These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
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This collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
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To celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
IntechOpen and Knowledge Unlatched formed a partnership to support researchers working in engineering sciences by enabling an easier approach to publishing Open Access content. Using the Knowledge Unlatched crowdfunding model to raise the publishing costs through libraries around the world, Open Access Publishing Fee (OAPF) was not required from the authors.
\n\n
Initially, the partnership supported engineering research, but it soon grew to include physical and life sciences, attracting more researchers to the advantages of Open Access publishing.
\n\n\n\n
These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\n\n
This collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\n\n
To celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
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In 2006 he obtained the PhD at the Faculty of Aerospace Engineering, Politehnica University of Bucharest in Aerospace Engineering field. From 1998 to 2005 he worked as assistant professor at Avionics Division of University of Craiova, while from 2005 to 2009 he was senior lecturer in inertial navigation systems at the same institution. Since 2009 he has been associate professor at the Avionics Division of University of Craiova. Between May 2008 and February 2009 he was postdoctoral fellow at the University of Quebec, Canada, institution wherewith he collaborates in research projects since 2002. He authored or co-authored 2 books and more than 100 papers in journals and conference proceedings of international and domestic scientific events. His research activities concern navigation systems, miniaturized inertial sensors, aircraft’s board equipments, automatic control systems (including intelligent control systems), and morphing aircraft structures. 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\r\n\tOn-road and off-road vehicles constitute an important part of the land transportation sector. Even the economic and chip crises cannot completely stop the production of vehicles in a product range that varies according to customer demand. The use of automobiles in the world is increasing day by day, and vehicle users demand from the sector smarter, more environmentally friendly, and safer vehicles. Vehicle dynamics is one of the most important aspects that all vehicle manufacturers and related researchers should compute and pay attention to before the production of vehicles. Modeling and simulation of dynamic elements of vehicle parts such as tires, steering, brakes, the integrated driver helped systems, etc., is a crucial step before prototyping.
\r\n
\r\n\tIn this book, the dynamics of vehicles will be deeply illustrated, from fundamental to futuristic approaches. The primary aim is to convey to the readers how important the dynamic analysis of vehicles is and how it affects their production, from simple to detailed.
\r\n
\r\n\tFinally, the effects of intelligent systems to be used in autonomous vehicles with developing technologies on vehicle dynamics and future perspectives will be analyzed.
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1. Introduction
1.1 Macrophages: innate and adaptive immunity
Macrophages are present as crucial members of a multitude of specialized cells that fortify our immune system by fighting against infection caused by pathogens [1]. Macrophages differentiate from tissue-infiltrated circulating monocytes, which originate from bone marrow resident myeloid precursors [2, 3]. All tissue macrophages, however, do not originate from monocytes. Although some macrophage origins have been studied carefully, the detailed molecular mechanisms toward the differentiation of different macrophage types remain mostly uncharacterized [4, 5, 6, 7]. Irrespective of their origin, most macrophages eliminate encountered pathogens through phagocytosis (element of innate immunity) and additionally present the foreign antigens derived from pathogens via major histocompatibility complex (MHC) molecules to lymphocytes leading to lymphocyte activation (element of adaptive immunity) [2, 8]. Cytoskeletal modulations and transcriptional activation programs intrinsically associated with macrophage-mediated immune functions (e.g. phagocytosis, autophagy/xenophagy) conform to the in-built maneuvering of macrophages as they confront with different kinds of pathogens. Several lines of evidence substantiate that Wnt signaling is important for the transcriptional programs and cytoskeletal modulations inherent to macrophages during immune surveillance and response to different kinds of infection [9, 10, 11, 12, 13].
1.2 Wnt signaling
Wnt signaling is an integral theme of tissue/organ morphogenesis, repair, and maintenance. Thus, it is not surprising that this central premise of life is also an important component of macrophage function [9, 10, 11, 12, 13, 14, 15, 16]. Wnts constitute a large family of secreted glycoprotein ligands, which bind to Frizzled and/or ROR cell surface receptors during various phases of tissue and organ development, morphogenesis, and homeostasis. Frizzleds are seven transmembrane-spanning receptors bearing homology to heterotrimeric G protein-coupled receptors, and RORs bear homology to tyrosine kinase receptors [17, 18, 19, 20]. Based on the gene database, there are about 19 Wnt ligands and about 12 and 2 Frizzled and ROR receptors, respectively [21, 22]. Whether all these gene products are expressed and functional in our system in different cellular contexts is unclear at this stage. Although there is evidence of co-receptor function by the ROR subtype receptors during Wnt-Frizzled signaling [22, 23], the degrees of coordination between the Frizzled and ROR receptors under different physiological conditions are yet to be characterized at the molecular level. Given the considerable homology among the respective members of the Wnt and Frizzled families, any one Wnt ligand may interact with multiple Frizzled receptors. Thus, the outcome of Wnt-Frizzled signaling in a particular cell type under a certain condition could be dependent precisely on the existing profile of Wnt-Frizzled stoichiometry [20].
Wnt signaling is broadly classified into two types—canonical or β-catenin-dependant and noncanonical or β-catenin-independent (Figure 1). The transcriptional coactivator β-catenin promotes gene expression by LEF/TCF family transcription factors in response to canonical Wnt signaling, and transcriptional activators such as NFκB, NFAT, and AP1 are associated with noncanonical Wnt signaling. Even though the ligands Wnt3A and Wnt5A are mostly considered as representatives of the canonical and noncanonical modes of Wnt signaling, respectively [21, 24], the mode of signaling is in reality governed by the receptor(s) receiving the Wnt signal as mentioned above and the associated adaptor molecule(s) transmitting it. Thus, some level of crosstalk between the two modes of signaling would not be uncommon. Interestingly, the intracellular adaptor molecule Disheveled acts as a mediator of both β-catenin-dependant and β-catenin-independent Wnt signaling. Heterotrimeric G proteins, which have been reported to couple with Frizzled receptors, add to the complexity of Wnt signaling [18, 25]. Whether heterotrimeric G proteins cooperate with Disheveled during canonical and noncanonical Wnt signaling is not known clearly. Although there is some evidence of the involvement of lipid molecules such as cholesterol in switching Disheveled between the canonical and noncanonical modes of Wnt signaling [25], the molecular details of such presumed conformational switches remain largely undefined. The reason behind the preference of cell surface coactivator receptors such as lipoprotein receptor-like protein (LRP) 5/6 for the canonical mode of Wnt signaling as opposed to the noncanonical mode also remains unclear (Figure 1).
Figure 1.
An overview of Wnt signaling cascade: in canonical mode of signaling, the association of Wnt-Fz and LRP activates a signaling cascade through Dvl and/or G-proteins that leads to inactivation of a GSK3 associated destruction complex which in the absence of Wnt would phosphorylate β-catenin for terminal destruction by proteasome. Via GSK3 inactivation, β-catenin gets stabilized and translocates to the nucleus where it acts as a co-activator of LEF/TCF (transcription factor). In the non-canonical mode of Wnt signaling (often β-catenin independent) the signaling cascade through Dvl and/or G-protiens leads to activation of Ca2+ mediated signaling where protein kinase C (PKC) and CaMKII gets activated and leads to translocation of NFκB, NFAT to the nucleus. Wnt also binds to ROR leading to activation of AP1. A crosstalk between the pathways is not uncommon.
1.3 Wnt signaling in immune system
Given that host cytoskeletal rearrangements encompassing phagocytosis and autophagy/xenophagy and transcriptional regulation of immune defense genes come into the direct line of control of pathogenic incursions and immune homeostasis [9, 10, 11, 12, 26], Wnt signaling aptly associates with host-pathogen interactions of macrophages at the crossroads of innate and adaptive immunity. The attributes of Wnt signaling and the microbe world being diverse, their mutual interactions in the various host defense programs are expected to be manifold. Although Wnt3A and Wnt5A are often represented as the prototypes for the two different modes of Wnt signaling (canonical and noncanonical) in the regulation of immune response, several molecular details of the balancing act of the Wnts in relation to the interactions of macrophages with different microbes remain unclear.
The primary objective of this chapter is to briefly summarize the conceptual advancement in the context of Wnt signaling and immune defense by macrophages, focusing mainly on transcriptional activation and the actin cytoskeleton-associated phagocytosis and autophagy machineries. Our aim is to also address unanswered questions, which may prove instrumental in bridging existing gaps in our evaluation of the Wnts in the context of macrophage host defense programs.
2. Sustenance of immune defense by macrophages through a steady state of transcriptional activation by Wnt signaling
2.1 Significance of constitutive transcriptional activation in macrophages by Wnt signaling
Macrophages have long been acknowledged for executing immune defense against microbial pathogens through diverse means of signaling that include several transcription factors including NFκB, AP1, and NFAT [27, 28, 29, 30]. The ability of macrophages to recognize and engulf pathogens, deliberate NADPH oxidase activity, and process antigens for presentation to MHC molecules and T cell activation place macrophages quite aptly at the crossroad of innate and adaptive immune defense programs [31, 32, 33]. Surely, macrophages have in-built mechanisms to execute innate immunity and translate it to adaptive immune response. However, not much is known about the molecular details of how macrophages are naturally geared to operate in such innate and adaptive modes of immune defense. We recently demonstrated that NF-κB (p65) [34], a transcription factor functioning at the core of our immune system, remains activated at a basal level in macrophages through a steady state of Wnt5A signaling. Administration of inhibitor of Wnt production2 (IWP2) to macrophages in culture or depletion of Wnt5A or Frizzled5 (putative Wnt5A receptor) gene expression in macrophages by silencing gene transcription through small interfering RNA blocks constitutive p65 activation and the steady-state immune activity of macrophages [10]. Sustained presence of the Wnt5A-p65 axis can potentially bridge innate and adaptive immune responses through regulation of the expression of immune response genes, such as CD14, interferons (IFN)s, and MHC, and elaboration of immune signaling networks that involve major immune response molecules such as the Toll-like receptors (TLR) and nucleotide-binding oligomerization domain-containing proteins (NOD) during challenge by pathogens [13, 35, 36]. The interrelation of this basal level Wnt5A-p65 signaling with other major transcription factors and coactivators of Wnt signaling that mediate immune response by macrophages remains to be deciphered at the molecular level.
2.2 NF-κB transcription factors
NF-κB transcription factors comprise a family of five members: p52, p50, p65 (RelA), c-Rel, and RelB, which regulate gene transcription as combinatorial dimers [34, 37, 38]. These dimers remain or become activated through different modes depending on the physiological context of cell signaling. In the classical mode of activation, the homo and heterodimers are translocated to the nucleus for gene expression after being released from the IκB-bound states in the cytoplasm in response to different stimuli that lead to proteasome-assisted IκB degradation through activation of the IκB kinase IKK2/β [34]. The p65 homo and heterodimers while being responsible for inflammatory gene expression are also significantly involved in the sustenance of innate immune response gene expression in a context-dependent manner [10]. Some of the NF-κB (p65) responsive immune response genes include CD14, MHC, and IFNs. A schematic of NF-κB activation is shown in Figure 2.
Figure 2.
