25, 26, 27]. However, the laterality of these hernias is a contentious issue and as in other studies, left side location has shown predominance [28, 29]. Nevertheless, the underlying reasons are unknown and laterality remains inconsequential to its management.
The majority of these hernias are asymptomatic and accordingly the diagnosis is difficult, especially when these are of smaller size. The intraparietal location with overlying tough external oblique aponeurosis and thick subcutaneous fat mask their detection during a clinical examination. However, in patients who present with symptoms, these may range from nonspecific abdominal pain to a palpable lump or a visible mass in the abdominal wall to dangerous features of incarceration with or without features of strangulation. The characteristic of pain depends on the size and contents of the hernia. This may be a dull, sharp, or even burning type. However, one symptom is usually constant, and the pain is aggravated with increased intraabdominal pressure and often after a heavy meal, exercise, walking and running, and is relieved with rest and lying down. Nonetheless, the occult nature of these hernias predisposes them to incarceration and the risk of strangulation requiring emergency laparotomy is up to 24% [30, 31, 32] which is way above the 5-year strangulation risk of umbilical hernia (4%) and inguinal hernia (2.5%) [33, 34].
In cases of a visible lump, it is delineated when the anterior abdominal wall is made taut and the patient is in the upright position, but disappears when the patient lies down. With the increase in size, the lump tends to expand laterally and caudally between the layers of two oblique muscles. Therefore, at times, the patient may present with a non-specific bulge without a definite well-demarcated palpable lump which may be due to a typical T-shaped hernial sac causing elevation of the intact external oblique aponeurosis. The diagnosis of hernia can be affirmed if the swelling can be reduced, but reappears in the upright position and especially with the manoeuvres that increase intraabdominal pressure such as coughing, straining or a Valsalva manoeuvre, and disappears on lying down.
Palpation of the hernia defect in most cases is difficult as these defects are small and are masked by the tough external oblique aponeurosis and subcutaneous fat. However, an attempt should be made to palpate the abdominal wall after making the musculature taut to identify any local tenderness indicating the point of the hernial orifice, which may be the only sign in case of occult or a subclinical Spigelian hernia. This may be attributed to the fact that reinforcing manoeuvres that increase intraabdominal pressure pushes out the preperitoneal fat or a hernial sac through the defect. Palpation of these structures against the inelastic margin of the hernial orifice and stimulation of stretch receptors located in the parietal peritoneum produce distinct point tenderness which is more of somatic pain in nature and hence is easily localised [35]. Although, not pathognomonic, this examination has high sensitivity and can help in screening patients with occult herniation. Sometimes, patients report extreme tactile hyperesthesia which is located just medial to the hernia defect. This is generally believed to be caused by mechanical irritation of the perforating branch of the corresponding intercostal nerve (Valleix phenomena) and this sign can aid in clinical diagnosis of a subclinical herniation [36]. For patients presenting with abdominal pain but no visible lump, radiological investigations like ultrasonogram and/or CT-scan of the abdomen can be of foremost importance. Furthermore, in cases where the diagnosis remains elusive even after radiological investigations, a diagnostic laparoscopy may be of help [28].
These hernias are most commonly located in the interparietal plane with no visible or palpable mass as discussed above, and only 50% of cases could be diagnosed clinically before any surgical intervention [17]. Their tendency to masquerade other clinical conditions presenting with abdominal pain requires a high index of clinical suspicion.
The most common symptoms are mild pain aggravated by coughing, straining, exercising and being relieved by lying down. Although, occasionally a lump may be noted, the diagnosis is often missed unless the patient presents with partial bowel obstruction. The clinical examination alone is believed to be 100% sensitive with a PPV of 36% when compared with operative findings [35].
The diagnostic imaging mainly aims at identifying the hernia defect, sac and its content.
It is a poor modality for diagnosing these hernias. It can neither aid in demonstrating the defect nor the content, especially the omentum or preperitoneal fat. However, in cases in which the sac contains a portion of the small or large bowel, barium studies can be of help. Besides, for diagnosing the complications of these hernias such as intestinal obstruction, a conventional x-ray can be used.
It is considered the investigation of choice and is usually the first-line imaging modality often used. It should be performed in patients presenting with obscure pain in the abdomen with or without a lump and is helpful both in clinical and subclinical hernias. It helps in the identification of a hernia defect, sac, and its content. It has the additional advantage of providing real-time scanning images by changing the patient’s position and performing manoeuvres that increase the intraabdominal pressure and precipitates any fascial defects or herniation of fat or viscus.
Using a 3.5 MHz transducer, the examination is first performed with the patient in the supine position and the abdominal wall relaxed. A screening USG is performed for intraabdominal viscera to rule out any potential intraabdominal pathology as a cause of pain. Next a higher denomination transducer, typically 5 MHz is used for the parietal wall structures. Scanning is begun at the lateral end of the rectus muscle with parasagittal sweeps. This helps in visualising the rectus muscle. In longitudinal scans, echogenic strips can be visualised, the deepest of which is the parietal layer, more superficial are the layers of the ventral wall. The hernia defect is seen as a disruption of these echogenic strips (Figure 3). The visualisation of the defect and the interparietal location of the sac represent the typical Spigelian hernia with omentum as its content. In difficult cases, the patient may be instructed to increase intraabdominal pressure through Valsalva manoeuvre, which may demonstrate the fascial disruption, and herniation of preperitoneal fat or abdominal viscus. In correlation with the operative findings, a real-time USG scan is believed to have a sensitivity of 90% and PPV of 100% [35].
