Selected population-based studies estimating incidence and prevalence of diabetic foot ulcers (adapted from LeMaster and Reiber, 2006) [7]
\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"6038",leadTitle:null,fullTitle:"Wireless Sensor Networks - Insights and Innovations",title:"Wireless Sensor Networks",subtitle:"Insights and Innovations",reviewType:"peer-reviewed",abstract:"Wireless sensor networks (WSNs) have emerged as a phenomenon of the twenty-first century with numerous kinds of sensor being developed for specific applications. The origins of WSNs can, however, be traced back to the early days of connectivity between computers and their peripherals. Work with distributed sensor networks is evidenced in the literature during the latter part of the 1970s, continuing in functionality increases in the 1980s and 1990s. As a configuration of independent devices in a data communications network, WSNs are now pre-eminent as working solutions to numerous precision data collection situations where software control of instruments and routing protocols are needed. In this book, the authors have chosen a selection of specific topics relating to WSNs: their design, development, implementation and function. Some operating topics are addressed such as power management, data interchange protocols, instrument reliability and system security. Other topics are more application oriented, where particular hardware and software configurations are described to deliver system solutions for specific needs. All are clearly written with considerable detail relating to each of the issues addressed by the authors. Each of the chapters provides a rationale for the topic being covered and some general WSN details where appropriate. The citations used in the chapters are comprehensively referred to, which adds depth to the information being presented.",isbn:"978-953-51-3562-3",printIsbn:"978-953-51-3561-6",pdfIsbn:"978-953-51-4635-3",doi:"10.5772/67388",price:119,priceEur:129,priceUsd:155,slug:"wireless-sensor-networks-insights-and-innovations",numberOfPages:208,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"e63cb7f71bc1fed54902b371cbe21a2a",bookSignature:"Philip Sallis",publishedDate:"October 4th 2017",coverURL:"https://cdn.intechopen.com/books/images_new/6038.jpg",numberOfDownloads:21284,numberOfWosCitations:35,numberOfCrossrefCitations:59,numberOfCrossrefCitationsByBook:2,numberOfDimensionsCitations:89,numberOfDimensionsCitationsByBook:2,hasAltmetrics:1,numberOfTotalCitations:183,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 20th 2017",dateEndSecondStepPublish:"March 13th 2017",dateEndThirdStepPublish:"June 9th 2017",dateEndFourthStepPublish:"September 7th 2017",dateEndFifthStepPublish:"November 6th 2017",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"10893",title:"Prof.",name:"Philip John",middleName:null,surname:"Sallis",slug:"philip-john-sallis",fullName:"Philip John Sallis",profilePictureURL:"https://mts.intechopen.com/storage/users/10893/images/5060_n.jpg",biography:"Dr. Philip Sallis is a Professor in Computer Science at the Auckland University of Technology in New Zealand. His research over the past 10 years has predominantly been in the field of GeoComputation with a focus on instrumentation and measurement, particularly in the context of agrometeorological applications of wireless sensor networks for data acquisition and subsequent dynamical systems modelling of micro-climates. In recent years, this work has extended to other areas of environmental sensor applications such as autonomous vehicles, pest control and sensory assistance for children with learning disabilities. With an academic career spanning more than 40 years, he has held university positions in England, Australia and New Zealand, including the senior roles as Head of School, Dean and Deputy Vice Chancellor. He is currently a Pro-Vice Chancellor assisting in the academic leadership of the Auckland University of Technology.",institutionString:null,position:null,outsideEditionCount:null,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"Auckland University of Technology",institutionURL:null,country:{name:"New Zealand"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"565",title:"Wireless Communication Network",slug:"computer-science-and-engineering-wireless-communication-network"}],chapters:[{id:"56900",title:"Mobile Wireless Sensor Networks: An Overview",doi:"10.5772/intechopen.70592",slug:"mobile-wireless-sensor-networks-an-overview",totalDownloads:2730,totalCrossrefCites:23,totalDimensionsCites:30,hasAltmetrics:0,abstract:"Mobile wireless sensor networks (MWSNs) have emerged and shifted the focus from the typical static wireless sensor networks to networks with mobile sensor nodes that are capable to sense the various types of events. Also, they can change their position frequently in a specific sensing area. The applications of the MWSNs can be widely divided into time-driven, event-driven, on-demand and tracking based applications. Mobile sensor node architecture, residual energy utilization, mobility, topology, scalability, localization, data collection routing, Quality of Service (QoS), etc., are the key factors to design an energy efficient MWSNs for some specific purpose. This chapter deals with an overview of the MWSNs and a few significant phenomena to design an energy efficient MWSNs to the large-scale environment.",signatures:"Velmani Ramasamy",downloadPdfUrl:"/chapter/pdf-download/56900",previewPdfUrl:"/chapter/pdf-preview/56900",authors:[{id:"206195",title:"Dr.",name:"Velmani",surname:"Ramasamy",slug:"velmani-ramasamy",fullName:"Velmani Ramasamy"}],corrections:null},{id:"56541",title:"Routing Protocols for Wireless Sensor Networks (WSNs)",doi:"10.5772/intechopen.70208",slug:"routing-protocols-for-wireless-sensor-networks-wsns-",totalDownloads:5817,totalCrossrefCites:19,totalDimensionsCites:28,hasAltmetrics:0,abstract:"Wireless sensor