An overview of NFKB activation pathway in the macrophage: During steady state a basal level of stimulus by Wnt signaling keeps IKK enough activated to result in inactivation of IκB and translocation of a certain pool of NFκB transcription factor (p65 homodimer) to the nucleus. A minimum pool of transcription factors contributes to survival and vigilance for immune response. In the activated state, during inflammation and chronic infection, stimuli (TNFα, LPS, IL1β) lead to an increase in NFκB combinatorial dimers in the nucleus.
2.3 Wnt5A signaling-mediated activation of transcription
As mentioned earlier in this chapter, Wnt5A is one of several members of the large family of Wnt glycoprotein ligands. Frizzled-5, Frizzled-4, and ROR1 are putative receptors for Wnt5A. It is to be noted that although modified versions of selective Wnt-Frizzled complex structures have been solved [39], none of the ligand-receptor complexes have been truly biochemically characterized in their physiological contexts. In the noncanonical mode of Wnt signaling of which Wnt5A is a representative, Wnt5A-Frizzled-ROR or Wnt5A-Frizzled-initiated signaling alters the activity of Rho/Rac family GTPases through differential activation of Disheveled [10, 40]. Within the Frizzled family of cell surface receptors, Frizzled2, Frizzled5, and Frizzled4 are some of the putative receptors for Wnt5A [17, 41, 42]. It is not known if Disheveled activation by Wnt5A signaling acts in concert with or is regulated by heterotrimeric G proteins, given that Frizzled receptors are homologous to heterotrimeric G protein-coupled receptors. The involvement of β-catenin by Wnt5A signaling is governed by the availability of receptors and cytoplasmic signaling intermediates [20, 43]. The subsequent activation of transcription factors such as AP1, NFAT, and NF-κB through complex signaling networks and crosstalk, either dependent or independent of nuclear translocation of β-catenin (explained in Figures 1 and 2), could lead to elaboration of context-dependent immune responses (Figure 3).
Figure 3.
A schematic of Wnt5A-p65 axis: Wnt5A binds with it’s putative receptor Frizzled5 (FZ) and transmits signal through intermediates like Disheveled (Dvl), trimeric G-proteins (Gα, β, ƴ ) activating Rac1. Activated Rac1 helps in translocation of NFκB from cytosol to nucleus via activation of IKK and proteasomal degradation of IKK-phosphorylated IκB. The translocated p65 in the nucleus helps to maintain expression of proteins such as CD14, IFNƴ, IFNb, MHC, needed for pathogen detection and clearance, and Bcl2, needed for cell survival. Amplification of signals by CD14-assisted molecules such as TLRs facilitate pathogen recognition and clearance.
The basal Wnt5A-Frizzled5 signaling-dependent NF-κB (p65) activity in macrophages that we observed is at least partly accountable for the steady-state expression of CD14/IFNβ, the promoter sequence of which at the genome level contains p65 binding elements [10, 13] (Figure 3). The constitutive p65 activity in the nucleus also contributes to sustaining Wnt5A expression [10]. Accordingly, the self-sustaining Wnt5A-p65 axis responsive CD14 and IFNβ expression helps to initiate and coordinate several aspects of macrophage function including interaction of pathogen recognition with TLR signaling, thus enabling adaptation to protective immune responses to bacteria, bacterial LPS (lipopolysaccharide), and virus as explained in Figure 3. The Wnt5A-NF-κB (p65) responsive gene expression declines upon exposing macrophages to an IKK2-specific inhibitor [10]. Wnt5A signaling is also responsible for a basal level of secretion of IFN-γ, another important regulator of innate immune signaling in macrophages. The steady-state Wnt5A signaling and NF-κB activity also promote macrophage survival through the expression of NF-κB-responsive survival genes such as Bcl2 [10]. These data are consistent with the dearth of survival of NF-κB-deficient mice due to different kinds of infection and apoptotic cell death [44]. The Wnt5A-Frizzled5 signaling-assisted constitutive p65 activity is dependent on Rac1 activation, which lies upstream of IKK2 activity [10]. The detailed mechanism of how the Rac1 GTPase activates IKK in a Wnt5A signaling-dependent mode is yet to be explored. It also remains to be tested how Wnt5A-responsive innate immune functions in macrophages relating to pathogen recognition and activation of several intracellular signaling pathways translate to adaptive immune responses encompassing antigen processing/presentation and lymphocyte activation.
2.4 Signaling and transcriptional activation by other Wnts
In light of the fact that Wnts comprise a large family of glycoprotein ligands sharing considerable amino acid sequence homology and bind to cell surface receptors that are equally homologous [21], the schemes of regulation and sustenance of immune responses in macrophages by Wnt signaling are likely to be manifold. Several reports have outlined the importance of canonical Wnt signaling and β-catenin in the development, sustenance, and elaboration of memory and effector T cells that comprise a crucially important component of immunity to infectious pathogens [45]. The role of the TCF family of transcription factors in this respect has generated considerable interest in our understanding of the importance of Wnt signaling in immune homeostasis. However, the precise role of canonical Wnt signaling by β-catenin and TCF transcription factors in macrophages in the generation and sustenance of T cell-mediated immunity remains unclear.
3. Role of Wnt signaling in macrophage phagocytosis: involvement of the actin cytoskeleton
3.1 Significance of phagocytosis
Phagocytosis of pathogens is one of the most important features of the host-pathogen communications and interactions mediated by macrophages. This element of host defense by macrophages not only operates toward host protection at the onset of infection but also makes room for the initiation and amplification of intracellular signals that can potentially mature to the generation of antigen-specific T cell responses and creation of immunological memory (explained in Figure 4).
Figure 4.
A schematic of maturation of pathogen containing vesicle and its outcome: After phagocytosis of pathogen there is fusion of early endosome and endoplasmic reticulum (ER) with the phagosome which helps in the maturation of the phagosome and fusion with lysosome. This is important for both innate and adaptive immunity.
As described earlier in this chapter, Wnt5A signaling aids in maintaining a steady-state expression of CD14 and IFNβ, two of the many molecules involved in innate immune defense. Although it is not exactly clear how CD14 and IFNβ fit into the program of phagocytosis in exact molecular terms, it is documented that while CD14 is instrumental in the recognition of structural motifs like lipopolysaccharide (LPS) intrinsic to certain pathogens, both CD14 and IFNβ facilitate pathogen clearance through the initiation and propagation of macrophage TLR signaling during phagocytosis and activation of immune responses [10, 13] (Figure 3). Following pathogen engulfment and phagosome formation during phagocytosis, macrophages rely mostly on endosomal and lysosomal proteases and NADPH oxidase-generated reactive oxygen species for both pathogen clearance as well as processing and presentation of antigenic peptides to MHC molecules for presentation to T lymphocytes [31, 46] and translation to memory.
3.2 Need for Wnt5A signaling-assisted actin rearrangement/assembly
At the core of all phagocytosis-related processes lies the involvement of the actin cytoskeleton through its influence on protein sorting/trafficking and intracellular organelle fusions that are crucial for the activation of phagosomal enzymes such as NADPH oxidase and phagosome maturation [31, 47]. Several cytoskeletal GTPases such as Rac1 and Disheveled, lipid rafts, and actin-nucleating proteins such as Arp2/3 and formins partake of the cytoskeletal actin modulations that accompany macrophage phagocytosis and phagosome maturation [47, 48, 49, 50]. There is evidence that Wnt5A signaling is important for such rearrangements of the actin cytoskeleton. Accordingly, Wnt5A signaling facilitates Rac1- Disheveled-lipid raft-dependent phagocytosis of bacteria and other foreign matter through modulations of the actin cytoskeleton [9]. Blockers of any of the cytoskeletal actin-associated signaling intermediates—Rac1, Disheveled, or lipid raft and cytochalasin-D, an inhibitor of actin assembly—are antagonistic to the effect of Wnt5A signaling on phagocytosis [9]. The influence of Wnt5A signaling on phagocytic uptake is usually dependent on the microbe under consideration, because while most bacterial species tested undergo facilitated phagocytic uptake by Wnt5A signaling in macrophages, phagocytic uptake of Leishmania donovani remains unaffected by it [11]. Perhaps Wnt5A-facilitated internalization encompasses distinct membranous domains depending on the availability of cognate receptors, which are not equally compatible with all microbes. That Wnt5A signaling also facilitates phagosome-lysosome fusion during phagosome maturation which is evident from the augmented appearance of lysosomal markers such as cathepsins in Wnt5A-induced phagosomes of bacteria-infected macrophages [12]. Wnt5A-facilitated alteration in cytoskeletal actin assembly that correlates with phagosome-lysosome fusion is concomitant with the killing of several microbes including bacterial pathogens (Pseudomonas aeruginosa, Streptococcus pneumoniae, etc.) and even Leishmania donovani, although it gets internalized independent of Wnt5A signaling [11, 12]. The mechanism of microbial killing is discussed at greater length in the following section of this chapter. Microbial killing is furthermore facilitated by Wnt5A-responsive NADPH oxidase activity, which is associated with cytoskeletal actin-dependent assembly of NADPH oxidase subunits [11]. Interestingly, nonpathogenic laboratory strains of bacteria that are engulfed by macrophages in increased numbers by Wnt5A signaling are not necessarily killed by it like the pathogenic bacterial strains [9, 12]. Such discrepancy in the fate of internalized microbes may be an outcome of notable differences in the interaction of different microbial components with Wnt5A-regulated cytoskeletal actin rearrangements. The interrelation between Wnt5A signaling and Ehrlichia infection is especially noteworthy in this context [51].
In light of the fact that the cytoskeletal actin-assisted phagosome is the originator and communicator of many signals generated by phagocytozed cargo-recognizing molecules such as TLR, NOD1, and NOD2 [35, 52, 53] (Figure 4), it is quite likely that the consequences of Wnt5A-assisted phagocytosis are numerous. Association of Wnt5A signaling with TLRs has already been reported [54]. Careful analysis of the consequences of such associations is important.
3.3 Role played by other Wnts and costimulatory molecules of Wnt signaling
Wnts other than Wnt5A are known to regulate macrophage phagocytosis as well. For example, the Drosophila Wnt has been reported to stimulate phagocytic uptake in the S2 cell, a macrophage-like line [55]. Moreover, Wnt1, Wnt7A, and Wnt3A have been reported as phagocytic modulators [56, 57]. The association or relation of these different modes of phagocytosis with Wnt5A signaling and cytoskeletal actin rearrangements is yet to be explored. At this point of our understanding of Wnt signaling with respect to phagocytosis, regulatory roles played by LRP5/6 and ROR, which act as co-receptors to Wnts [22, 58], remain unclear. It also remains to be seen if the influence of Wnt5A signaling on phagocytosis is in the canonical or noncanonical mode or is in fact an intermediary between the two depending on the context of infection, the available receptors, and coactivators.
4. Wnt signaling-induced actin-dependent autophagy-assisted xenophagy by macrophages and the potential link with antigen processing/presentation
4.1 Autophagy-assisted xenophagy
Several pathogenic microorganisms try to adapt to the intracellular milieu of macrophage creating a niche for their survival [59, 60, 61]. Nevertheless, as described earlier in this chapter, the host macrophage tries maneuvering elimination of infection by pathogens by several means. It has been reported that following phagocytosis of microbes by macrophages, the host autophagy machinery comes into play in the ultimate event of clearance of bacteria and other engulfed microbes (xenophagy) through coordinated alterations of the actin cytoskeleton. Autophagy involves the turnover and clearance of damaged organelles and proteins by the cell under both normal conditions as well as under stress in the maintenance of cellular homeostasis [62, 63]. During infection with pathogens, the autophagy program is often utilized for the incapacitation and eradication of engulfed pathogens [26, 64].