Dynamic USG of the abdominal wall showing a Spigelian hernial sac (1.6 cm) penetrating through the Spigelian fascia, seen here as a broken line in the muscle-fascial plane. The right rectus muscle is marked as “R” in yellow.
It is considered as effective as the USG for demonstration of the hernial orifice. Additionally, it provides better information of abdominal wall resistance. Overall, the CT scan has a sensitivity and PPV of 100% each when compared with operative findings [35]. But, the USG is easier to perform, is a clinic procedure, is less expensive and can help in the dynamic analysis of the patient for which it is an excellent screening tool for the lesion. In cases where USG gives inadequate or equivocal information, a CT scan should be added.
On many occasions, the preoperative diagnosis may remain obscure until surgical exploration is performed. In a study by Weiss et al., approximately 50 percent of cases are diagnosed on exploration [37].
Therefore, for diagnosing Spigelian hernias, a dynamic USG and CT scan are useful when used in tandem with the clinical examination. In cases of uncertainty, diagnostic laparoscopy can be used in a symptomatic patient.
Depending on its location, a Spigelian hernia may mimic intra-abdominal pathologies which can present with pain such as acute appendicitis, twisted ovarian cyst, tubo-ovarian pathologies, mesenteric lymphadenitis, biliary colic, peptic ulcer pain, pancreatic pain or mesenteric ischemia [35]. Many times one may confuse it with any other disease entity of the abdominal parietal wall too. If the hernia is palpable at the location of pain and if it is reducible, the diagnosis is easy. In instances when the lump is palpable in a typical location but not reducible, the differential diagnoses include hematoma of rectus abdominis muscle, lipoma, chronic abscess, lymphadenopathy, other ventral hernias, solid tumours of the abdominal wall such as a desmoid tumour [35]. In cases where it is not palpable and the patient presents with non-specific pain or if a mass is present in the ventral wall, which is irreducible, the first step is directed towards identifying the nature of the swelling by a dynamic USG. If a Spigelian hernia is suspected, the attempt should be made to localise the hernial orifice. USG can help in differentiating hematoma, abscess, lipoma or seroma. Myotendinitis of rectus abdominis or external oblique muscle can mimic the tenderness present in subclinical cases. In cases where the defect is not found, and diagnosis is obscured, patients should be worked up and investigated for gastrointestinal and genitourinary disorders. An abdominal CT scan reinforces the diagnosis or helps in excluding the differential diagnoses, particularly whether the pain arises from the intra-abdominal pathologies or from the parietal abdominal wall. It is important to keep in mind that in a difficult clinical situation where the diagnosis is elusive or when a subclinical Spigelian hernia is suspected, every effort should be made to rule out an intra-abdominal pathology first. In the pursuit of diagnosing a suspected Spigelian hernia, an important intra-abdominal pathology should not be missed.
Spigelian hernias are the subgroup of primary ventral hernias and the European Hernia Society (EHS) classification system is most commonly used for their classification [38]. However, Webber et al. (2017) have described three clinical stages which reflect the natural history of the condition and provide universality for their management (Table 1) [12].
Stages | Anatomy | Clinical Feature | Treatment |
---|---|---|---|
I | Defect: <2 cm Content: interstitial fat only with no peritoneal component | Intermittent, well-localised pain but no palpable swelling | Open surgery: they are not visible laparoscopically |
II | Defect: 2–5 cm Content: peritoneal component present | Palpable swelling | Laparoscopy/Open repair |
III | Defect: >5 cm | Large hernia with distortion the of abdominal wall | Open repair |
Clinical stages of Spigelian hernia.
Operative management of these hernias is advisable as the risk of strangulation or incarceration has been reported up to 25% [39]. Initially open anterior approach with primary closure of the defect or mesh placement in cases where primary closure was not possible was advised. With the technical progress of laparoscopy, its use in the diagnosis and repair of Spigelian hernias has made it the method of choice [40]. It provides the benefits of minimally invasive surgery like reduced post-operative pain, less chance of infection, shorter hospital stays, reduction in morbidity and better cosmesis. However, according to the recent EHS guidelines, it is suggested that Spigelian hernia should be repaired with mesh. The approach, either open or laparoscopic may depend on the surgeon’s expertise, because the strength of recommendation is weak as limited comparative data is available [41]. A randomised trial comparing 11 conventional and 11 laparoscopic repairs in elective Spigelian hernia surgery revealed significant advantages for laparoscopic repair in terms of morbidity (wound complications) and hospital stay [42].
The most popular laparoscopic repairs are the Intraperitoneal Onlay Mesh (IPOM) technique (35%), Total Extraperitoneal Patch (TEP) approach (30%), Transabdominal Preperitoneal (TAPP) approach (22%), and laparoscopic suturing techniques [43, 44]. The TEP repair of Spigelian hernia offers the advantage of avoiding breach in the peritoneal layer as it accesses only through the preperitoneal space. Although, studies have failed to demonstrate the superiority of the extraperitoneal approach over intraperitoneal repair, the intraperitoneal laparoscopic Spigelian hernia repair is considered the gold standard because of its technical advantages [45].
A transverse incision is placed over the lump and the external oblique is incised in its direction to expose the peritoneal sac which can simply be inverted (Figure 4). The hernia defect can be closed with sutures but in cases of larger defect, a mesh should be used which is placed either in preperitoneal space or above the fascia.
Open surgical repair of a subclinical Spigelian hernia containing protrusion of preperitoneal fat only (sacless).