networks (WSNs) are achieving importance with the passage of time. Out of massive usage of wireless sensor networks, few applications demand quick data transfer including minimum possible interruption. Several applications give importance to throughput and they have not much to do with delay. It all rest on the applications desires that which parameter is more favourite. The knowledge of network structure and routing protocol is very important and it should be appropriate for the requirement of the usage. In the end a performance analysis of different routing protocols is made using a WLAN and a ZigBee based Wireless Sensor Network.",signatures:"Noman Shabbir and Syed Rizwan Hassan",downloadPdfUrl:"/chapter/pdf-download/56541",previewPdfUrl:"/chapter/pdf-preview/56541",authors:[{id:"206600",title:"Mr.",name:"Noman",surname:"Shabbir",slug:"noman-shabbir",fullName:"Noman Shabbir"},{id:"206601",title:"Mr.",name:"Syed Rizwan",surname:"Hassan",slug:"syed-rizwan-hassan",fullName:"Syed Rizwan Hassan"}],corrections:null},{id:"56295",title:"Gradient Descent Localization in Wireless Sensor Networks",doi:"10.5772/intechopen.69949",slug:"gradient-descent-localization-in-wireless-sensor-networks",totalDownloads:1314,totalCrossrefCites:3,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Meaningful information sharing between the sensors of a wireless sensor network (WSN) necessitates node localization, especially if the information to be shared is the location itself, such as in warehousing and information logistics. Trilateration and multilateration positioning methods can be employed in two-dimensional and three-dimensional space respectively. These methods use distance measurements and analytically estimate the target location; they suffer from decreased accuracy and computational complexity especially in the three-dimensional case. Iterative optimization methods, such as gradient descent (GD), offer an attractive alternative and enable moving target tracking as well. This chapter focuses on positioning in three dimensions using time-of-arrival (TOA) distance measurements between the target and a number of anchor nodes. For centralized localization, a GD-based algorithm is presented for localization of moving sensors in a WSN. Our proposed algorithm is based on systematically replacing anchor nodes to avoid local minima positions which result from the moving target deviating from the convex hull of the anchors. We also propose a GD-based distributed algorithm to localize a fixed target by allowing gossip between anchor nodes. Promising results are obtained in the presence of noise and link failures compared to centralized localization. Convergence factor issues are discussed, and future work is outlined.",signatures:"Nuha A.S. Alwan and Zahir M. Hussain",downloadPdfUrl:"/chapter/pdf-download/56295",previewPdfUrl:"/chapter/pdf-preview/56295",authors:[{id:"58431",title:"Prof.",name:"Zahir",surname:"Hussain",slug:"zahir-hussain",fullName:"Zahir Hussain"},{id:"205727",title:"Prof.",name:"Nuha A. S.",surname:"Alwan",slug:"nuha-a.-s.-alwan",fullName:"Nuha A. S. Alwan"}],corrections:null},{id:"56751",title:"A Novel Hybrid Methodology Applied Optimization Energy Consumption in Homogeneous Wireless Sensor Networks",doi:"10.5772/intechopen.70207",slug:"a-novel-hybrid-methodology-applied-optimization-energy-consumption-in-homogeneous-wireless-sensor-ne",totalDownloads:1164,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"A wireless sensor network’s lifetime is influenced directly by the sensors power management that composes the network. The models applied to the problem aims to optimize the energy usage managing the sensors activation in time intervals, activating only the minimum number of sensors respecting the coverage and connectivity restrictions. However, this problem’s class has a significant computational complexity and many applications. It is necessary to implement methodologies to find the optimal solution, increasing the network’s size, becoming closer to the real ones. This research’s objective is to present a method based on a Partition Heuristic aggregating the Generate and Solve method, improving the results, and increasing the network’s instances size, while maintaining the flexibility and reliability when applied to the homogeneous wireless sensors networks with coverage and connectivity restrictions.",signatures:"Plácido Rogerio Pinheiro, Álvaro Meneses Sobreira Neto, Alexei\nBarbosa Aguiar and Pedro Gabriel Calíope Dantas Pinheiro",downloadPdfUrl:"/chapter/pdf-download/56751",previewPdfUrl:"/chapter/pdf-preview/56751",authors:[{id:"115439",title:"Dr.",name:"Plácido",surname:"Pinheiro",slug:"placido-pinheiro",fullName:"Plácido Pinheiro"},{id:"210269",title:"Mr.",name:"Pedro",surname:"Pinheiro",slug:"pedro-pinheiro",fullName:"Pedro Pinheiro"},{id:"213547",title:"Ms.",name:"Alvaro",surname:"Sobreira Neto",slug:"alvaro-sobreira-neto",fullName:"Alvaro Sobreira Neto"},{id:"213578",title:"MSc.",name:"Alexei",surname:"Aguiar",slug:"alexei-aguiar",fullName:"Alexei Aguiar"}],corrections:null},{id:"56762",title:"WSN in Conservation Management",doi:"10.5772/intechopen.70383",slug:"wsn-in-conservation-management",totalDownloads:1512,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"A wireless sensor network (WSN) utilising a mesh configuration is a cost-effective and labour-saving solution for remotely monitoring traps and tracking devices used in conservation management. The unintentional introduction of stoats and rats into a once pristine ecosystem has resulted in the devastation of large parts of New Zealand’s native flora and fauna. Other equally harmful mammalian species, including possum, for their fur, and domestic cats, were introduced intentionally. Abundant vegetation and a lack of predators lead to rampant population growth, further exacerbating their destructive impact. Effective monitoring, trapping and control of