4.2 Role of Wnt signaling and cytoskeletal actin in autophagy-assisted xenophagy
Wnt signaling has been reported to play a significant role in the autophagy-assisted xenophagy of engulfed microbes by macrophages. Wnt5A signaling, for instance, has been documented to be an integral component of this theme in the killing of several bacterial pathogens through utilization of a Rac1-Disheveled-actin cytoskeleton circuit that involves interactions among several autophagy-associated proteins like microtubule-associated protein 1B-light chain 3B (LC3B), autophagy-related 5 (ATG5), ATG7, and Unc-51-like autophagy-activating kinase 1 (ULK1) [12]. The different nuances of Wnt5A signaling in connection with the actin cytoskeleton are depicted in Figure 5. Pathogen killing through autophagy machinery is blocked with the use of cytochalasin-D, an inhibitor of actin assembly as well as with inhibitors to Rac1 and Disheveled [12]. Although Wnt5A-assisted killing of L. donovani in macrophages has not been shown to directly involve autophagy, electron micrographs of L. donovani harboring parasitophorous vacuoles, which display distinct membranous aggregates, suggest that L. donovani containing parasitophorous vacuoles may be subjected to lysis by the host autophagy circuit activated by Wnt5A signaling [11]. The inactivation or lysis of microbe-carrying vacuoles, which happens in due course through fusion of autophagy-destined phagosome or autophagosome with the lysosome, may also be facilitated by Wnt5A signaling [12]. Although cholesterol and other lipids are known to partake of both Wnt5A signaling and actin dynamics [65, 66], at this stage much remains unknown about the specific roles of cholesterol and other lipids in the process of actin modulation during phagocytosis and autophagic clearance of bacteria and other microbes. It also remains to be seen if Wnt5A signaling during autophagy belongs strictly to the noncanonical mode or canonical mode based on the involvement of β-catenin.
Figure 5.
Schematic of Wnt5A signaling aided bacterial killing: Both autocrine and paracrine modes of Wnt5A signaling can lead to increase in phagocytosis of pathogenic bacteria. After phagocytosis, the Wnt5A mediated cytoskeletal modulation leads to fusion of early endosome and lysosome with the pathogen containing phagosome. Wnt5A signaling also activates Rac1 and Unc like kinase 1 (Ulk1) for initiation of autophagy. The subsequent steps of maturation lead to killing of pathogen in an autophagy dependent process (xenophagy).
4.3 Potential link with antigen presentation/adaptive immunity
In view of the fact that the autophagic or rather xenophagic removal of pathogens by macrophages involves reorganization and fusion of intracellular vesicles associated with at least partial lysis of pathogens, the processing and presentation of pathogen antigens to MHC molecules are a likely event during xenophagy in infected macrophages [67, 68]. Thus, autophagosome formation, autophagosome lysosome fusion, and T cell activation by the presentation of processed pathogenic antigens may prevail as a continuum during immune defense depending on the nature and degree of the infection. Given the intrinsic association of Wnt signaling with cytoskeletal dynamics and autophagy [11, 12], it is quite likely that Wnt signaling will influence the antigen processing and presentation linked with autophagy in infected macrophages. Detailed investigation in this respect, although important, remains to be documented.
5. Concluding remarks
Given the important role played by Wnt ligands in the transmission of signals associated with cytoskeletal modulation and transcriptional regulation which are part and parcel of host-pathogen communications [27, 28, 29, 69], a combination of Wnt signal transduction cascades is expected to hold a fundamental standing in the immune defense program operated by macrophages in both innate and adaptive immunity. Phagocytosis, autophagy/xenophagy (intracellular microbial killing), and a steady-state expression of immune defense molecules through transcriptional regulation appear as some of the major players of the immune defense program operated by Wnt signaling.
In respect of transcriptional regulation of immune defense molecules by steady-state Wnt5A-signaling as described in this chapter [10], it is not understood exactly what dictates the nuclear translocation of p65 and not the other NFκB isoforms for specific modes of gene expression. Additionally, how this regulation fits in with the activity of other major transcription factors like NFAT and AP1 in the macrophage is also not clearly understood. Moreover, details of the context dependence of Wnt5A signaling, wherein a certain level and mode of signal transmission will be beneficial for immune response, but excess will cause inflammation and disorder [70, 71, 72], remain largely unclear. Besides, a clear concept of how actin cytoskeleton-associated proteins such as Rac1 promote both NFκB activity as well as cytoskeletal rearrangements for phagocytosis and autophagy is yet to be achieved [10, 12]. Whether nuclear translocation of NFκB is a natural function of actin assembly or is executed by a separate pool of Rac1 associated cytoskeletal proteins is an important matter that deserves investigation.
With regard to phagocytosis and autophagy-assisted xenophagy, the molecular details of the actin rearrangements with actin binding proteins and the processing and presentation of antigens remain to be deciphered. This brings into question how different host-pathogen interactions within macrophages are guided by modulations of the actin cytoskeleton. Of special interest in this context is the interaction of the actin cytoskeleton with pathogenic mycobacteria, which thrive in self-generated niches within macrophages [60, 73]. The interrelation between different modes of Wnt signaling and mycobacterial infection, although much studied [74, 75], needs to be better understood with respect to actin dynamics. Now that Wnt5A signaling has been shown to play a major role in the regulation of actin cytoskeletal modulation and autophagy [11, 12, 76], future experiments addressing whether this can also facilitate the adaptive immune response through antigen processing and presentation may prove fruitful.
At this juncture of our understanding of Wnt signaling and immune response by macrophages, it is important to know how the different Wnt ligands operate in the regulation of immune response by the different types of macrophages that are distributed in different tissues under the varied conditions of intracellular milieu and infection. Macrophages (microglia) present in the brain and spinal cord maintain an active immune defense scheme against pathogens that affect the central nervous system. Alveolar and airway macrophages likewise protect the respiratory tract and lungs from the toxic effect of infectious agents. Peritoneal macrophages of the peritoneum and Kupffer cells of the liver also encounter and confront infectious agents for host protection. Quite naturally, the roles played by Wnt signaling in the combat mechanism of each macrophage type in its paradigm of immune defense is expected to be different at least to some extent on account of potential variations in cellular environmental cues and modes of host-pathogen interactions.
Acknowledgments
This work was supported by DBT, Government of India (BT/PR7106/MED/29/639/2012), Institutional funding (BSC0114, BSC0116). SJ was supported by the Research Scholar Fellowship from CSIR, Government of India and by The Company of Biologists, Journal of Cell Biology.
Conflict of interest
The authors declare that there is no conflict of interest.
\n',keywords:"macrophage, Wnt, phagocytosis, actin cytoskeleton, transcription, immunity",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/67817.pdf",chapterXML:"https://mts.intechopen.com/source/xml/67817.xml",downloadPdfUrl:"/chapter/pdf-download/67817",previewPdfUrl:"/chapter/pdf-preview/67817",totalDownloads:994,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:2,totalAltmetricsMentions:0,impactScore:1,impactScorePercentile:66,impactScoreQuartile:3,hasAltmetrics:0,dateSubmitted:"November 17th 2018",dateReviewed:"April 19th 2019",datePrePublished:"July 4th 2019",datePublished:"March 25th 2020",dateFinished:"June 24th 2019",readingETA:"0",abstract:"Infection with pathogenic microbes is a global threat. Macrophages play a fundamental role in promoting host resistance to deadly infections from pathogenic microbes by virtue of a well-orchestrated immune defense system. Phagocytosis and obliteration of invading pathogens by macrophages are an innate immune function that not only sustains immune homeostasis but also bolsters adaptive immune response through antigen processing and presentation. Wnt signaling, where Wnt, a secreted glycoprotein which interacts with Frizzled and ROR cell surface receptors to initiate cellular interactions, could be vital for the immune response executed and propagated by macrophages in both innate and adaptive immune responses. The goal of this chapter is to describe how Wnt signaling influences phagocytosis, autophagy, and transcriptional activation to enable the macrophage to exercise its immune response program to resist infection.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/67817",risUrl:"/chapter/ris/67817",book:{id:"8590",slug:"macrophage-activation-biology-and-disease"},signatures:"Suborno Jati and Malini Sen",authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1 Macrophages: innate and adaptive immunity",level:"2"},{id:"sec_2_2",title:"1.2 Wnt signaling",level:"2"},{id:"sec_3_2",title:"1.3 Wnt signaling in immune system",level:"2"},{id:"sec_5",title:"2. Sustenance of immune defense by macrophages through a steady state of transcriptional activation by Wnt signaling",level:"1"},{id:"sec_5_2",title:"2.1 Significance of constitutive transcriptional activation in macrophages by Wnt signaling",level:"2"},{id:"sec_6_2",title:"2.2 NF-κB transcription factors",level:"2"},{id:"sec_7_2",title:"2.3 Wnt5A signaling-mediated activation of transcription",level:"2"},{id:"sec_8_2",title:"2.4 Signaling and transcriptional activation by other Wnts",level:"2"},{id:"sec_10",title:"3. Role of Wnt signaling in macrophage phagocytosis: involvement of the actin cytoskeleton",level:"1"},{id:"sec_10_2",title:"3.1 Significance of phagocytosis",level:"2"},{id:"sec_11_2",title:"3.2 Need for Wnt5A signaling-assisted actin rearrangement/assembly",level:"2"},{id:"sec_12_2",title:"3.3 Role played by other Wnts and costimulatory molecules of Wnt signaling",level:"2"},{id:"sec_14",title:"4. Wnt signaling-induced actin-dependent autophagy-assisted xenophagy by macrophages and the potential link with antigen processing/presentation",level:"1"},{id:"sec_14_2",title:"4.1 Autophagy-assisted xenophagy",level:"2"},{id:"sec_15_2",title:"4.2 Role of Wnt signaling and cytoskeletal actin in autophagy-assisted xenophagy",level:"2"},{id:"sec_16_2",title:"4.3 Potential link with antigen presentation/adaptive immunity",level:"2"},{id:"sec_18",title:"5. 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Cholesterol-dependent actin remodeling via RhoA and Rac1 activation by the Streptococcus pneumoniae toxin pneumolysin. Proceedings of the National Academy of Sciences. 2007;104(8):2897-2902'},{id:"B66",body:'Woods A, James CG, Wang G, Dupuis H, Beier F. Control of chondrocyte gene expression by actin dynamics: A novel role of cholesterol/Ror-α signalling in endochondral bone growth. Journal of Cellular and Molecular Medicine. 2009;13(9b):3497-3516'},{id:"B67",body:'Crotzer VL, Blum JS. Autophagy and its role in MHC-mediated antigen presentation. The Journal of Immunology. 2009;182(6):3335-3341'},{id:"B68",body:'English L, Chemali M, Duron J, Rondeau C, Laplante A, Gingras D, et al. Autophagy enhances the presentation of endogenous viral antigens on MHC class I molecules during HSV-1 infection. Nature Immunology. May 2009;10(5):480'},{id:"B69",body:'Mostowy S, Shenoy AR. The cytoskeleton in cell-autonomous immunity: Structural determinants of host defence. Nature Reviews. 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Frontiers in Immunology. 26 Dec 2016;7:635'},{id:"B75",body:'Villaseñor T, Madrid-Paulino E, Maldonado-Bravo R, Urbán-Aragón A, Pérez-Martínez L, Pedraza-Alva G. Activation of the Wnt pathway by Mycobacterium tuberculosis: a Wnt–Wnt situation. Frontiers in Immunology. 1 Feb 2017;8:50'},{id:"B76",body:'Witze ES, Litman ES, Argast GM, Moon RT, Ahn NG. Wnt5a control of cell polarity and directional movement by polarized redistribution of adhesion receptors. Science. 2008;320(5874):365-369'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Suborno Jati",address:null,affiliation:'
Division of Cancer Biology and Inflammatory Disorder, CSIR-Indian Institute of Chemical Biology, Kolkata, India
Division of Cancer Biology and Inflammatory Disorder, CSIR-Indian Institute of Chemical Biology, Kolkata, India
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1. Introduction
In diabetes (DM), chronic complications related to the direct or indirect effects of prolonged hyperglycemia on the vasculature have been classified into macrovascular and microvascular complications, depending on the size of affected vessels and the pathophysiological mechanisms involved. Microvascular disease includes retinopathy, nephropathy and neuropathy.