Once the hernial sac contents are reduced, the preperitoneal flap is raised and dissected for 5 cm around the hernial defect. The mesh is placed in the extraperitoneal space and the peritoneal flap is closed. The TAPP provides the opportunity to explore the abdominal cavity, although a potential drawback may be the possibility of intraperitoneal adhesions after the surgery, the chances of which, however, are almost similar to that of other laparoscopic surgery. At times, difficulty in the closure of the peritoneal flap may be encountered because of the thin and fragile peritoneum in this location [45].
The extraperitoneal space is created by open access and a balloon is used to create and enlarge the working space. The hernial sac is identified and closed. A large mesh is used to cover the hernia defect and is fixed to the abdominal wall. Although, this approach prevents access to the intraperitoneal cavity for inspection of any concomitant pathology, it reduces the risk of adhesions [46] besides possible benefit to explore and treat the concomitant direct inguinal hernia [47]. TEP repair is expensive due to the price of balloon dissector, technically challenging with a longer learning curve [48] and can be used only if the hernia is located below the arcuate line [49].
Intraperitoneal access is gained using either closed or open techniques. The hernial site is identified and port placement is done in the form of an arc or a circle with the centre at the defect site which should be at least 10 cm away. The contents are reduced and a coated mesh is fixed to obtain an overlap of at least 5 cm around the defect. It provides the opportunity to explore the abdominal cavity and therefore is helpful in emergency conditions with the incarcerated hernia [50, 51]. It is also believed to be the easiest to learn and safe to perform [52]. Nonetheless, the main limitation to this technique is the risk of hematoma formation and nerve entrapment after tack or stapler application. The use of fibrin sealant in place of tacks provides the solution [53].
The use of robotics on ventral wall hernias are easier due to a 360-degree rotation, camera use, surgical forceps and excellent visualisation of the defect. The placement of sutures also makes the procedure easier. The postoperative pain score reported is also lower [54]. Although, robotic-assisted Spigelian hernia surgery provides technical advantage and reliability, further studies with longer follow-ups are required for conclusive analysis [55].
Postoperative complications include seroma and hematoma formation, surgical site infection, abdominal viscera injury, mesh infection, and recurrence. Nerve entrapment during mesh-tacker placement can lead to abdominal pain syndromes [55].
Spigelian aponeurosis extends caudally up to the pubic tubercle and is found medial to the inferior epigastric artery within the Hasselbach’s triangle. Hernias penetrating the fascia transversalis here are conveniently called the low Spigelian hernias. These hernias usually contain preperitoneal fat but occasionally the bladder may also be involved.
Direct inguinal hernias are located at a similar triangle and may therefore cause diagnostic confusion. Differentiating these hernias from the direct inguinal hernia is important because the risk of incarceration is higher. Due to a small but well-defined hernia orifice, hernioplasty is easier to perform with a lesser chance of recurrence. Digital palpation with the little finger in the inguinal canal in standing position and Valsalva manoeuvre touches the first phalanx in case of low Spigelian hernia and the middle one in direct inguinal hernia. This technique has been proposed to distinguish between these two hernias, but can be uncomfortable and even painful for the patient. The diagnosis can be confirmed by radiological investigation and final assessment is best done intraoperatively [56]. Although, very rare, if both the hernias are found it is most likely due to weakness of Spigelian fascia around the insertion of rectus abdominis [45].
The diagnosis of a small Spigelian hernia is extremely challenging, given its rarity combined with nonspecific pain symptoms. Secondly, often due to its intramural location, its detection by palpation can be extremely difficult. Therefore, a great deal of clinical intelligence is invested in its preoperative diagnosis and the ignorance of its existence can cumulate to catastrophic complications of strangulation. Often only a point tenderness corresponding to the site of the defect is the only finding on palpation of the abdominal wall after making the muscles taut [57]. These hernias are small and often may contain only the preperitoneal fat protrusion through the fascial defect (Figure 4), which is something similar to the sacless epigastric hernia. As mentioned previously, only less than half of the cases are detected preoperatively. Therefore, patients presenting with non-specific pain in the abdomen should alert the astute clinician for the possibility of a Spigelian hernia. Once the diagnosis is established, treatment is elementary with surgery being the treatment of choice in symptomatic cases.
Spigelian hernias are notoriously difficult to diagnose. If these are visible and palpable, diagnosis is straight forward. But if the hernia is subclinical, it is difficult to diagnose, and only radiological investigations such as a dynamic USG or CT-scan of the abdomen wall can pick up the lesion. A strong clinical suspicion helps to diagnose the occult variety, which presents as non-specific abdominal pain, otherwise about 50% remain undiagnosed until surgery. Due to the high risk of incarceration and strangulation, these hernias should be operated early. Open conventional surgery has been largely replaced by laparoscopic mesh hernioplasty.
Authors declare no conflict of interest.
Nil.