mammalian pests have proven difficult, time-consuming and expensive, primarily relying on socially controversial methods such as aerially delivered toxins. Despite advances in technology, costly and time-intensive manual checking of lures, toxins, traps and tracking devices remains a limiting factor. Together with WSN-based remote monitoring capability, these advances look set to have a significant impact. This chapter discusses opportunities for WSN in conservation management. It outlines a mammalian pest management project utilising a series of possum-specific self-resetting traps. A WSN designed for remotely monitoring possum trap activity is detailed, and the process for reconfiguring and presenting field-trial data via alpha-numeric and graphical user interface applications is described.",signatures:"Akbar Ghobakhlou and Shane Inder",downloadPdfUrl:"/chapter/pdf-download/56762",previewPdfUrl:"/chapter/pdf-preview/56762",authors:[{id:"209937",title:"Dr.",name:"Akbar",surname:"Ghobakhlou",slug:"akbar-ghobakhlou",fullName:"Akbar Ghobakhlou"},{id:"214817",title:"Dr.",name:"Shane",surname:"Inder",slug:"shane-inder",fullName:"Shane Inder"}],corrections:null},{id:"56452",title:"Recent Advances on Implantable Wireless Sensor Networks",doi:"10.5772/intechopen.70180",slug:"recent-advances-on-implantable-wireless-sensor-networks",totalDownloads:1642,totalCrossrefCites:5,totalDimensionsCites:6,hasAltmetrics:1,abstract:"Implantable electronic devices are undergoing a miniaturization age, becoming more efficient and yet more powerful as well. Biomedical sensors are used to monitor a multitude of physiological parameters, such as glucose levels, blood pressure and neural activity. A group of sensors working together in the human body is the main component of a body area network, which is a wireless sensor network applied to the human body. In this chapter, applications of wireless biomedical sensors are presented, along with state-of-the-art communication and powering mechanisms of these devices. Furthermore, recent integration methods that allow the sensors to become smaller and more suitable for implantation are summarized. For individual sensors to become a body area network (BAN), they must form a network and work together. Issues that must be addressed when developing these networks are detailed and, finally, mobility methods for implanted sensors are presented.",signatures:"Hugo Dinis and Paulo M. Mendes",downloadPdfUrl:"/chapter/pdf-download/56452",previewPdfUrl:"/chapter/pdf-preview/56452",authors:[{id:"206606",title:"Ph.D. Student",name:"Hugo",surname:"Dinis",slug:"hugo-dinis",fullName:"Hugo Dinis"},{id:"206910",title:"Prof.",name:"Paulo M.",surname:"Mendes",slug:"paulo-m.-mendes",fullName:"Paulo M. Mendes"}],corrections:null},{id:"56436",title:"Low-Cost Energy-Efficient Air Quality Monitoring System Using Wireless Sensor Network",doi:"10.5772/intechopen.70138",slug:"low-cost-energy-efficient-air-quality-monitoring-system-using-wireless-sensor-network",totalDownloads:2259,totalCrossrefCites:5,totalDimensionsCites:10,hasAltmetrics:0,abstract:"Due to rapid industrialization and urbanization, Mauritius is witnessing an unprecedented increase in air pollution. The release of hazardous gases such as carbon monoxide and sulphur dioxide are not only harmful to the health of the population but are also causing irreversible impact to the environment. Currently, there are only two fixed air quality monitoring units on the island and therefore, air pollution cannot be monitored in real-time. The objective of this chapter is to describe the implementation of a low-cost and energy-efficient air quality monitoring system using wireless sensor network (WSN) that can be easily deployed in highly polluted areas of Mauritius. A Hierarchical Based Genetic Algorithm (HBGA) is proposed to address the issue of sensor nodes with limited energy. Based on hierarchical routing and genetic algorithm, HBGA has been designed to extend the lifetime of the network by minimizing the energy consumption. The proposed air quality monitoring system uses an air quality index that can be easily interpreted. The evaluation results confirm the potential of the proposed system for real-time temporal and spatial monitoring of air quality. Moreover, it possible for the general public to have access to the air quality monitoring results in real time.",signatures:"Kavi Kumar Khedo and Vishwakarma Chikhooreeah",downloadPdfUrl:"/chapter/pdf-download/56436",previewPdfUrl:"/chapter/pdf-preview/56436",authors:[{id:"28763",title:"Associate Prof.",name:"Kavi",surname:"Khedo",slug:"kavi-khedo",fullName:"Kavi Khedo"},{id:"206500",title:"Mr.",name:"Vishwakarma",surname:"Chikhooreeah",slug:"vishwakarma-chikhooreeah",fullName:"Vishwakarma Chikhooreeah"}],corrections:null},{id:"56752",title:"Modern Clustering Techniques in Wireless Sensor Networks",doi:"10.5772/intechopen.70382",slug:"modern-clustering-techniques-in-wireless-sensor-networks",totalDownloads:2442,totalCrossrefCites:2,totalDimensionsCites:6,hasAltmetrics:0,abstract:"Wireless sensor networks (WSNs) are employed in various applications from healthcare to military. Due to their limited, tiny power sources, energy becomes the most precious resource for sensor nodes in such networks. To optimize the usage of energy resources, researchers have proposed several ideas from diversified angles. Clustering of nodes plays an important role in conserving energy of WSNs. Clustering approaches focus on resolving the conflicts arising in effective data transmission. In this chapter, we have outlined a few modern energy-efficient clustering approaches to improve the lifetime of WSNs. The proposed clustering methods are: (i) fuzzy-logic-based cluster head election, (ii) efficient sleep duty cycle for sensor nodes, (iii) hierarchical clustering, and (iv) estimated energy harvesting. Classical clustering approaches such as low energy adaptive clustering hierarchy (LEACH) and selected contemporary clustering methods are considered for comparing the performance of proposed approaches. The proposed modern clustering approaches exhibit better lifetime compared to the selected benchmarked protocols.",signatures:"I.S. Akila, S.V. Manisekaran and R. Venkatesan",downloadPdfUrl:"/chapter/pdf-download/56752",previewPdfUrl:"/chapter/pdf-preview/56752",authors:[{id:"205909",title:"Dr.",name:"I.S.",surname:"Akila",slug:"i.s.