Diabetic retinopathy, one of the first manifestations of microvascular disease, remains today, despite improvements in monitoring and treatment, one of the leading causes of blindness worldwide. Epidemiological studies estimate that approximately 40% of subjects with DM type I over 40 years of age have retinal microvascular changes, of which 8.2% exhibit impaired visual acuity [1, 2]. Both DM types are associated with impaired retinal microcirculation. After 20 years from the onset of DM, almost all patients with type 1 DM (T1DM) and over 60% of those with type 2 DM (T2DM) will be affected [3]. Furthermore, decreased vision as a result of diabetic retinopathy has a negative impact on the quality of life of patients and their ability to successfully manage DM [4].
Diabetic foot results from diabetic neuropathy and/or peripheral arterial disease and affects annually between 9.1 to 26.1 million [5]. It is a chronic disabling and progressive complication, with potential deformities, chronic ulcerations and infections. Diabetic foot ulcers (DFUs) are encountered in 15% of DM patients, of whom 15-20% reach amputations. The latter lead to increased morbidity and decreased quality of life, but also an important burden on national healthcare systems, with increased health costs and hospitalization [6, 7].
2. Diabetic retinopathy
2.1 Risk factors
2.1.1 DM duration and poor glycemic control
Diabetic retinopathy (DR) is a chronic complication associated with long DM duration and poor glycemic control, the overall incidence of DR and of vision-threatening forms of DR (VTDR) being higher in T1DM than in T2DM [8]. The United Kingdom Prospective Diabetes Study (UKPDS) showed that both the incidence and progression of DR correlate with elevated HbA1c, emphasizing the importance of good glycemic control to prevent visual impairment [9]. Every 1% decrease in HbA1c leads to a 40% reduction in the risk of developing retinopathy, a 25% reduction in the risk of progression to vision-threatening retinopathy, and a 15% reduction in the risk of blindness [10].
2.1.2 Arterial hypertension
The correlations between cardiovascular risk factors and the occurrence and evolution of DR are still a subject of study. However, there is clear evidence that the processes of arteriolosclerosis and the mechanical trauma to the vascular endothelium caused by elevated systolic and diastolic blood pressure are both cofactors in worsening DR. Some but not all studies have shown a negative impact of high blood pressure on DR [9, 11, 12]. The UKPDS has demonstrated a significant correlation between systolic arterial hypertension and DR incidence in T2DM. Thus, patients with blood pressure (BP) > 140 mmHg have a 2.8 times higher risk of developing DR than those with BP <125 mmHg. In the study of Lurbe et al. [13], in a cumulative exposure model, HbA1c and elevated diastolic BP values are predictive factors for the occurrence and progression of RD. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), diastolic BP emerged as a significant risk factor for DR progression in T1DM, but no correlations were found for systolic BP or T2DM [14, 15]. Therapeutic lowering BP was found to have a protective role on retinal lesions in several studies supporting the recommendations for tight blood pressure control to further prevent visual loss n T2DM [9, 14, 16].
2.1.3 Lipidic disorders and serum LDL
Unlike glycemic control, the role of serum lipids in DR pathogenesis is less clear. There is no parameter in the lipid profile that is strictly associated with the incidence or progression of DR. However, elevated total cholesterol, LDL-cholesterol, Apo B and Apo B/Apo A ratio are correlated with the appearance of hard exudates, these being lipoprotein extravasations in the retinal capillaries. Hadjadj et al. showed that serum triglyceride levels are correlated with the occurrence of nephropathy and retinopathy in patients with T1DM [17]. Several randomized trials confirmed that the treatment of dyslipidemia can prevent the development of DR [14, 15, 18, 19, 20, 21].
2.1.4 Genetic predisposition
Several studies have revealed that in young adults with T1DM, genetic predisposition for the development of DR is connected with the presence of HLA DR3/DR4 antigens. Furthermore, different alleles for codification of cytokines and chemokines, as well as vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)beta1 were characterized, explaining different predisposition for DR in diabetic patients. VEGF plays a key role in increased microvascular permeability and neovascularization in proliferative diabetic retinopathy. The VEGF gene is located on chromosome 6 (6p21.3) and is highly polymorphic in the promoter region, correlated with VEGF expression and activity. In a study by Buranczynska et al., the presence of the D allele at −2549 in the promoter region of the VEGF gene enhanced gene expression [22]. The DD genotype was associated with DR but not with nephropathy, suggesting a cell-specific target of the VEGF isoform. In a study of Jalal and Kalia, regarding the polymorphism of VEGF genes in India, allele A and AA genotype of rs2146323 were significantly correlated both with incidence and with severity of DR [23]. Awata et al. described C (−634) G polymorphism of VEGF gene to be related to macular edema as well as diabetic retinopathy [24]. Ray et al. identified VEGF −460 C genotype to increase VEGF basal promoter activity by 71%, leading to a 2.5 increased risk of proliferative DR [25]. TGF beta signaling is considered to have an immunosuppressive role in the retina. Disorders affecting this pathway lead, at least in experimental animal models, to loss of pericytes, microaneurysms and leakage, finding resembling diabetic retinopathy [26]. Beránek et al. found a more frequent incidence of 915G/C (R25P) polymorphism of TGF beta gene in patients with DR compared to control subjects [27].
2.1.5 Pregnancy
Hormonal alterations during pregnancy were found to be an independent risk factor both for onset and for progression of DR, especially PDR, posing many challenges regarding the management of these patients [28, 29, 30]. Another mechanism is pregnancy-induced hypertension and pre-eclampsia [31].
2.1.6 Ocular and systemic inflammation
Recent studies focus on the significance of inflammation in the developments of DR [32, 33, 34, 35, 36]. There is strong evidence that ischemia and retinal hypoxia induce release of VEGF and inflammatory molecules at the level of endothelial and glial cells. Furthermore, several studies support the idea that ocular inflammatory disorders, such as prolonged post cataract surgery healing, uveitis, keratitis, are related to DR progression [32, 33, 34, 35, 36].
There are increased evidences that chronic systemic inflammation is also related to increased risk of DR onset and progression. In an experimental animal model, recurrent exposure to systemic LPS leads to injury of capillary endothelium and in vivo thinning of the retina in hyperglycemic mice, but not in healthy controls [37]. There are clinical evidences of increased incidence of DR and PDR in long standing non-healing foot ulcer, that could be explained due to the associated chronic low-grade systemic inflammation [38, 39, 40, 41, 42].
2.1.7 Antidiabetic treatment and macular edema
The correlations between antidiabetic mellitus medication and the risk of macular edema is still a subject of research. In a comprehensive systematic review and meta-analyses, Zhu and col. found that insulin use, as well as thiazolinedione (TZD) and meglitinide might increase the risk of macular edema, metformin has no statistically significant effect, while the use of sulfonylureas seems to have a protective role [43]. The physiopathological mechanisms are not completely understood, but experimental studies indicate that insulin and TZD may induce changes in retinal flow and increased expression of VEGF and breakdown of retinal-vascular barrier [43, 44, 45, 46].
2.2 Pathophysiology
The pathological changes that lead to diabetic retinopathy are attributable to 3 main factors:
small vessel wall damage:
changes in blood flow
alterations in platelet function
2.2.1 Lesions in small vessel wall
Microvascular changes in the retinal capillaries are due to chronic hyperglycemia by different mechanisms, such as:
2.2.1.1 Aldose-reductase and intracellular polyol pathway
Aldose reductase is an enzyme that converts glucose to sorbitol, which induces osmotic stress by intracellular accumulation. In animal models, this phenomenon leads to microaneurysmal dilatations of the vascular wall, basal membrane thickening and loss of the pericytes [47]. However, experimental studies of treatment with aldose reductase inhibitors have not obtained satisfactory clinical results.
2.2.1.2 Advanced glycosylated end products (AGEs)
Chronic hyperglycemia leads to non-enzymatic glycation or glycoxidation of proteins, resulting in accumulation of AGEs. This process affects both intra- and extracellular proteins, resulting in functional impairment. Deposits of AGEs in the extracellular matrix and subendothelial space lead to permanent alterations of intercellular junctions, monocyte migration and activation of nuclear factor (NF)-κB along with activation of pro-inflammatory pathways [48, 49]. In experimental models, increased AGEs accumulation is associated with loss of pericytes and microaneurysm formation in retinal capillaries [50].
2.2.1.3 Oxidative stress and ROS
Hyperglycemia induces mitochondrial dysfunction and endoplasmic reticulum stress, with increased production of free radicals and reactive oxygen species (ROS) accumulation [49]. These degrade lipids, proteins and ribonucleic acid (RNA) chains. Furthermore, experimental studies have proved a “hyperglycemic memory”: in subjects with long periods of poor glycemic control, reversal of hyperglycemia fails to normalize increased oxidative activity in the retina [51]. Treatment with antioxidants and vitamin E alleviates endothelial dysfunction, but does not prevent the onset and progression of DR and other microvascular complications. Isolated experimental blockade of each of these pathways does not stop retinal microvascular damage, suggesting that the effects of hyperglycemia are manifested at the cellular and extracellular levels. Recently, experimental and clinical studies have demonstrated that inflammation biomarkers and pathways play a significant role in the aggravation of lesions and the evolution towards retinal neovascularization. A large array of cytokines and chemokines were found in increased concentrations in patients with DM, both in ocular samples and in serum: interleukin (Il)1beta, Il 2, 4, 6, 8, TNFalfa and (monocyte chemoattractant protein) MCP-1 [38, 42, 52, 53, 54]. Recent works have revealed that the TXNIP/NLRP3 Inflammasome activation pathways may contribute to pathologic neovascularization encountered in advanced stages of PDR [50, 54, 55].