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The nanoparticles’ unique physical and chemical properties render them most appropriate for a number of specialist applications.",book:{id:"9109",slug:"engineered-nanomaterials-health-and-safety",title:"Engineered Nanomaterials",fullTitle:"Engineered Nanomaterials - Health and Safety"},signatures:"Takalani Cele",authors:[{id:"305934",title:"Dr.",name:"Takalani",middleName:null,surname:"Cele",slug:"takalani-cele",fullName:"Takalani Cele"}]},{id:"72636",title:"Nanocomposite Materials",slug:"nanocomposite-materials",totalDownloads:2139,totalCrossrefCites:5,totalDimensionsCites:11,abstract:"Nanocomposites are the heterogeneous/hybrid materials that are produced by the mixtures of polymers with inorganic solids (clays to oxides) at the nanometric scale. Their structures are found to be more complicated than that of microcomposites. They are highly influenced by the structure, composition, interfacial interactions, and components of individual property. Most popularly, nanocomposites are prepared by the process within in situ growth and polymerization of biopolymer and inorganic matrix. With the rapid estimated demand of these striking potentially advanced materials, make them very much useful in various industries ranging from small scale to large to very large manufacturing units. With a great deal to mankind with environmental friendly, these offer advanced technologies in addition to the enhanced business opportunities to several industrial sectors like automobile, construction, electronics and electrical, food packaging, and technology transfer.",book:{id:"10072",slug:"nanotechnology-and-the-environment",title:"Nanotechnology and the Environment",fullTitle:"Nanotechnology and the Environment"},signatures:"Mousumi Sen",authors:[{id:"310218",title:"Dr.",name:"Mousumi",middleName:null,surname:"Sen",slug:"mousumi-sen",fullName:"Mousumi Sen"}]},{id:"38951",title:"Carbon Nanotube Transparent Electrode",slug:"carbon-nanotube-transparent-electrode",totalDownloads:3985,totalCrossrefCites:3,totalDimensionsCites:5,abstract:null,book:{id:"3077",slug:"syntheses-and-applications-of-carbon-nanotubes-and-their-composites",title:"Syntheses and Applications of Carbon Nanotubes and Their Composites",fullTitle:"Syntheses and Applications of Carbon Nanotubes and Their Composites"},signatures:"Jing Sun and Ranran Wang",authors:[{id:"153508",title:"Prof.",name:"Jing",middleName:null,surname:"Sun",slug:"jing-sun",fullName:"Jing Sun"},{id:"153596",title:"Ms.",name:"Ranran",middleName:null,surname:"Wang",slug:"ranran-wang",fullName:"Ranran Wang"}]},{id:"49413",title:"Electrodeposition of Nanostructure Materials",slug:"electrodeposition-of-nanostructure-materials",totalDownloads:3732,totalCrossrefCites:1,totalDimensionsCites:7,abstract:"We are conducting a multi-disciplinary research work that involves development of nanostructured thin films of semiconductors for different applications. Nanotechnology is widely considered to constitute the basis of the next technological revolution, following on from the first Industrial Revolution, which began around 1750 with the introduction of the steam engine and steelmaking. Nanotechnology is defined as the design, characterization, production, and application of materials, devices and systems by controlling shape and size of the nanoscale. The nanoscale itself is at present considered to cover the range from 1 to 100 nm. All samples prepared in thin film forms and the characterization revealed their nanostructure. The major exploitation of thin films has been in microelectronics, there are numerous and growing applications in communications, optical electronics, coatings of all kinds, and in energy generation. A great many sophisticated analytical instruments and techniques, largely developed to characterize thin films, have already become indispensable in virtually every scientific endeavor irrespective of discipline. Among all these techniques, electrodeposition is the most suitable technique for nanostructured thin films from aqueous solution served as samples under investigation. The electrodeposition of metallic layers from aqueous solution is based on the discharge of metal ions present in the electrolyte at a cathodic surface (the substrate or component.) The metal ions accept an electron from the electrically conducting material at the solid- electrolyte interface and then deposit as metal atoms onto the surface. The electrons necessary for this to occur are either supplied from an externally applied potential source or are surrendered by a reducing agent present in solution (electroless reduction). The metal ions themselves derive either from metal salts added to solution, or by the anodic dissolution of the so-called sacrificial anodes, made of the same metal that is to be deposited at the cathode.",book:{id:"4718",slug:"electroplating-of-nanostructures",title:"Electroplating of Nanostructures",fullTitle:"Electroplating of Nanostructures"},signatures:"Souad A. M. Al-Bat’hi",authors:[{id:"174793",title:"Dr.",name:"Mohamad",middleName:null,surname:"Souad",slug:"mohamad-souad",fullName:"Mohamad Souad"}]},{id:"71346",title:"Application of Nanomaterials in Environmental Improvement",slug:"application-of-nanomaterials-in-environmental-improvement",totalDownloads:1691,totalCrossrefCites:0,totalDimensionsCites:13,abstract:"In recent years, researchers used many scientific studies to improve modern technologies in the field of reducing the phenomenon of pollution resulting from them. In this chapter, methods to prepare nanomaterials are described, and the main properties such as mechanical, electrical, and optical properties and their relations are determined. The investigation of nanomaterials needed high technologies that depend on a range of nanomaterials from 1 to 100 nm; these are scanning electron microscopy (SEM), transmission electron microscopy (TEM), and X-ray diffractions (XRD). The applications of nanomaterials in environmental improvement are different from one another depending on the type of devices used, for example, solar cells for producing clean energy, nanotechnologies in coatings for building exterior surfaces, and sonochemical decolorization of dyes by the effect of