-akila",fullName:"I.S. Akila"},{id:"207190",title:"Dr.",name:"S.V.",surname:"Manisekaran",slug:"s.v.-manisekaran",fullName:"S.V. Manisekaran"},{id:"207192",title:"Dr.",name:"R.",surname:"Venkatesan",slug:"r.-venkatesan",fullName:"R. Venkatesan"}],corrections:null},{id:"56523",title:"Fuzzy Adaptive Setpoint Weighting Controller for WirelessHART Networked Control Systems",doi:"10.5772/intechopen.70179",slug:"fuzzy-adaptive-setpoint-weighting-controller-for-wirelesshart-networked-control-systems",totalDownloads:1167,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Gain range limitation of conventional proportional‐integral‐derivative (PID) controllers has made them unsuitable for application in a delayed environment. These controllers are also not suitable for use in a Wireless Highway Addressable Remote Transducer (WirelessHART) protocol networked control setup. This is due to stochastic network‐induced delay and uncertainties such as packet dropout. The use of setpoint weighting strategy has been proposed to improve the performance of the PID in such environments. However, the stochastic delay still makes it difficult to achieve optimal performance. This chapter proposes an adaptation to the setpoint weighting technique. The proposed approach will be used to adapt the setpoint weighting structure to variation in WirelessHART network‐induced delay through fuzzy inference. Result comparison of the proposed approach with both setpoint weighting and proportional‐integral (PI) control strategy shows improved setpoint tracking and load regulation. For the first‐, second‐ and third‐order systems considered, analysis of the results in the time domain shows that in terms of overshoot, undershoot, rise time, and settling times, the proposed approach outperforms both the setpoint weighting and the PI controller. The approach also shows faster recovery from disturbance effect.",signatures:"Sabo Miya Hassan, Rosdiazli Ibrahim, Nordin Saad, Vijanth Sagayan\nAsirvadam, Kishore Bingi and Tran Duc Chung",downloadPdfUrl:"/chapter/pdf-download/56523",previewPdfUrl:"/chapter/pdf-preview/56523",authors:[{id:"206524",title:"MSc.",name:"Sabo",surname:"Hassan",slug:"sabo-hassan",fullName:"Sabo Hassan"},{id:"206525",title:"Dr.",name:"Rosdiazli",surname:"Ibrahim",slug:"rosdiazli-ibrahim",fullName:"Rosdiazli Ibrahim"},{id:"206529",title:"Dr.",name:"Nordin",surname:"Saad",slug:"nordin-saad",fullName:"Nordin Saad"},{id:"206530",title:"Dr.",name:"Vijanth Sagayan",surname:"Asirvadam",slug:"vijanth-sagayan-asirvadam",fullName:"Vijanth Sagayan Asirvadam"},{id:"206532",title:"Mr.",name:"Tran",surname:"Chung",slug:"tran-chung",fullName:"Tran Chung"},{id:"206540",title:"Ph.D. Student",name:"Kishore",surname:"Bingi",slug:"kishore-bingi",fullName:"Kishore Bingi"}],corrections:null},{id:"56824",title:"A Hybrid Sink Repositioning Technique for Data Gathering in Wireless Sensor Networks",doi:"10.5772/intechopen.70335",slug:"a-hybrid-sink-repositioning-technique-for-data-gathering-in-wireless-sensor-networks",totalDownloads:1242,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Wireless sensor network (WSN) is a wireless network that consists of spatially distributed autonomous devices using sensors to cooperatively investigate physical or environmental conditions. WSN has a hundreds or thousands of nodes that can communicate with each other and pass data from one node to another. Energy can be supplied to sensor nodes by batteries only and they are configured in a harsh environment in which the batteries cannot be charged or recharged simply. Sensor nodes can be randomly installed and they autonomously organize themselves into a communication network. The main constraint in wireless sensor networks is limited energy supply at the sensor nodes so it is important to deploy the sink at a position with respect to the specific area which is the area of interest; which would result in minimization of energy consumption. Sink repositioning is very important in modern day wireless sensor network since repositioning the sink at regular interval of time can balance the traffic load thereby decreasing the failure rate of the real time packets. More attention needs to be given on the Sink repositioning methods in order to increase the efficiency of the network. Existing work on sink repositioning techniques in wireless sensor networks consider only static and mobile sink. Not much importance is given to the hybrid sink deployment techniques. Multiple sink deployment and sink mobility can be considered to perform sink repositioning. Precise information of the area being monitored is needed to offer an ideal solution by the sink deployment method but this method is not a realistic often. To reallocate the sink, its odd pattern of energy must be considered. In this chapter a hybrid sink repositioning technique is developed for wireless sensor network where static and mobile sinks are used to gather the data from the sensor nodes. The nodes with low residual energy and high data generation rate are categorized as urgent and the nodes with high residual energy and low data generation rate are categorized as non-urgent. Static sink located within the center of the network collects the data from the urgent nodes. A relay is selected for each urgent sensor based on their residual energy. The urgent sensor sends their data to the static sink through these relay. Mobile sink collects the data from the non-urgent sensors. The performance of the proposed technique is compared with mobile base station placement scheme mainly based on the performance according to the metrics such as average end-to-end delay, drop, average packet delivery ratio and average energy consumption. 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Every emergency physician has seen diabetic foot ulcers in their nascent stage, at a stage requiring minimal treatment with good follow-up, when they require aggressive treatment, and at a stage when amputation is a foregone conclusion. Ulcerations of the foot in diabetics are common; most diabetics will get them. Not only are they disabling, they also are limb- and life-threatening. [1]