2.2.1.4 Nitric oxide (NO) deficiency
Hyperglycemia induces decreased synthesis and increased consumption of NO by multiple pathways: activation of protein kinase C (PKC) in endothelial cells, oxidation of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) via aldose reductase pathway, and non-enzymatic production of superoxide by AGEs. NO plays key roles in microcirculation, by regulation of arteriolar tone, platelet stabilization and preventing leukocyte adherence at the vascular wall. Decreased local levels of NO promotes vasoconstriction, microvascular occlusions and secondary retinal ischemia.
2.2.2 Changes in blood flow and platelet function
General changes in blood favor small vessel obstructions with secondary retinal ischemia:
increased hematocrit and blood viscosity related to high liver synthesis of fibrinogen and alfa2 globulins
more rigid erythrocytes, with increased tendency to thrombosis
increased platelet adhesion and aggregation
activation of peripheral leukocytes, increased adherence to endothelial cells via beta-2 integrin expression and synthesis of mediators of inflammation
2.2.2.1 Pigmented Epitelium Derived Factor (PEDF) decrease and retinal neurodegeneration
PEDF is a trophic factor expressed by a multitude of retinal cells, an antagonist of VEGF. It decreases vascular permeability and plays an antioxidant role, protecting retinal cells from ROS. In the experimental setting, PEDF is decreased in aqueous and vitreous humor, early in preclinical stages of DR. The pathogenic mechanisms are supposed to be related with decreased insulin, as well as increased toxic mediators, such as glutamate. These early changes may induce mild changes in color vision, contrast sensitivity, visual field and electroretinogram oscillatory potentials [56, 57, 58, 59, 60].
All these molecular mechanisms may lead to:
alteration of tight junctions in endothelial cells, compromising the blood-retinal barrier, increasing extravasation of fluid in the retinal space and the formation of lipoprotein exudates and retinal edema
loss of pericytes, with the appearance of focal vascular dilations and microaneurysms
thickening, hyalinization of the basement membranes, with loss of elasticity of the vascular wall and autoregulatory capacity. This, together with the alterations of blood flow and platelets, favors microvascular occlusions, with the appearance of ischemic, hypoxic retinal areas.
The first areas affected by thrombosis and ischemia are in the middle retinal periphery, and the answer is to release a range of mediators, of which the key role is played by VEGF, which promotes retinal neovascularization and interruption of blood flow in many areas (optical disc, macula, iridocorneal angle and iris). The response to retinal hypoperfusion, a maladaptive protective mechanism, leads to the appearance of fragile new vessels, prone to repeated bleeding and leakage, ultimately destroying normal retinal architecture (Figure 1).
Figure 1.
Pathogenesis of diabetic retinopathy.
2.3 Clinical manifestations of DR
Fundus examination documents the presence and severity of retinal lesions. Clinical signs include:
Microaneurysms: tiny round red dots, typically located initially temporal to the fovea; sometimes hard to be differentiated from dot hemorrhages in ophthalmoscopy; they are best shown by fluorescein angiography
Retinal hemorrhages: a) “dot-blot” hemorrhages result from the venous end of the capillaries and are located in the middle layer of the retina; b) “flame-shaped” hemorrhages arise from pre-capillary arterioles and are located more superficially in the retinal nerve fiber layer
Retinal edema: elevated, white-greyish appearance of the involved area; may be a consequence of leakage and fluid accumulation or of retinal ischemia (intracellular retinal edema). When foveal region is involved, it may assume a cystoid appearance and fluorescein angiography reveal a flower-petal pattern
Hard exudates: these are well delineated, small, bright yellowish retinal lesions, formed by extravasated lipoproteins and lipid-filled macrophages and are mainly located in the outer plexiform layer. They are considered a sign of current or previous macular edema. When located in the macular region, they tend to organize in a circinate manner. They could resorb spontaneously months after the leakage is stopped, otherwise, chronic leakage leads to enlargement of the exudates and cholesterol accumulation.
“Cotton wool” spots: these are small, whitish, fluffy superficial lesions, that cover the underlying retinal vessels and bear the significance of focal retinal ischemia and infarction. They are composed by neuronal debris and can disappear in time by autolysis and phagocytosis.
Venous loops and venous beading (VB): these frequently occur adjacent to areas of nonperfusion and bear the significance of increasing retinal ischemia
Intraretinal microvascular abnormalities (IRMA): these are arteriolo-venous shunts, bypassing the capillary bed, and are considered an indicator of capillary occlusion and retinal ischemia. Together with VB, they are considered the most significant predictor of progression to PDR [58].
Neovessels: these are thin, with a single cell layer wall, extremely fragile, with a lace-like appearance and may be situated at the surface of the optic disk or elsewhere, in general at the periphery of the areas of non-perfusion. They can be best evidenced by fluorescein angiography and optical coherence tomography (OCT).
2.4 Staging of DR
Dr is classically referred as: non-proliferative (NPDR) and proliferative (PDR). The classification is determined by the presence of retinal neovascularization. Recent Guidelines of International Council of Ophthalmology for Diabetic Eye Care recommends the following staging system, based on findings encountered in ophthalmoscopy, to be used in clinical practice (Table 1).
DR
Findings on Dilated Ophthalmoscopy
No apparent DR
No abnormalities
Mild NPDR*
Microaneurysms only
Moderate NPDR
Microaneurysms + other signs:
dot and blot hemorrhages
hard exudates
cotton wool spots
Severe NPDR
Moderate NPDR with any of the following:
Intraretinal hemorrhages ≥20 in each quadrant;
Definite venous beading (VB) in 2 quadrants;
Intraretinal microvascular abnormalities (IRMA) in 1 quadrant;
and no signs of proliferative retinopathy
PDR*
Severe non-proliferative DR + one of the followings:
Neovascularization
Vitreous/preretinal hemorrhage
Table 1.
International Classification of Diabetic Retinopathy [57].
*NPDR: non proliferative diabetic retinopathy; *PDR: proliferative diabetic retinopathy
The ICO guidelines also refer to the location, extension of the diabetic macular edema (DME), as it is an important cause of decreased vision in DR, even in the absence of neovessels. Central involved DME is considered to be an area of retinal thickening in the macula that does involve the central subfield zone (of 1 mm in diameter).
2.5 Clinical forms of DR associated with high risk of vision loss
Diabetic maculopathy is the most frequent cause of decreased vision encountered in patients with T2DM. It can be manifest in every stage of the DR and represents the involvement of the fovea by hard exudates, macular edema due to fluid extravasation or by macular ischemia. In early stages, the loss of vision is mild; however, if untreated, it can may to permanent photoreceptor damage.
DME is considered clinically significant if [61, 62, 63]:
located at or within 500 μm of the center of the macula
hard exudates at or within 500 μm of the center if associated with thickening of adjacent retina
the area of retinal thickening is larger than one optic disc area and is located within 1 disc diameter of the center of macula
2.5.1 Advanced diabetic ocular disease
Advanced diabetic disease can remain asymptomatic for a long period of time, due to slow proliferation of the retinal neovessels and their location, usually in mid-periphery. It consists of retinal neovessels that grow into elevated fibrovascular membranes that enter the vitreous body, leading to serious complications: vitreous hemorrhage and retinal detachment [62]. Proliferation of the abnormal vessels at the level of iris and iridocorneal angle led to neovascular glaucoma, with poor clinical outcomes. Ophthalmological periodical screening is extremely important in early identifying and referral to laser therapy. In advanced stages, serious complications appear and the vision loss is irreversible.
Diabetic maculopathy is the most frequent cause of decreased vision encountered in patients with T2DM.
2.6 Diagnosis of DR
Early detection of DR depends on educating DM subjects, as well as their families, friends, and health care providers about the importance of regular eye examination. This holds true for asymptomatic subjects as well.
Initial ophthalmological examination in a patient with suspected/confirmed DR should include the following:
Visual acuity
Measurement of intraocular pressure (IOP), due to the possible risk of developing neovascular glaucoma
Slit-lamp exam +/- gonioscopy if iris neovascularization is observed or IOP is elevated
Fundus examination with dilated pupil
A variety of imaging techniques are useful to detect, classify and monitor DR, as well as efficacy of treatment: fundus photography, fluorescein angiography, optic coherence tomography (OCT) and OCT angiography.
2.6.1 Ophthalmoscopy and Fundus Photography
Currently, the two most sensitive methods are retinal photography and slit-lamp examination through dilated pupils. Direct ophthalmoscopy by ophthalmologists or trained technicians yields 80% sensitivity and >90% specificity [64]. It is cheap and is considered the method of choice. Fundus photography has the advantage of creating a permanent record, and for that reason, it is the preferred method for retinopathy assessment (Figures 2–4).
Figure 2.
“Background” diabetic retinopathy: few dot hemorrhages (blue arrows) (Dr. Ana Dascalu’s private collection, Emergency University Hospital Bucharest, Ophthalmology Department).
Figure 3.
Retinophotography: Severe NPRD: multiple dot and blot hemorrhages, hard exudates, cotton wool spots (blue arrows), macular edema, VB (green arrow) and IRMA (black arrows) (Dr. Daniela Stana’s private collection, Emergency University Hospital Bucharest, Ophthalmology Department, PhD thesis).
Figure 4.
Incipient PDR: large ischemic area situated temporally to the macular region, with hard exudates, dots hemorrhages, venous loops, IRMA and intraretinal neovessels; in the mid periphery, pigmented lesions post laser photocoagulation (Dr Ana Dascalu’s private collection, Emergency University Hospital Bucharest, Ophthalmology Department).
2.6.2 Fluorescein angiography
Fluorescein angiography is an invasive, costly, and time-consuming technique but is a sensitive method to detect vascular changes due to rupture of the inner and outer blood retinal barrier in the course of DR [63, 65, 66]. The retinal vasculature is visualized with great accuracy: the examiner may identify tiny microaneurysms and differentiate between microaneurysms (hyperfluorescent) and punctiform hemorrhage (hypofluorescence by masking effect). It is an indispensable exploration before planning different laser treatment, for example to distinguish retinal edema by leakage (which appears white due to dye accumulation) from ischemic retinal edema (which appears as hypofluorescent). In the latter case, the application of laser impacts is not recommended because it leads to exacerbation of retinal ischemia (Figure 5).
Figure 5.
Fluorescein Angiography: Severe NPRD: numerous microaneurysms (hyperfluorescent dots), areas of non-perfusion (hypofluorescent, blue arrows), venous loops and IRMA, with diffuse leakage (hyperfluorescent, red arrow) (Dr Daniela Stana’s private collection, PhD Thesis, Emergency University Hospital Bucharest, Ophthalmology Department).
2.6.3 Optical coherence tomography (OCT) and OCT-angiography (OCT-A)
OCT is a completely non-invasive, reproducible and quantifiable. It provides high-resolution images of the retinal layers, choroid, vitreous gel, and the vitreoretinal interface and has become the gold standard for diagnosis, assessment of treatment response, and follow-up up of patients with diabetic macular edema.
OCT angiography (OCTA) is a new non-invasive imaging technique that employs motion contrast imaging to high-resolution volumetric blood flow information, rapidly generating images similar to angiographic images [63, 65, 66, 67]. It provides a highly detailed view of the retinal vasculature, which allows for accurate delineation of the foveal avascular zone (FAZ) and detection of subtle microvascular abnormalities, including FAZ enlargement, areas of capillary non-perfusion, and intraretinal cystic spaces [66]. The possibility of detecting microvascular changes in diabetic eyes before the presence of visible microaneurysms may have important implications in the future. In this sense, OCTA could be able to quickly identify subjects at risk of DM (Figures 6 and 7).