nanocomposite.",book:{id:"10072",slug:"nanotechnology-and-the-environment",title:"Nanotechnology and the Environment",fullTitle:"Nanotechnology and the Environment"},signatures:"Ali Salman Ali",authors:[{id:"313275",title:"Associate Prof.",name:"Ali",middleName:null,surname:"Salman",slug:"ali-salman",fullName:"Ali Salman"}]}],onlineFirstChaptersFilter:{topicId:"208",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81438",title:"Research Progress of Ionic Thermoelectric Materials for Energy Harvesting",slug:"research-progress-of-ionic-thermoelectric-materials-for-energy-harvesting",totalDownloads:24,totalDimensionsCites:0,doi:"10.5772/intechopen.101771",abstract:"Thermoelectric material is a kind of functional material that can mutually convert heat energy and electric energy. It can convert low-grade heat energy (less than 130°C) into electric energy. Compared with traditional electronic thermoelectric materials, ionic thermoelectric materials have higher performance. The Seebeck coefficient can generate 2–3 orders of magnitude higher ionic thermoelectric potential than electronic thermoelectric materials, so it has good application prospects in small thermoelectric generators and solar power generation. According to the thermoelectric conversion mechanism, ionic thermoelectric materials can be divided into ionic thermoelectric materials based on the Soret effect and thermocouple effect. They are widely used in pyrogen batteries and ionic thermoelectric capacitors. The latest two types of ionic thermoelectric materials are in this article. The research progress is explained, and the problems and challenges of ionic thermoelectric materials and the future development direction are also put forward.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Jianwei Zhang, Ying Xiao, Bowei Lei, Gengyuan Liang and Wenshu Zhao"},{id:"77670",title:"Thermoelectric Elements with Negative Temperature Factor of Resistance",slug:"thermoelectric-elements-with-negative-temperature-factor-of-resistance",totalDownloads:72,totalDimensionsCites:0,doi:"10.5772/intechopen.98860",abstract:"The method of manufacturing of ceramic materials on the basis of ferrites of nickel and cobalt by synthesis and sintering in controllable regenerative atmosphere is presented. As the generator of regenerative atmosphere the method of conversion of carbonic gas is offered. Calculation of regenerative atmosphere for simultaneous sintering of ceramic ferrites of nickel and cobalt is carried out. It is offered, methods of the dilated nonequilibrium thermodynamics to view process of distribution of a charge and heat along a thermoelement branch. The model of a thermoelement taking into account various relaxation times of a charge and warmth is constructed.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Yuri Bokhan"},{id:"79236",title:"Processing Techniques with Heating Conditions for Multiferroic Systems of BiFeO3, BaTiO3, PbTiO3, CaTiO3 Thin Films",slug:"processing-techniques-with-heating-conditions-for-multiferroic-systems-of-bifeo3-batio3-pbtio3-catio",totalDownloads:96,totalDimensionsCites:0,doi:"10.5772/intechopen.101122",abstract:"In this chapter, we have report a list of synthesis methods (including both synthesis steps & heating conditions) used for thin film fabrication of perovskite ABO3 (BiFeO3, BaTiO3, PbTiO3 and CaTiO3) based multiferroics (in both single-phase and composite materials). The processing of high quality multiferroic thin film have some features like epitaxial strain, physical phenomenon at atomic-level, interfacial coupling parameters to enhance device performance. Since these multiferroic thin films have ME properties such as electrical (dielectric, magnetoelectric coefficient & MC) and magnetic (ferromagnetic, magnetic susceptibility etc.) are heat sensitive, i.e. ME response at low as well as higher temperature might to enhance the device performance respect with long range ordering. The magnetoelectric coupling between ferromagnetism and ferroelectricity in multiferroic becomes suitable in the application of spintronics, memory and logic devices, and microelectronic memory or piezoelectric devices. In comparison with bulk multiferroic, the fabrication of multiferroic thin film with different structural geometries on substrate has reducible clamping effect. A brief procedure for multiferroic thin film fabrication in terms of their thermal conditions (temperature for film processing and annealing for crystallization) are described. Each synthesis methods have its own characteristic phenomenon in terms of film thickness, defects formation, crack free film, density, chip size, easier steps and availability etc. been described. A brief study towards phase structure and ME coupling for each multiferroic system of BiFeO3, BaTiO3, PbTiO3 and CaTiO3 is shown.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Kuldeep Chand Verma and Manpreet Singh"},{id:"78034",title:"Quantum Physical Interpretation of Thermoelectric Properties of Ruthenate Pyrochlores",slug:"quantum-physical-interpretation-of-thermoelectric-properties-of-ruthenate-pyrochlores",totalDownloads:78,totalDimensionsCites:0,doi:"10.5772/intechopen.99260",abstract:"Lead- and lead-yttrium ruthenate pyrochlores were synthesized and investigated for Seebeck coefficients, electrical- and thermal conductivity. Compounds A2B2O6.5+z with 0 ≤ z < 0.5 were defect pyrochlores and p-type conductors. The thermoelectric data were analyzed using quantum physical models to identify scattering mechanisms underlying electrical (σ) and thermal conductivity (κ) and to understand the temperature dependence of the Seebeck effect (S). In the metal-like lead ruthenates with different Pb:Ru ratios, σ (T) and the electronic thermal conductivity κe (T) were governed by ‘electron impurity scattering’, the lattice thermal conductivity κL (T) by the 3-phonon resistive process (Umklapp scattering). In the lead-yttrium ruthenate solid solutions (Pb(2-x)YxRu2O(6.5±z)), a metal–insulator transition occurred at 0.2 moles of yttrium. On the metallic side (<0.2 moles Y) ‘electron impurity scattering’ prevailed. On the semiconductor/insulator side between x = 0.2 and x = 1.0 several mechanisms were equally likely. At x > 1.5 the Mott Variable Range Hopping