It is estimated that approximately 15% of diabetic people world-wide will at some stage develop diabetic foot ulceration. The prevalence of active foot ulceration varies from approximately 1% in certain European and North American studies to more than 11% in reports from some African countries (table 1). Although there have been many developments in recent years which encourage optimism for future improvement in diabetic foot care, there is still much to be done; the recent data from the Netherlands show that with a concerted team approach, it is possible to increase the numbers of foot clinics with the provision of podiatry services by more than 100%. However, many countries still lack proper podiatry and specialist nursing provision and there remains much to be done in the next millennium to improve the lot of the diabetic patient with foot problems. [2,3] In general, in diabetic patients, the incidence of foot ulcers ranges from 1.0% to 4.1%, and the incidence of lower-extremity amputations ranges from 2.1 to 13.7 per 1000. [4-6]
Rith-Najarian | \n\t\t\tChippewa Indian residents with diabetes | \n\t\t\t266 | \n\t\t\t- | \n\t\t\t0.6 (Non-neuropathic subjects) | \n\t\t\tFull thickness plantar foot lesion | \n\t\t\tRetrospective review of medical records/clinical examinations | \n\t\t
Walters | \n\t\t\tRegistered patients with diabetes from 10 UK general practices | \n\t\t\t1077 | \n\t\t\t2.9 (current) 7.4 (History of ulcer) | \n\t\t\t- | \n\t\t\tWagner grade ≥1 foot lesion | \n\t\t\tDirect examination and structured interview | \n\t\t
Moss | \n\t\t\tPopulation-based samples of persons with diabetes | \n\t\t\t1834 | \n\t\t\t10.6 (History of ulcers at baseline) | \n\t\t\t2.2 | \n\t\t\t??? | \n\t\t\tMedical history questionnaire administered at baseline and 4 years later | \n\t\t
Kumar | \n\t\t\tType 2 diabetes patients registered in three UK cities | \n\t\t\t811 | \n\t\t\t1.4 (Current) 5.3 (History of ulcer) | \n\t\t\t- | \n\t\t\tWagner grade ≥1 foot lesion | \n\t\t\tDirect exam by trained observers (current), and structured interview (history of ulcer) | \n\t\t
Abbott | \n\t\t\tRandomized controlled trial cohort | \n\t\t\t1035 | \n\t\t\t- | \n\t\t\t3.6 | \n\t\t\tFull-thickness lesion requiring hospital treatment | \n\t\t\tDirect examination at least every 13 weeks | \n\t\t
Ramsey | \n\t\t\tRegistered adult type 1 or 2 diabetes patients in a large HMO (1992-1995) | \n\t\t\t8905 | \n\t\t\t- | \n\t\t\t1.9 | \n\t\t\tICD-codes: 707.1 (ulcer of lower leg) | \n\t\t\tMedical billing record audit | \n\t\t
Abbott | \n\t\t\tRegistered type 1 and 2 diabetes patients in six UK districts | \n\t\t\t9710 | \n\t\t\t1.7 (Current) | \n\t\t\t2.2 | \n\t\t\tWagner grade ≥1 foot lesion | \n\t\t\tClinical examination (plus chart review) | \n\t\t
Muller | \n\t\t\t1993-1998 registered type 2 diabetes patients | \n\t\t\t3827 person-years | \n\t\t\t- | \n\t\t\t2.1 | \n\t\t\tFull-thickness skin loss on the foot | \n\t\t\tAbstracted medical records | \n\t\t
Centers for Disease Control and Prevention (US) | \n\t\t\tUS BRFSS respondents with diabetes, 2000-2002 | \n\t\t\tNS | \n\t\t\t11.8 (History of ulcer) | \n\t\t\t- | \n\t\t\tFoot sore that did not heal for >4 weeks | \n\tRandom-digit-dialed telephone interview | \n
Selected population-based studies estimating incidence and prevalence of diabetic foot ulcers (adapted from LeMaster and Reiber, 2006) [7]
???, not specified.
The nerves of the leg and foot serve to propel the body through the actions of the legs, feet, and toes while maintaining balance, both while the body is moving and when it is at rest. Sensory nerves are of course present throughout the lower extremities; however, with the exception of the bottom of the foot, they play a lesser role here than in the upper extremities. Primarily, this section of the peripheral nervous system sends and receives signals regarding locomotion of the body. Some of the impulses are sent from various parts of the brain and spinal cord; some come from sense organs located in the joints, ligaments, and tendons; and some come from the muscles themselves.
Nerves of foot. (adapted from Encyclopedia Britanica 2007)
The nerves of the leg and foot include the sacral plexus, lumbar plexus, femoral nerve, sciatic nerve, common fibular nerve, superficial fibular nerve, saphenous nerve, sural nerve, the deep and superficial peroneal nerves, and the tibial nerve (figure 1).
The nerves deliver messages to the brain that bring information about the angles and position of joints, the length and tension of muscles, or even the speed of movements so that through the interaction of the nervous system with the muscles of the lower extremities, balance may be maintained. The average nerve running from the base of the spine to the tip of a toe is about three feet long. This includes a major neural transmission network within the legs that produces contractions of groups of muscles and is responsible for larger muscular functions, such as running, walking or swimming. Finer nerve bundles command the many small bones of the toes to create the constant, subtle shifting of the feet that keeps us from falling down.
Peripheral neuropathy is damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness.