Figure 6.
Optical coherence tomography (OCT) macular change analysis (before and 1 month after intravitreal anti = VEGF): hard exudates intraretinal edema with disorganization of the normal foveal architecture; macular and paramacular temporal edema decreases in area and height (Dr. Ana Dascalu’s private collection, Emergency University Hospital Bucharest, Ophthalmology Department).
Figure 7.
OCT-A: (a) enlargement of FAZ and perifoveolar area of microvascular abnormalities; (b) mild FAZ enlargement, multiple microaneurysms (Dr. Daniela Stana’s private collection, PhD Thesis, Emergency University Hospital Bucharest, Ophthalmological Department).
2.7 Treatment
2.7.1 Primary prevention
Follow-up of patients with DR involves the ophthalmologist and the diabetologist. Extensive studies in large groups of diabetic patients have shown the beneficial role of strict control of blood glucose, hypertension and dyslipidemia in both preventing and slowing the progression of DR. DCCT and UKPDS showed the importance of a good glycemic control in preventing microvascular damage in diabetes [68, 69]. Furthermore, every decrease with 10 mm Hg of systolic blood pressure is associated with a reduction of 35% in the risk of DR progression and of 50% in the risk of blindness [69]. Maintaining HbA1c below 7.0% (53 mmol/mol) and a systolic blood pressure below 140 mmHg is considered a realistic therapeutic target in clinical practice. Currently, the recommended serum lipid levels in DM are an optimal LDL cholesterol concentration of <100 mg/dl and desirable triglycerides levels of <150 mg/dl [69, 70, 71, 72].
2.7.2 Retinopathy screening
DR remains clinically silent, a long period of time until damages become irreversible. Ophthalmologic monitoring of DM subjects is essential. Frequency of screening depends on the severity of DR and the co-existence of risk factors. The follow-up schedule recommended by the ICO (International Council of Ophthalmology) Guidelines for Diabetic Eye Care is presented in Table 2 [61].
DR staging
Follow-up Schedule for ophthalmologists
Therapy
No apparent DR
1-2 years
Observation
Mild NPDR
6-12 months
Observation
Moderate NPDR
3-6 month
Observation
Severe NPDR
<3 months;
Pan-retinal photocoagulation should be considered
Proliferative DR
<1 month;
Pan-retinal photocoagulation
Stable (Treated) PDR
6-12 months
Observation
Diabetic Macular Edema severity
Follow-up Schedule for management by ophthalmologists
Noncentral-involved DME
3-6 month;
Focal laser photocoagulation should be considered
Central-involved DME
1-3 month;
Focal laser photocoagulation/ anti- VEGF therapy should be considered
Stable DME
3-6 month
Observation
Table 2.
ICO Guidelines for Diabetic Eye Care: screening and follow-up schedule for diabetic retinopathy.
2.7.3 Laser photocoagulation
2.7.3.1 Classical laser
Laser therapy has been used in DR for over 60 years and remains the mainstay of treating the ischemic retina. Applied early in severe NPDR and PDR, laser therapy leads to the prevention/regression of neovascularization and to the remission of retinal edema. Clinical studies confirm the effectiveness of laser photocoagulation by reducing vision loss by approximately 50% in patients with PDR. It is based on application of 1000-2000 laser shots, lasting 100 milliseconds, 200-250 mW of power with a size of 200-500 micrometers at the level of the middle and extreme periphery of the retina, spaced at a distance by a spot diameter, in order to destroy the VEGF-secreting ischemic retina. Immediate complications are related to eye discomfort (tingling sensation/low-intensity pain) and mild ocular inflammation (caused by retinal burns). For this reason, it is recommended to space the laser photocoagulation in 3-4 sessions. In the long run, potential complications include hemeralopia, “fan shaped” visual field changes, or even concentric narrowing of the visual field through widening of scars and subretinal fibrosis. Other less frequent side effects are membrane injury, with secondary choroidal neovascularization, damage of ciliary nerves with permanently mydriasis and loss of accommodation, uveal effusion, angle closure glaucoma, serous retinal detachment, and vitreous hemorrhage [73, 74, 75].
2.7.3.2 Multispot laser
This technique allows the delivery of laser shots in a much shorter time and in a semi-automatic manner. These are much finer and at a lower intensity, threshold or subthreshold, causing lesser heat and consequently inflammation in the pigmented retinal epithelium. Clinical studies have shown that the effectiveness of the method is similar to classical laser, but fewer complications are encountered regarding retinal scarring and the impact on the visual field.
2.7.3.3 Laser photocoagulation in diabetic macular edema (DME)
In the case of exudative non-central DME, laser treatment may be considered as an alternative or in combination with intravitreal injections with anti-VEGF. In this case, the laser spots are finer, with a size of 50-100 μm, and lower energy. Laser treatment is inefficient in the case of ischemic macular edema, and so fluorangiography is necessary before therapeutic planning. In the early treatment diabetic retinopathy study (ETDRS) study, when comparing laser photocoagulation with no treatment, there was a decrease in DME from 24% to 12% after 3 years follow-up, while visual acuity improved in only 3% of patients [76].
2.7.4 Intravitreal anti-VEGF
Clinical and experimental studies have revealed increased VEGF concentration in ocular samples early in the evolution of DR, documenting its role both in increased vascular permeability and in vascular proliferation. Hence, anti-VEGF agents were used first in the treatment of DME and later in PDR management [77] (Table 3).
Description of the molecule
FDA approval
Dose
Pegaptanib (Macugen; Eyetech Inc, Cedar Knolls, NJ, USA)
RNA aptamer that binds to the heparin binding site of the VEGF-A165 isomer
For wet age related macular degeneration only
0.3 mg /0.09ml
Bevacizumab (Avastin; Genentech, San Francisco, CA, USA)
Ranibizumab (Lucentis; Genentech, San Francisco, CA, USA/Novartis Ophthalmics, Basel, Switzerland)
Recombinant fragment of the humanized anti-VEGF monoclonal antibody; increased binding affinity for all VEGF isoforms
Yes
0.3 or 0.5 mg in 0.05 mL
Aflibercept (Eylea; Regeneron, Tarrytown, NY, USA)
Recombinant fusion protein of the binding domains of human VEGF-R1 and VEGF-R2, fused with the Fc domain of human IgG1 bind VEGF with greater affinity compared to other anti VEGF and prevent activation of VEGF-R
Yes
2mg/0.05mL
Table 3.
Anti VEGF agents used in DME treatment.
Clinical studies showed that Pegaptanib is the least effective in preventing neovascularization. Comparative studies between bevacizumab, ranibizumab and aflibercept found that they are all effective to decrease DME. However, aflibercept is most powerful in subjects with worse visual acuity [77, 78]. Still, the effect of intravitreal anti- VEGF is temporary and intravitreal therapy should be repeated according to clinical outcome.
2.7.5 Intravitreal steroids
In cases of DME resistant to anti-VEGF therapy after 3 monthly injections, intravitreal triamcinolone injection or fluocinolone are a therapeutic alternative to reduce DME and improve vision [79]. Their main untoward effects are cataract and transient increase of intraocular pressure.
2.7.6 Surgical management of DR
Vitreoretinal surgery is crucial in managing advanced DR, in order to mitigate visual loss. Its main indications include vitreous hemorrhage interfering with photocoagulation, tractional and combined tractional and rhegmatogenous retinal detachment, dense premacular hemorrhage and DME with with vitreo-macular traction [80]. The objectives of surgical removal of the vitreous (vitrectomy) include removal of vitreous opacity (usually blood) and/or fibrovascular proliferation, relieving retinal traction, achieving retinal reattachment, and allowing completion of scatter laser photocoagulation. A large case series showed that sight threatening complications are rare and in approximately 90% of cases, vision is improved or stabilized [81]. Vitrectomy may also be beneficial for maculopathy when traction from the vitreous gel contributes to fluid accumulation.
3. Diabetic foot ulcers (DFUs)
3.1 Risk factors
The main risk factors of DFUs include DM duration and high HbA1c [82, 83, 84, 85, 86, 87, 88]. The EURO-Diab group has identified hypertension, smoking and lipid disorders (hypertriglyceridemia, hypercholesterolemia) as additional risk factors [82, 83]. In Western countries, the male sex appears to be more commonly affected, with a risk ratio of 1.6. The co-existence of other microvascular complications (DR, nephropathy) increases the risk of DFUs.
Precipitating trauma is important. However, history of trauma is only identified in 48% of patients with DFUs. By contrast, foot injury without an apparent cause usually results from repeated minor injuries by inappropriate footwear [88, 89, 90]. Amin and Doupis have estimated that 45-60% of DFUs are mainly due to neuropathy, while 45% of DFUs are due to both diabetic neuropathy and peripheral arterial disease [87]. Like DR, diabetic neuropathy is also a very frequent DM complication and its prevalence increases with DM duration [90]. The other important driver of DFUs is ischemia from peripheral arterial disease (PAD). Visual impairment, foot deformities and past history of DFU also increase the risk of DFUs [85, 86].
3.2 Pathophysiology
The underlying mechanisms of DFUs include diabetic neuropathy, PAD and infection.
Diabetic neuropathy may affect the motor, sensory and autonomic nerves. Thickening of the basement membranes, endothelial hyperplasia in the vasa nervorum lead to thinning of the vascular lumen and secondary ischemia [90, 91]. On the other hand, metabolic disorders caused by chronic hyperglycemia, with the formation of AGEs, polyol pathways, increased oxidative stress levels and enzymatic activation of PKC also have direct toxic effects on nerve fibers.
Autonomic neuropathy causes arteriolo-venular shunts with secondary decreased blood flow in capillaries, but also anhidrosis, resulting in dry skin, thin, prone to cracking and ulceration. Sensory neuropathy leads to sensory (inability to feel warm/cold, pain, pressure), rendering the foot prone to undetected acute or chronic traumas [90, 91]. Motor neuropathy leads to imbalance between plantar flexors and extensors, with characteristic deformities, such as hammer toe, claw toe etc, and leading to high planter pressures in some small foot areas [92, 93, 94].
PAD leads to lower-extremity ischemia. In diabetes, it is usually located in the infra-popliteal arteries, less so at the iliofemoral level [89, 95]. Ischemia portends even more ominous outcomes [91, 96].
Pesently, micro and macrocirculatory disorders are considered not as separate entities, but more as a continuum in DM [97], neovascularization of vasa vasorum, with secondary hemorrhages and platelet aggregation facilitating the progression of atherosclerosis and intraluminal obstruction.
DFUs are frequently infected. The most common germs involved are staphylococci and streptococci, but deep infections are usually polymicrobial including gram positive, gram negative and even anaerobic germs [98, 99]. Chronic hyperglycemia and chronic hypoxia predispose to severe infections [99].
3.2.1 Clinical signs-staging systems
DFU represents any full-thickness ulcer below the ankle in DM. The initial signs and symptoms depend on the pathophysiological mechanism involved (neuropathy and/or PAD). Subjects with diabetic neuropathy are usually initially asymptomatic, but a minority of them may later develop neuropathic symptoms (numbness, paresthesia, lancinating or burning pain) with nocturnal exacerbation. In the event of PAD, intermittent claudication or even ischemic rest pain and gangrene may develop (Figure 8).