mechanism was active. S (T) was discussed for Pb-Y-Ru pyrochlores in terms of the effect of minority carrier excitation at lower- and a broadening of the Fermi distribution at higher temperatures. The figures of merit of all of these pyrochlores were still small (≤7.3 × 10−3).",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Sepideh Akhbarifar"},{id:"77635",title:"Optimization of Thermoelectric Properties Based on Rashba Spin Splitting",slug:"optimization-of-thermoelectric-properties-based-on-rashba-spin-splitting",totalDownloads:124,totalDimensionsCites:0,doi:"10.5772/intechopen.98788",abstract:"In recent years, the application of thermoelectricity has become more and more widespread. Thermoelectric materials provide a simple and environmentally friendly solution for the direct conversion of heat to electricity. The development of higher performance thermoelectric materials and their performance optimization have become more important. Generally, to improve the ZT value, electrical conductivity, Seebeck coefficient and thermal conductivity must be globally optimized as a whole object. However, due to the strong coupling among ZT parameters in many cases, it is very challenging to break the bottleneck of ZT optimization currently. Beyond the traditional optimization methods (such as inducing defects, varying temperature), the Rashba effect is expected to effectively increase the S2σ and decrease the κ, thus enhancing thermoelectric performance, which provides a new strategy to develop new-generation thermoelectric materials. Although the Rashba effect has great potential in enhancing thermoelectric performance, the underlying mechanism of Rashba-type thermoelectric materials needs further research. In addition, how to introduce Rashba spin splitting into current thermoelectric materials is also of great significance to the optimization of thermoelectricity.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Zhenzhen Qin"},{id:"75364",title:"Challenges in Improving Performance of Oxide Thermoelectrics Using Defect Engineering",slug:"challenges-in-improving-performance-of-oxide-thermoelectrics-using-defect-engineering",totalDownloads:214,totalDimensionsCites:0,doi:"10.5772/intechopen.96278",abstract:"Oxide thermoelectric materials are considered promising for high-temperature thermoelectric applications in terms of low cost, temperature stability, reversible reaction, and so on. Oxide materials have been intensively studied to suppress the defects and electronic charge carriers for many electronic device applications, but the studies with a high concentration of defects are limited. It desires to improve thermoelectric performance by enhancing its charge transport and lowering its lattice thermal conductivity. For this purpose, here, we modified the stoichiometry of cation and anion vacancies in two different systems to regulate the carrier concentration and explored their thermoelectric properties. Both cation and anion vacancies act as a donor of charge carriers and act as phonon scattering centers, decoupling the electrical conductivity and thermal conductivity.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Jamil Ur Rahman, Gul Rahman and Soonil Lee"}],onlineFirstChaptersTotal:6},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:287,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:10,numberOfPublishedChapters:103,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"7",title:"Biomedical Engineering",doi:"10.5772/intechopen.71985",issn:"2631-5343",scope:"Biomedical Engineering is one of the fastest-growing interdisciplinary branches of science and industry. The combination of electronics and computer science with biology and medicine has improved patient diagnosis, reduced rehabilitation time, and helped to facilitate a better quality of life. Nowadays, all medical imaging devices, medical instruments, or new laboratory techniques result from the cooperation of specialists in various fields. The series of Biomedical Engineering books covers such areas of knowledge as chemistry, physics, electronics, medicine, and biology. This series is intended for doctors, engineers, and scientists involved in biomedical engineering or those wanting to start working in this field.",coverUrl:"https://cdn.intechopen.com/series/covers/7.jpg",latestPublicationDate:"May 13th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:12,editor:{id:"50150",title:"Prof.",name:"Robert",middleName:null,surname:"Koprowski",slug:"robert-koprowski",fullName:"Robert Koprowski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTYNQA4/Profile_Picture_1630478535317",biography:"Robert Koprowski, MD (1997), PhD (2003), Habilitation (2015), is an employee of the University of Silesia, Poland, Institute of Computer Science, Department of Biomedical Computer Systems. For 20 years, he has studied the analysis and processing of biomedical images, emphasizing the full automation of measurement for a large inter-individual variability of patients. Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"10",title:"Animal Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/10.jpg",isOpenForSubmission:!0,editor:{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. Dr. Rutland has also written popular science books for the public. https://orcid.org/0000-0002-2009-4898. www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:null,institution:{name:"University of Nottingham",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null},{id:"11",title:"Cell Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/11.jpg",isOpenForSubmission:!0,editor:{id:"133493",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",profilePictureURL:"https://mts.intechopen.com/storage/users/133493/images/3091_n.jpg",biography:"Prof. Dr. Angel Catalá \r\nShort Biography Angel Catalá was born in Rodeo (San Juan, Argentina). He studied \r\nchemistry at the Universidad Nacional de La Plata, Argentina, where received aPh.D. degree in chemistry (Biological Branch) in 1965. From\r\n1964 to 1974, he worked as Assistant in Biochemistry at the School of MedicineUniversidad Nacional de La Plata, Argentina. From 1974 to 1976, he was a Fellowof the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor oBiochemistry at the Universidad Nacional de La Plata, Argentina. He is Member ofthe National Research Council (CONICET), Argentina, and Argentine Society foBiochemistry and Molecular Biology (SAIB). His laboratory has been interested for manyears in the lipid peroxidation of biological membranes from various tissues and different species. Professor Catalá has directed twelve doctoral theses, publishedover 100 papers in peer reviewed journals, several chapters in books andtwelve edited books. Angel Catalá received awards at the 40th InternationaConference Biochemistry of Lipids 1999: Dijon (France). W inner of the Bimbo PanAmerican Nutrition, Food Science and Technology Award 2006 and 2012, South AmericaHuman Nutrition, Professional Category. 