The four cardinal patterns of peripheral neuropathy are polyneuropathy, mononeuropathy, mononeuritis multiplex and autonomic neuropathy. The most common form is (symmetrical) peripheral polyneuropathy, which mainly affects the feet and legs. The form of neuropathy may be further broken down by cause, or the size of predominant fiber involvement, i.e., large fiber or small fiber peripheral neuropathy. Frequently the cause of a neuropathy cannot be identified and it is designated as being idiopathic.
Neuropathy may be associated with varying combinations of weakness, autonomic changes, and sensory changes. Loss of muscle bulk or fasciculations, a particular fine twitching of muscle, may be seen. Sensory symptoms encompass loss of sensation and "positive" phenomena including pain. Symptoms depend on the type of nerves affected (motor, sensory, or autonomic) and where the nerves are located in the body. One or more types of nerves may be affected. Common symptoms associated with damage to the motor nerve are muscle weakness, cramps, and spasms. Loss of balance and coordination may also occur. Damage to the sensory nerve can produce tingling, numbness, and a burning pain. Pain associated with this nerve is described in various ways such as the following: burning, freezing, or electric-like, extreme sensitivity to touch. The autonomic nerve damage causes problems with involuntary functions leading to symptoms such as abnormal blood pressure and heart rate, reduced ability to perspire, constipation, bladder dysfunction (e.g., incontinence), and sexual dysfunction. [8-10]
Sensory neuropathy affects the nerves that carry messages from the skin, bones and muscles to the brain. As the name suggests, it tends to influence the senses, in particular touch, and affects how we feel temperature, pain and other sensations. It is the most common form of neuropathy, mainly occurring in nerves in the feet and legs, but can sometimes occur in the arms and hands. It can lead to a loss of feeling and a failure to sense pain. For example, if you trod on something sharp, stepped in to a hot bath or wore ill-fitting shoes, you may not be aware of damage to your feet. This lack of sensation can lead to damage becoming worse, and the potential for infection. Neuropathic ulcers may also occur. [11]
The symptoms of sensory neuropathy can include pain and numbness, tingling in the hands, legs or feet and extreme sensitivity to touch. Some treatments are available to help with the pain and tablets that are usually used for depression but can also have a calming effect on the nerves.
A test should be carried out at least every year, to check for signs of this type of neuropathy.
Motor neuropathy affects the nerves that transmit signals to the muscles enabling them to carry out movements like walking and moving the hands. Sometimes painful, it causes muscle weakness and, in areas like the thigh, muscle wasting can occur. However it is possible for some people to recover from this condition after a period of time.
If the nerves that supply the small muscles in your feet are affected, motor neuropathy can lead to the development of foot deformities and alteration in the pressure distribution with walking or activity. Wasting of these muscles may ultimately cause collapse of the arch and loss of stability, which results in forming the \'rocker bottom\' or Charcot’s foot, where a loss of sensation and weakened muscles cause bones in the foot to fracture or break when stressed. As you may not feel the damage, subsequently you may not heal properly and this can result in the shape of the foot becoming distorted. Your podiatrist will know more about treatments for this. [12]
The final type of nerve problem is an “autonomic neuropathy.” In this type of neuropathy, the nerves that control sweating are damaged. Dry skin occurs as a result of damage to these nerves. Sweating is important for heat reduction but it is also important for skin moisture balance. Without sweat, the skin dries out and cracks. This can be dangerous because germs can enter through the cracks and cause infection. Dry and cracked skin should be treated with prescription moisturizing creams and regular professional foot care. Autonomic neuropathy is a form of polyneuropathy which affects the non-voluntary, non-sensory nervous system (i.e., the autonomic nervous system) affecting mostly the internal organs such as the bladder muscles, the cardiovascular system, the digestive tract, and the genital organs. These nerves are not under a person\'s conscious control and function automatically. Autonomic nerve fibers form large collections in the thorax, abdomen and pelvis outside spinal cord, however they have connections with the spinal cord and ultimately the brain. Most commonly autonomic neuropathy is seen in persons with long-standing diabetes mellitus type 1 and 2. In most but not all cases, autonomic neuropathy occurs alongside other forms of neuropathy, such as sensory neuropathy.
Autonomic neuropathy is one cause of malfunction of the autonomic nervous system, but not the only one; some conditions affecting the brain or spinal cord can also cause autonomic dysfunction, such as multiple system atrophy, and therefore cause similar symptoms to autonomic neuropathy.
The signs and symptoms of autonomic neuropathy include the following:
Urinary bladder conditions: bladder incontinence or urine retention
Gastrointestinal tract: dysphagia, abdominal pain, nausea, vomiting, malabsorption, fecal incontinence, gastroparesis, diarrhea, constipation
Cardiovascular system: disturbances of heart rate (tachycardia, bradycardia), orthostatic hypotension, inadequate increase of heart rate on exertion
Other areas: hypoglycemia unawareness, genital impotence, sweat disturbances. [9]
Most diabetics experience some type of neuropathy, a leading predisposing factor to development of ulcers. More than 60% of diabetic foot ulcers are the result of underlying neuropathy. [11,13] Diabetics have altered peripheral sensation of the foot, with loss of the protective sensation that renders the individual unaware of the beginning of an ulcer or the actual ulceration process. Diabetic neuropathy also alters the microcirculation of the foot, resulting in a reduced distribution of blood to the areas of need. Nerve damage in diabetic neuropathy occurs when blood sugar is poorly controlled for prolonged periods of time. Involvement of these nerves results in loss of the normal protective sensation that we rely upon to avoid injury. Loss of the normal pain threshold may result in prolonged and repetitive trauma to the foot. Overcompensation by other muscles can lead to other foot deformities including \'hammer\' or \'claw\' toes. These abnormalities lead to pressure points that are then at great risk for ulceration. Even the dry, brittle skin caused by diminished sweating is due to neuropathy affecting specialized nerves within the skin. This makes the skin prone to cracking and fissuring, thus allowing entry of bacteria even in the absence of a large sore. Subsequent infection and abscess formation may damage far more tissue than is apparent from the overlying ulcer.