Figure 8.
Distal toe gangrene and extensive infection and inflammation at the level of the forefoot and mid foot (Dr. Dragos Serban’s private collection).
Usually, DFUs develop in an area exposed to increased pressure, with a non-healing tendency, often neglected in early stages due to diminished pain sensation. In the vent of infection, signs of local inflammation may be added (redness, swelling, pain, pus secretion etc).
Several staging systems were developed in order to characterize the pathogenic pathway and the severity and extension of ulcer. The International Working Group on the Diabetic Foot Risk Classification System (IWGDF) refers mainly at the severity of neuropathy and coexistence or not of the peripheral ischemia [100], while the Wagner classification describes the extension and depth [101] (Tables 4 and 5).
Patient history is necessary to provide information on DM duration, glycemic control, associated risk factors and any prior lesions/amputations.
Clinical examination should look for skin disorders, foot deformities, nail lesions, blisters etc. also be documented. It must also include an evaluation of neuropathic deficits, PAD and infection. Signs of limb threatening infection include bullae, ecchymoses, soft tissue crepitus and rapid spread of infection [102, 103].
Evaluation of sensory neuropathy is very important to establish whether the patient has lost the protective sensation, making him prone to accidental trauma. Hot/cold discrimination, pain perception, light touch and vibration perception, as well as protective sensation must be tested [95, 96, 97, 98, 99]. The latter is best assessed by the 10 g Semmes Weinstein monofilament or the measurement of the vibration perception threshold (VPT) with a neurothesiometer [93, 94, 95, 102, 103]. Tendon reflexes and muscular strength are also a part of the examination [95, 96, 97, 98, 99]. Finally, sudomotor dysfunction (reduced sweat production) is best examined by the Neuropad indicator test, which is based on a colour change from blue to pink [96, 97]. Indeed, this test has recently been identified as an independent risk factor of DFUs at 5 years [104].
3.3.1.1 Peripheral neuropathy screening
Evaluation of bilateral sensorial neuropathy in clinical practice requires neurological trained specialist and electrophysiological tests, which an increased burden on the national healthcare systems. In order to better select the patients who are more probably affected by neuropathy, a simpler tool was developed in 1994, namely Michigan Neuropathy Screening Instrument (MNSI) [105, 106]. It comprises a 2-step evaluation: first, a 15-item self-administered questionnaire that is scored by summing abnormal responses, followed by lower extremity examination (deformities, non-healing ulcers), assessment of ankle reflexes and of vibratory sensation. According to Herman and col., a score of more than 4 should raise the suspicion of peripheral sensorial neuropathy [106].
3.3.1.2 Peripheral arterial disease
Documenting the presence and the severity of ischemia is extremely important. Examination includes: a) palpation of peripheral pulses at the dorsalis pedis and the posterior tibial arteries; b) measurement of the ankle-brachial index (ABI) by a Doppler device [99, 100]. ABI evaluates the ratio of systolic arterial pressure at the brachial over the ankle level [107, 108]. Normal values range between 0.9-1.3, while values exceeding 1.3 point to calcified, uncompressible arteries, in which case the test cannot be used [99]. Similarly, one may measure the toe-brachial index (TBI), given that small digital arteries are rarely calcified: TBI<0.7 confirms the diagnosis of PAD [108]. More sophisticated evaluation (ultrasound, angiography) are used when necessary, especially to guide interventional treatment [95, 96, 97, 98, 99].
3.3.1.3 Assessment of the severity of the infection
If infection is suspected, it is best to use a tissue culture to identifying pathogens [109, 110]. X-rays, computed tomography and magnetic resonance imaging are used to evaluate bone infection or abscess formation, as well as to guide surgical treatment [86, 96, 97].
3.4 DFU management
3.4.1 Prophylaxis of DFU
Patients at risk of DFU should be managed by an interdisciplinary approach, including a diabetologist, a vascular surgeon, a podiatrist, a general surgeon, an orthopedic surgeon, a plastic surgeon and other specialists [82, 94, 102]. Stringent glycemic control is essential both in primary prevention of DFU and in ensuring wound healing. Management of high blood pressure and dyslipidemia is also important [86, 96, 97].
High-risk patients need education about the importance of wearing comfortable footwear, rigorous local hygiene, keeping feet dry and avoiding possible causes of local trauma (including barefoot walking) and frequent self-examinations [86, 96, 97]. Callus debridement, off-loading, and correct treatment of nail pathology are simple but extremely efficient measures for the prevention of foot ulcers [86, 96, 97]. LEADER trial suggests that treatment with liraglutide in patients with type 2 diabetes and at high risk of CV events did not increase the risk of DFU events and was associated with a significantly lower risk of DFU-related amputations compared with placebo [109].
3.4.2 Therapeutic management of DFUs: main principles
Management of DFUs is aimed at correcting the pathogenic triad of neuropathy, PAD and infection. Off-loading with appropriate footwear and/or casts, debridement of callus and/or necrotic tissue, revascularization (by-pass grafting or intraluminal angioplasty) and infection control are the top priorities [86, 96, 97]. These may be aided by special dressings, skin substitutes, growth factors and other modalities [111, 112, 113, 114, 115, 116]. Special care must be taken to recognize and promptly deal with emergencies requiring surgery and other urgent interventions [117].
4. Conclusions
Diabetic retinopathy and diabetic foot ulcer are both disabling complications, with a significant impact on the patient\'s quality of life and healthcare systems [118]. Microvascular impairment and local inflammation play a significant role in the both pathological mechanisms. Prevention and early detection, along with optimal control of blood sugar, hyperlipemia and arterial hypertension are the most efficacious measures against these fearful complications.
Conflict of interest
Peter Kempler has received honoraria from and/or is an advisory member of the following companies: Ely Lilly, Novo Nordisk, Novartis, Miro, Boehringer-Ingelheim, Woerwag-Pharma, Pfizer, Sanofi, Di-Care Zrt., 77 Elektronika Kft., Teva, Astra-Zeneca.
\n',keywords:"microvascular complications, diabetic retinopathy, risk factors, ophthalmoscopy, angiography, laser photocoagulation, diabetic foot, diabetic neuropathy, treatment",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/75635.pdf",chapterXML:"https://mts.intechopen.com/source/xml/75635.xml",downloadPdfUrl:"/chapter/pdf-download/75635",previewPdfUrl:"/chapter/pdf-preview/75635",totalDownloads:336,totalViews:0,totalCrossrefCites:2,dateSubmitted:"September 22nd 2020",dateReviewed:"February 9th 2021",datePrePublished:"March 10th 2021",datePublished:"September 22nd 2021",dateFinished:"March 10th 2021",readingETA:"0",abstract:"Diabetic retinopathy and diabetic foot ulcer are the most frequent, but also the most disabling complications of diabetes mellitus, with a sinister impact on patients’ quality of life. Microvascular changes related to the deleterious effect of chronic hyperglycemia play an important role in the pathophysiology of both clinical entities by multiple molecular pathways. Vision-threating diabetic retinopathy may be treated by laser photocoagulation, anti-vascular endothelial growth factor (VEGF) agents and vitreoretinal surgery. Diabetic foot lesions are best treated by revascularization if needed, off-loading, infection control and therapeutic adjuncts (e.g. special dressings). Treatment should ideally be offered by a multidisciplinary expert team. Prevention and early detection, along with adequate control of glucose, lipids and arterial hypertension are of paramount importance to avoid and mitigate these fearful complications.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/75635",risUrl:"/chapter/ris/75635",signatures:"Ana Maria Dascalu, Dragos Serban, Nikolaos Papanas, Peter Kempler, Manfredi Rizzo, Daniela Stana, Gabriela Roman and Anca Pantea Stoian",book:{id:"9517",type:"book",title:"Type 2 Diabetes",subtitle:"From Pathophysiology to Cyber Systems",fullTitle:"Type 2 Diabetes - From Pathophysiology to Cyber Systems",slug:"type-2-diabetes-from-pathophysiology-to-cyber-systems",publishedDate:"September 22nd 2021",bookSignature:"Anca Pantea Stoian",coverURL:"https://cdn.intechopen.com/books/images_new/9517.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83881-904-0",printIsbn:"978-1-83881-903-3",pdfIsbn:"978-1-83881-905-7",isAvailableForWebshopOrdering:!0,editors:[{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",slug:"anca-pantea-stoian",fullName:"Anca Pantea Stoian"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"37582",title:"Dr.",name:"Nikolaos",middleName:null,surname:"Papanas",fullName:"Nikolaos Papanas",slug:"nikolaos-papanas",email:"papanasnikos@yahoo.gr",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",fullName:"Anca Pantea Stoian",slug:"anca-pantea-stoian",email:"ancastoian@yahoo.com",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",institution:{name:"Carol Davila University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"303184",title:"Dr.",name:"Manfredi",middleName:null,surname:"Rizzo",fullName:"Manfredi Rizzo",slug:"manfredi-rizzo",email:"manfredi.rizzo@unipa.it",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/303184/images/system/303184.png",institution:{name:"University of Palermo",institutionURL:null,country:{name:"Italy"}}},{id:"323765",title:"Prof.",name:"Gabriela",middleName:null,surname:"Roman",fullName:"Gabriela Roman",slug:"gabriela-roman",email:"groman@umfcluj.ro",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"333677",title:"Assistant Prof.",name:"Ana Maria",middleName:null,surname:"Dascalu",fullName:"Ana Maria Dascalu",slug:"ana-maria-dascalu",email:"ana.dascalu@umfcd.ro",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"349820",title:"Dr.",name:"Dragos",middleName:null,surname:"Serban",fullName:"Dragos Serban",slug:"dragos-serban",email:"dragos.serban@umfcd.ro",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"349821",title:"Dr.",name:"Daniela",middleName:null,surname:"Stana",fullName:"Daniela Stana",slug:"daniela-stana",email:"dr.danielastana@yahoo.