2006 award in pharmacology, Bernardo\r\nHoussay, in recognition of his meritorious works of research. Angel Catalá belongto the Editorial Board of Journal of lipids, International Review of Biophysical ChemistryFrontiers in Membrane Physiology and Biophysics, World Journal oExperimental Medicine and Biochemistry Research International, W orld Journal oBiological Chemistry, Oxidative Medicine and Cellular Longevity, Diabetes and thePancreas, International Journal of Chronic Diseases & Therapy, International Journal oNutrition, Co-Editor of The Open Biology Journal.",institutionString:null,institution:{name:"National University of La Plata",institutionURL:null,country:{name:"Argentina"}}},editorTwo:null,editorThree:null},{id:"12",title:"Human Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/12.jpg",isOpenForSubmission:!0,editor:{id:"195829",title:"Prof.",name:"Kunihiro",middleName:null,surname:"Sakuma",slug:"kunihiro-sakuma",fullName:"Kunihiro Sakuma",profilePictureURL:"https://mts.intechopen.com/storage/users/195829/images/system/195829.jpg",biography:"Professor Kunihiro Sakuma, Ph.D., currently works in the Institute for Liberal Arts at the Tokyo Institute of Technology. He is a physiologist working in the field of skeletal muscle. He was awarded his sports science diploma in 1995 by the University of Tsukuba and began his scientific work at the Department of Physiology, Aichi Human Service Center, focusing on the molecular mechanism of congenital muscular dystrophy and normal muscle regeneration. His interest later turned to the molecular mechanism and attenuating strategy of sarcopenia (age-related muscle atrophy). His opinion is to attenuate sarcopenia by improving autophagic defects using nutrient- and pharmaceutical-based treatments.",institutionString:null,institution:{name:"Tokyo Institute of Technology",institutionURL:null,country:{name:"Japan"}}},editorTwo:null,editorThree:{id:"331519",title:"Dr.",name:"Kotomi",middleName:null,surname:"Sakai",slug:"kotomi-sakai",fullName:"Kotomi Sakai",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000031QtFXQA0/Profile_Picture_1637053227318",biography:"Senior researcher Kotomi Sakai, Ph.D., MPH, works at the Research Organization of Science and Technology in Ritsumeikan University. She is a researcher in the geriatric rehabilitation and public health field. She received Ph.D. from Nihon University and MPH from St.Luke’s International University. Her main research interest is sarcopenia in older adults, especially its association with nutritional status. Additionally, to understand how to maintain and improve physical function in older adults, to conduct studies about the mechanism of sarcopenia and determine when possible interventions are needed.",institutionString:null,institution:{name:"Ritsumeikan University",institutionURL:null,country:{name:"Japan"}}}},{id:"13",title:"Plant Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/13.jpg",isOpenForSubmission:!0,editor:{id:"332229",title:"Prof.",name:"Jen-Tsung",middleName:null,surname:"Chen",slug:"jen-tsung-chen",fullName:"Jen-Tsung Chen",profilePictureURL:"https://mts.intechopen.com/storage/users/332229/images/system/332229.png",biography:"Dr. Jen-Tsung Chen is currently a professor at the National University of Kaohsiung, Taiwan. He teaches cell biology, genomics, proteomics, medicinal plant biotechnology, and plant tissue culture. Dr. Chen\\'s research interests include bioactive compounds, chromatography techniques, in vitro culture, medicinal plants, phytochemicals, and plant biotechnology. He has published more than ninety scientific papers and serves as an editorial board member for Plant Methods, Biomolecules, and International Journal of Molecular Sciences.",institutionString:"National University of Kaohsiung",institution:{name:"National University of Kaohsiung",institutionURL:null,country:{name:"Taiwan"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:43,paginationItems:[{id:"81796",title:"Apoptosis-Related Diseases and Peroxisomes",doi:"10.5772/intechopen.105052",signatures:"Meimei Wang, Yakun Liu, Ni Chen, Juan Wang and Ye Zhao",slug:"apoptosis-related-diseases-and-peroxisomes",totalDownloads:3,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"The Metabolic Role of Peroxisome in Health and Disease",coverURL:"https://cdn.intechopen.com/books/images_new/10837.jpg",subseries:{id:"11",title:"Cell Physiology"}}},{id:"81723",title:"Peroxisomal Modulation as Therapeutic Alternative for Tackling Multiple Cancers",doi:"10.5772/intechopen.104873",signatures:"Shazia Usmani, Shadma Wahab, Abdul Hafeez, Shabana Khatoon and Syed Misbahul Hasan",slug:"peroxisomal-modulation-as-therapeutic-alternative-for-tackling-multiple-cancers",totalDownloads:3,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"The Metabolic Role of Peroxisome in Health and Disease",coverURL:"https://cdn.intechopen.com/books/images_new/10837.jpg",subseries:{id:"11",title:"Cell Physiology"}}},{id:"81638",title:"Aging and Neuropsychiatric Disease: A General Overview of Prevalence and Trends",doi:"10.5772/intechopen.103102",signatures:"Jelena Milić",slug:"aging-and-neuropsychiatric-disease-a-general-overview-of-prevalence-and-trends",totalDownloads:14,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Senescence",coverURL:"https://cdn.intechopen.com/books/images_new/10935.jpg",subseries:{id:"11",title:"Cell Physiology"}}},{id:"81566",title:"New and Emerging Technologies for Integrative Ambulatory Autonomic Assessment and Intervention as a Catalyst in the Synergy of Remote Geocoded Biosensing, Algorithmic Networked Cloud Computing, Deep Learning, and Regenerative/Biomic Medicine: Further Real",doi:"10.5772/intechopen.104092",signatures:"Robert L. 