The development of neuropathy in affected patients has been shown in animal and
Neuropathy in diabetic patients is manifested in the motor, autonomic, and sensory components of the nervous system. [14] Damage to the innervations of the intrinsic foot muscles leads to an imbalance between flexion and extension of the affected foot. This produces anatomic foot deformities that create abnormal bony prominences and pressure points, which gradually cause skin breakdown and ulceration.
As trauma occurs at the affected site, patients are often unable to detect the insult to their lower extremities. As a result, many wounds go unnoticed and progressively worsen as the affected area is continuously subjected to repetitive pressure and shear forces from ambulation and weight bearing. [15-20]
Peripheral arterial disease is a contributing factor to the development of foot ulcers in up to 50% of cases. [21] It commonly affects the tibial and peroneal arteries of the calf. Endothelial cell dysfunction and smooth cell abnormalities develop in peripheral arteries as a consequence of the persistent hyperglycemic state. [22] There is a resultant decrease in endothelium-derived vasodilators leading to constriction. Further, the hyperglycemia in diabetes is associated with an increase in thromboxane A2, a vasoconstrictor and platelet aggregation agonist, which leads to an increased risk for plasma hypercoagulability. [23] There is also the potential for alterations in the vascular extracellular matrix leading to stenosis of the arterial lumen. [23] Moreover, smoking, hypertension, and hyperlipidemia are other factors that are common in diabetic patients and contribute to the development of peripheral arterial disease. [14] Cumulatively, this leads to occlusive arterial disease that results in ischemia in the lower extremity and an increased risk of ulceration in diabetic patients.
The extracellular matrix (ECM) is the non-cellular component present within all tissues and organs, and not only does provides essential physical scaffolding for the cellular constituents but also initiates crucial biochemical and biomechanical cues that are required for tissue morphogenesis, differentiation and homeostasis. The importance of the ECM is vividly illustrated by the wide range of syndromes, which can be anything from minor to severe, that arise from genetic abnormalities in ECM proteins. Although, fundamentally, the ECM is composed of water, proteins and polysaccharides, each tissue has an ECM with a unique composition and topology that is generated during tissue development through a dynamic and reciprocal, biochemical and biophysical dialogue between the various cellular components (e.g. epithelial, fibroblast, adipocyte, endothelial elements) and the evolving cellular and protein microenvironment. Indeed, the physical, topological, and biochemical composition of the ECM is not only tissue-specific, but is also markedly heterogeneous. Cell adhesion to the ECM is mediated by ECM receptors, such as integrins, discoidin domain receptors and syndecans. Adhesion mediates cytoskeletal coupling to the ECM and is involved in cell migration through the ECM. Moreover, the ECM is a highly dynamic structure that is constantly being remodeled, either enzymatically or non-enzymatically, and its molecular components are subjected to a myriad of post-translational modifications. Through these physical and biochemical characteristics the ECM generates the biochemical and mechanical properties of each organ, such as its tensile and compressive strength and elasticity, and also mediates protection by a buffering action that maintains extracellular homeostasis and water retention. In addition, the ECM directs essential morphological organization and physiological function by binding growth factors (GFs) and interacting with cell-surface receptors to elicit signal transduction and regulate gene transcription.
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework (stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells of connective tissue in animals. Inactive fibroblasts, which are also called fibrocytes, are smaller and spindle shaped. Although disjointed and scattered when they have to cover a large space, fibroblasts when crowded often locally align in parallel clusters.
Fibroblasts make collagens, glycosaminoglycans, reticular and elastic fibers, glycoproteins found in the extracellular matrix and cytokine TSLP. Growing individuals\' fibroblasts are dividing and synthesizing ground substance. Tissue damage stimulates fibrocytes and induces the mitosis of fibroblasts. Unlike the epithelial cells lining the body structures, fibroblasts do not form flat monolayers and are not restricted by a polarizing attachment to a basal lamina on one side, although they may contribute to basal lamina components in some situations Fibroblasts can also migrate slowly over substratum as individual cells, again in contrast to epithelial cells. While epithelial cells form the lining of body structures, it is fibroblasts and related connective tissues which sculpt the "bulk" of an organism.
Keratinocyte is the predominant cell type in the epidermis, the outermost layer of the skin, constituting 95% of the cells found there. Those keratinocytes found in the basal layer (Stratum germinativum) of the skin are sometimes referred to as "basal cells" or "basal keratinocytes.
Wounds to the skin will be repaired in part by the migration of keratinocytes to fill in the gap created by the wound. The first set of keratinocytes to participate in that repair come from the bulge region of the hair follicle and will only survive transiently. Within the healed epidermis they will be replaced by keratinocytes originating from the epidermis. At the opposite, epidermal keratinocytes, can contribute to
Diabetic nephropathy (DN) is a serious complication in diabetes and is characterized by excessive deposition of extracellular matrix proteins in the mesangium and basement membrane. Major typical morphological changes are the result of changes in the extracellular matrix (ECM). One important ECM component, the proteoglycans (PGs), shows a more complex pattern of changes in DN. PGs in basement membranes are decreased. The amounts and structures of heparan sulfate chains are changed, and such changes affect levels of growth factors regulating cell proliferation and ECM synthesis, with cell attachment affecting endothelial cells. Enzymes modulating heparan sulfate structures, such as heparanase and sulfatases, are implicated in DN. Other enzyme classes also modulate ECM proteins and PGs, such as matrix metalloproteinases and serine proteases, such as plasminogen activator, as well as their corresponding inhibitors. The levels of these enzymes and inhibitors are changed in plasma and in the kidneys in DN. Several growth factors, signaling pathways, and hyperglycemia per se affect ECM synthesis and turnover in DN. Therefore, ECM components are being evaluated to be used as markers for DN. [24-27]
Matrix metalloproteinases (MMPs) are a family of nine or more highly homologous Zn(++)-endopeptidases that collectively cleave most if not all of the constituents of the extracellular matrix.