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"352506",title:"Prof.",name:"Peter",middleName:null,surname:"Kempler",fullName:"Peter Kempler",slug:"peter-kempler",email:"kempler.peter@med.semmelweis-univ.hu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Diabetic retinopathy",level:"1"},{id:"sec_2_2",title:"2.1 Risk factors",level:"2"},{id:"sec_2_3",title:"2.1.1 DM duration and poor glycemic control",level:"3"},{id:"sec_3_3",title:"2.1.2 Arterial hypertension",level:"3"},{id:"sec_4_3",title:"2.1.3 Lipidic disorders and serum LDL",level:"3"},{id:"sec_5_3",title:"2.1.4 Genetic predisposition",level:"3"},{id:"sec_6_3",title:"2.1.5 Pregnancy",level:"3"},{id:"sec_7_3",title:"2.1.6 Ocular and systemic inflammation",level:"3"},{id:"sec_8_3",title:"2.1.7 Antidiabetic treatment and macular edema",level:"3"},{id:"sec_10_2",title:"2.2 Pathophysiology",level:"2"},{id:"sec_10_3",title:"2.2.1 Lesions in small vessel wall",level:"3"},{id:"sec_10_4",title:"2.2.1.1 Aldose-reductase and intracellular polyol pathway",level:"4"},{id:"sec_11_4",title:"2.2.1.2 Advanced glycosylated end products (AGEs)",level:"4"},{id:"sec_12_4",title:"2.2.1.3 Oxidative stress and ROS",level:"4"},{id:"sec_13_4",title:"2.2.1.4 Nitric oxide (NO) deficiency",level:"4"},{id:"sec_15_3",title:"2.2.2 Changes in blood flow and platelet function",level:"3"},{id:"sec_15_4",title:"2.2.2.1 Pigmented Epitelium Derived Factor (PEDF) decrease and retinal neurodegeneration",level:"4"},{id:"sec_18_2",title:"2.3 Clinical manifestations of DR",level:"2"},{id:"sec_19_2",title:"2.4 Staging of DR",level:"2"},{id:"sec_20_2",title:"2.5 Clinical forms of DR associated with high risk of vision loss",level:"2"},{id:"sec_20_3",title:"2.5.1 Advanced diabetic ocular disease",level:"3"},{id:"sec_22_2",title:"2.6 Diagnosis of DR",level:"2"},{id:"sec_22_3",title:"2.6.1 Ophthalmoscopy and Fundus Photography",level:"3"},{id:"sec_23_3",title:"2.6.2 Fluorescein angiography",level:"3"},{id:"sec_24_3",title:"2.6.3 Optical coherence tomography (OCT) and OCT-angiography (OCT-A)",level:"3"},{id:"sec_26_2",title:"2.7 Treatment",level:"2"},{id:"sec_26_3",title:"2.7.1 Primary prevention",level:"3"},{id:"sec_27_3",title:"Table 2.",level:"3"},{id:"sec_28_3",title:"2.7.3 Laser photocoagulation",level:"3"},{id:"sec_28_4",title:"2.7.3.1 Classical laser",level:"4"},{id:"sec_29_4",title:"2.7.3.2 Multispot laser",level:"4"},{id:"sec_30_4",title:"2.7.3.3 Laser photocoagulation in diabetic macular edema (DME)",level:"4"},{id:"sec_32_3",title:"Table 3.",level:"3"},{id:"sec_33_3",title:"2.7.5 Intravitreal steroids",level:"3"},{id:"sec_34_3",title:"2.7.6 Surgical management of DR",level:"3"},{id:"sec_37",title:"3. Diabetic foot ulcers (DFUs)",level:"1"},{id:"sec_37_2",title:"3.1 Risk factors",level:"2"},{id:"sec_38_2",title:"3.2 Pathophysiology",level:"2"},{id:"sec_38_3",title:"Table 4.",level:"3"},{id:"sec_40_2",title:"3.3 Diagnosis",level:"2"},{id:"sec_40_3",title:"3.3.1 Clinical examination",level:"3"},{id:"sec_40_4",title:"3.3.1.1 Peripheral neuropathy screening",level:"4"},{id:"sec_41_4",title:"3.3.1.2 Peripheral arterial disease",level:"4"},{id:"sec_42_4",title:"3.3.1.3 Assessment of the severity of the infection",level:"4"},{id:"sec_45_2",title:"3.4 DFU management",level:"2"},{id:"sec_45_3",title:"3.4.1 Prophylaxis of DFU",level:"3"},{id:"sec_46_3",title:"3.4.2 Therapeutic management of DFUs: main principles",level:"3"},{id:"sec_49",title:"4. Conclusions",level:"1"},{id:"sec_53",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Ciulla TA, Amador AG, Zinman B. Diabetic retinopathy and diabetic macular edema: pathophysiology, screening, and novel therapies. 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Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, Romania
Ophthalmology Department, Emergency University Hospital Bucharest, Romania
Diabetes Centre-Diabetic Foot Clinic, Second Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, Greece
Diabetes, Nutrition and Metabolic Diseases Department, “Carol Davila” University of Medicine, Romania
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They are considered as the biotechnologically valuable bacteria that are exploited for its secondary metabolite production. Approximately, 10,000 bioactive metabolites are produced by Actinobacteria, which is 45% of all bioactive microbial metabolites discovered. Especially Streptomyces species produce industrially important microorganisms as they are a rich source of several useful bioactive natural products with potential applications. Though it has various applications, some Actinobacteria have its own negative effect against plants, animals, and humans. On this context, this chapter summarizes the general characteristics of Actinobacteria, its habitat, systematic classification, various biotechnological applications, and negative impact on plants and animals.",book:{id:"5056",slug:"actinobacteria-basics-and-biotechnological-applications",title:"Actinobacteria",fullTitle:"Actinobacteria - Basics and Biotechnological Applications"},signatures:"Ranjani Anandan, Dhanasekaran Dharumadurai and Gopinath\nPonnusamy Manogaran",authors:[{id:"48914",title:"Dr.",name:"Dharumadurai",middleName:null,surname:"Dhanasekaran",slug:"dharumadurai-dhanasekaran",fullName:"Dharumadurai Dhanasekaran"}]},{id:"35104",title:"Restriction Fragment Length Polymorphism Analysis of PCR-Amplified Fragments (PCR-RFLP) and Gel Electrophoresis - Valuable Tool for Genotyping and Genetic Fingerprinting",slug:"restriction-fragment-length-polymorphism-analysis-of-pcr-amplified-fragments-pcr-rflp-and-related-te",totalDownloads:34054,totalCrossrefCites:6,totalDimensionsCites:26,abstract:null,book:{id:"1770",slug:"gel-electrophoresis-principles-and-basics",title:"Gel Electrophoresis",fullTitle:"Gel Electrophoresis - Principles and Basics"},signatures:"Henrik Berg Rasmussen",authors:[{id:"114068",title:"Dr.",name:"Henrik",middleName:null,surname:"Rasmussen",slug:"henrik-rasmussen",fullName:"Henrik Rasmussen"}]},{id:"50471",title:"Molecular Mechanisms of Skin Aging and Rejuvenation",slug:"molecular-mechanisms-of-skin-aging-and-rejuvenation",totalDownloads:5110,totalCrossrefCites:6,totalDimensionsCites:13,abstract:"The aging process in the skin is complex and influenced by more intrinsic and extrinsic factors than any other body organ. The effects of these two types of factors overlap for the most part. The combined effects of these two aging processes also affect dermal matrix alterations. The main clinical signs of skin aging include wrinkling and irregular pigmentation, which are influenced by a combination of intrinsic and extrinsic (e.g., UV radiation, heat, smoking, and pollutants) factors. Histologically, collagen decreases, and the dermis is replaced by abnormal elastic fibers as a cause of wrinkle formation through the loss of skin elasticity. There have been numerous studies of skin aging performed to elucidate the underlying molecular mechanisms and to develop various antiaging therapeutics and preventive strategies. We summarized the molecular mechanisms and treatments of skin aging. Mainly UV radiation induces ROS formation and DNA damage, leading to increased production of MMPs and decreased production of collagen in keratinocytes and fibroblasts, which reflect the central aspects of skin aging. Besides UV radiation exposure, extrinsic factors including tobacco smoking, exposure to environmental pollutants, infrared radiation, and heat contribute to premature skin aging. Like UV radiation, these factors cause ROS formation and increase expression of MMPs, thus accelerating skin aging by inducing extracellular matrix (ECM) degradation. Accumulated collagen fibrils inhibit the new collagen synthesis and account for the further degradation of the ECM through this positive feedback loop. Accumulating evidence for molecular mechanisms of skin aging should provide clinicians with an expanding spectrum of therapeutic targets in the treatment of skin aging.",book:{id:"5258",slug:"molecular-mechanisms-of-the-aging-process-and-rejuvenation",title:"Molecular Mechanisms of the Aging Process and Rejuvenation",fullTitle:"Molecular Mechanisms of the Aging Process and Rejuvenation"},signatures:"Miri Kim and Hyun Jeong Park",authors:[{id:"47695",title:"Prof.",name:"Hyun Jeong",middleName:null,surname:"Park",slug:"hyun-jeong-park",fullName:"Hyun Jeong Park"},{id:"185767",title:"Prof.",name:"Miri",middleName:null,surname:"Kim",slug:"miri-kim",fullName:"Miri Kim"}]},{id:"62731",title:"An Introductory Chapter: Secondary Metabolites",slug:"an-introductory-chapter-secondary-metabolites",totalDownloads:9738,totalCrossrefCites:33,totalDimensionsCites:52,abstract:null,book:{id:"6670",slug:"secondary-metabolites-sources-and-applications",title:"Secondary Metabolites",fullTitle:"Secondary Metabolites - Sources and Applications"},signatures:"Durairaj Thirumurugan, Alagappan Cholarajan, Suresh S.S. 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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:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. 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. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. 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He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. 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Saxena",hash:"d92a4085627bab25ddc7942fbf44cf05",volumeInSeries:2,fullTitle:"Current Perspectives in Human Papillomavirus",editors:[{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Bacterial Infectious Diseases",value:3,count:2},{group:"subseries",caption:"Parasitic Infectious Diseases",value:5,count:4},{group:"subseries",caption:"Viral Infectious Diseases",value:6,count:7}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:2},{group:"publicationYear",caption:"2021",value:2021,count:4},{group:"publicationYear",caption:"2020",value:2020,count:3},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:1}],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:"27",type:"subseries",title:"Multi-Agent Systems",keywords:"Collaborative Intelligence, Learning, Distributed Control System, Swarm Robotics, Decision Science, Software Engineering",scope:"Multi-agent systems are recognised as a state of the art field in Artificial Intelligence studies, which is popular due to the usefulness in facilitation capabilities to handle real-world problem-solving in a distributed fashion. The area covers many techniques that offer solutions to emerging problems in robotics and enterprise-level software systems. Collaborative intelligence is highly and effectively achieved with multi-agent systems. Areas of application include swarms of robots, flocks of UAVs, collaborative software management. Given the level of technological enhancements, the popularity of machine learning in use has opened a new chapter in multi-agent studies alongside the practical challenges and long-lasting collaboration issues in the field. It has increased the urgency and the need for further studies in this field. We welcome chapters presenting research on the many applications of multi-agent studies including, but not limited to, the following key areas: machine learning for multi-agent systems; modeling swarms robots and flocks of UAVs with multi-agent systems; decision science and multi-agent systems; software engineering for and with multi-agent systems; tools and technologies of multi-agent systems.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/27.jpg",hasOnlineFirst:!1,hasPublishedBooks:!1,annualVolume:11423,editor:{id:"148497",title:"Dr.",name:"Mehmet",middleName:"Emin",surname:"Aydin",slug:"mehmet-aydin",fullName:"Mehmet Aydin",profilePictureURL:"https://mts.intechopen.com/storage/users/148497/images/system/148497.jpg",biography:"Dr. Mehmet Emin Aydin is a Senior Lecturer with the Department of Computer Science and Creative Technology, the University of the West of England, Bristol, UK. His research interests include swarm intelligence, parallel and distributed metaheuristics, machine learning, intelligent agents and multi-agent systems, resource planning, scheduling and optimization, combinatorial optimization. Dr. Aydin is currently a Fellow of Higher Education Academy, UK, a member of EPSRC College, a senior member of IEEE and a senior member of ACM. In addition to being a member of advisory committees of many international conferences, he is an Editorial Board Member of various peer-reviewed international journals. 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