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Beloborodova",profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"9731",title:"Oxidoreductase",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/9731.jpg",slug:"oxidoreductase",publishedDate:"February 17th 2021",editedByType:"Edited by",bookSignature:"Mahmoud Ahmed Mansour",hash:"852e6f862c85fc3adecdbaf822e64e6e",volumeInSeries:19,fullTitle:"Oxidoreductase",editors:[{id:"224662",title:"Prof.",name:"Mahmoud Ahmed",middleName:null,surname:"Mansour",slug:"mahmoud-ahmed-mansour",fullName:"Mahmoud Ahmed Mansour",profilePictureURL:"https://mts.intechopen.com/storage/users/224662/images/system/224662.jpg",institutionString:"King Saud bin Abdulaziz University for Health Sciences",institution:{name:"King Saud bin Abdulaziz University for Health Sciences",institutionURL:null,country:{name:"Saudi Arabia"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"9742",title:"Ubiquitin",subtitle:"Proteasome Pathway",coverURL:"https://cdn.intechopen.com/books/images_new/9742.jpg",slug:"ubiquitin-proteasome-pathway",publishedDate:"December 9th 2020",editedByType:"Edited by",bookSignature:"Xianquan Zhan",hash:"af6880d3a5571da1377ac8f6373b9e82",volumeInSeries:18,fullTitle:"Ubiquitin - Proteasome Pathway",editors:[{id:"223233",title:"Prof.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",profilePictureURL:"https://mts.intechopen.com/storage/users/223233/images/system/223233.png",institutionString:"Shandong First Medical University",institution:{name:"Affiliated Hospital of Shandong Academy of Medical Sciences",institutionURL:null,country:{name:"China"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"9002",title:"Glutathione System and Oxidative Stress in Health and Disease",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/9002.jpg",slug:"glutathione-system-and-oxidative-stress-in-health-and-disease",publishedDate:"August 26th 2020",editedByType:"Edited by",bookSignature:"Margarete Dulce Bagatini",hash:"127defed0a50ad5ed92338dc96e1e10e",volumeInSeries:17,fullTitle:"Glutathione System and Oxidative Stress in Health and Disease",editors:[{id:"217850",title:"Dr.",name:"Margarete Dulce",middleName:null,surname:"Bagatini",slug:"margarete-dulce-bagatini",fullName:"Margarete Dulce Bagatini",profilePictureURL:"https://mts.intechopen.com/storage/users/217850/images/system/217850.jpeg",institutionString:"Universidade Federal da Fronteira Sul",institution:{name:"Universidade Federal da Fronteira Sul",institutionURL:null,country:{name:"Brazil"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Proteomics",value:18,count:3},{group:"subseries",caption:"Metabolism",value:17,count:6},{group:"subseries",caption:"Cell and Molecular Biology",value:14,count:8},{group:"subseries",caption:"Chemical Biology",value:15,count:10}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:3},{group:"publicationYear",caption:"2021",value:2021,count:7},{group:"publicationYear",caption:"2020",value:2020,count:12},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:2}],authors:{paginationCount:249,paginationItems:[{id:"274452",title:"Dr.",name:"Yousif",middleName:"Mohamed",surname:"Abdallah",slug:"yousif-abdallah",fullName:"Yousif Abdallah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274452/images/8324_n.jpg",biography:"I certainly enjoyed my experience in Radiotherapy and Nuclear Medicine, particularly it has been in different institutions and hospitals with different Medical Cultures and allocated resources. Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University, Kuwait. His research interests include optimization, computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, and intelligent systems. Prof. Sarfraz has been a keynote/invited speaker at various platforms around the globe. He has advised/supervised more than 110 students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He has authored and/or edited around seventy books. Prof. Sarfraz is a member of various professional societies. He is a chair and member of international advisory committees and organizing committees of numerous international conferences. He is also an editor and editor in chief for various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:"Beijing University of Technology",institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Lakhno Igor Victorovich was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:null},{id:"318905",title:"Prof.",name:"Elvis",middleName:"Kwason",surname:"Tiburu",slug:"elvis-tiburu",fullName:"Elvis Tiburu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"336193",title:"Dr.",name:"Abdullah",middleName:null,surname:"Alamoudi",slug:"abdullah-alamoudi",fullName:"Abdullah Alamoudi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"318657",title:"MSc.",name:"Isabell",middleName:null,surname:"Steuding",slug:"isabell-steuding",fullName:"Isabell Steuding",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"318656",title:"BSc.",name:"Peter",middleName:null,surname:"Kußmann",slug:"peter-kussmann",fullName:"Peter Kußmann",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"338222",title:"Mrs.",name:"María José",middleName:null,surname:"Lucía Mudas",slug:"maria-jose-lucia-mudas",fullName:"María José Lucía Mudas",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}},{id:"147824",title:"Mr.",name:"Pablo",middleName:null,surname:"Revuelta Sanz",slug:"pablo-revuelta-sanz",fullName:"Pablo Revuelta Sanz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}}]}},subseries:{item:{id:"15",type:"subseries",title:"Chemical Biology",keywords:"Phenolic Compounds, Essential Oils, Modification of Biomolecules, Glycobiology, Combinatorial Chemistry, Therapeutic peptides, Enzyme Inhibitors",scope:"Chemical biology spans the fields of chemistry and biology involving the application of biological and chemical molecules and techniques. In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. 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Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. 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