In diabetic foot ulcers there is an excess of MMPs and a decrease of the tissue inhibitors of MMPs (TIMPs). This imbalance is probably one cause of impaired healing. However, little is known about changes in MMPs during wound healing. A high level of MMP-1 seems essential to wound healing, while an excess of MMP-8 and -9 is deleterious, and could be a target for new topical treatments. The MMP-1/TIMP-1 ratio is a predictor of wound healing in diabetic foot ulcers. [28]
Early recognition and management of risk factors is important for reducing morbidity of foot ulceration. These risk factors, as investigated by several teams, [29-33] include age, sex (being male), diabetes duration and type, insulin use, past history of diabetic foot ulcer (DFU) and amputation, lower limb bypass procedures, biomechanical factors such as glycaemia level and poor glycaemic control, dyslipidaemia, sensory and autonomic neuropathy (foot insensitivity to the 5.07 monofilament), absence of reflex and limited joint motion, muscle weakness, callus formation, Charcot deformity, hammer/claw toe deformity, abnormal Achilles tendon reflex, greater body mass (≥20kg), arterial insufficiency, vascular disease, skin dryness and fissure (caused by autonomic neuropathy), reduced skin oxygenation and foot perfusion (defined as ankle-brachial index ABI<0.9, toe systolic pressure <45 mmHg, 13mmHg orthostatic blood pressure fall and 15mmHg higher dorsal foot transcutaneous PO2), diastolic hypertension, impaired vision, as well as socio-environmental risk factors in some communities, such as smoking habits, alcohol consumptions, lack of proper diabetes educations, low income, racial distribution (African Americans, Hispanic Americans and Native Americans face a higher risk), poor personal hygiene and self-care.
Smoking, hypertension, and hyperlipidemia are considered as risk factors due to their effects on the increased occurrence of peripheral arterial occlusive disease in diabetics, which typically involves the tibial and peroneal arteries, but leaves the dorsalis pedis artery unaffected. [14]
There are controversies on some other factor, as some studies could not find a relationship between them and DFU occurrence. They include height, hallux blood pressure, and other foot deformities. [34,35] Also, although some studies could not find a statistically significant association between the length of diabetes and the risk of DFU, other studies mentioned it could be predictive. [36]
Wounds that are penetrated to bone, wounds older than 30 days, recurrent wounds, and presence of peripheral vascular disease increase the risk of wound infections. [37]
The majority (80%) of DFUs is the consequences of neuropathies due to decreasing pain sensation and perception of pressure, to causing muscle imbalance that can lead to anatomic deformities, and to impairing the microcirculation and the integrity of the skin. Therefore, risk factors in neuropathy should also be considered as risk factors in DFU. They include unbalanced age, sex (male gender), duration of diabetes, higher glycemia level, higher levels of LDL and triglycerides, higher von Willebrand factor levels and urinary albumin excretion rate, hypertension, depression and atherosclerosis (ischemia). [34,38,39]
Diabetic foot ulcers usually start with the following symptoms:
Atrophic integument
Any break in the skin resulted from abnormal wear and tear, injury, or infection
Sores, ulcers, or blisters on the foot or lower leg
Persistent pain, which can be a symptom of sprain, strain, bruise, overuse, improperly fitting shoes, or underlying infection.
Calluses and corns that may be a sign of chronic trauma to the foot
A claudicating or difficulty walking that can be sign of joint problems, serious infection, or improperly fitting shoes
Discoloration in feet: black, blue, or red
Cold feet
Absent pulses
Swollen foot or ankle
Odor
Fever or chills in association with a wound that can be a sign of a limb-threatening or life-threatening infection
Redness, which can be a sign of infection, especially when surrounding a wound, or of abnormal rubbing of shoes or socks.
Swelling of the feet or legs, which can be a sign of underlying inflammation or infection, improperly fitting shoes, or poor venous circulation.
New or lasting numbness in the feet or legs, a sign of nerve damage from diabetes
Signs of poor blood circulation, such as:
Pain in the legs that increases with walking but improves with rest (claudication)
Absence of pedal hair or pallor on elevation (coupled with other symptoms)
Hard shiny skin on the legs
Toenail fungus, athlete\'s foot, and ingrown toenails, which may lead to more serious bacterial infections
Drainage of pus from a wound is usually a sign of infection. Persistent bloody drainage is also a sign of a potentially serious foot problem.
Several schemes have been used to classify diabetic foot ulcers, but none of them has been accepted universally. Following is a list of the most used classifications: [40]
Wagner-Meggitt, the most popular method that was described by Meggitt (1976) and Wagner (1982), [41,42] has been used for decades to classify DFUs in six grades based on the wound’s depths and extent of gangrene (table 2):
Grade 0 | \n\t\tIntact skin (only foot symptoms like pain exist) | \n\t
Grade 1 | \n\t\tSuperficial ulcer | \n\t
Grade 2 | \n\t\tDeep ulcer to tendon, bone or joint | \n\t
Grade 3 | \n\t\tDeep ulcer with abscess or osteomyelitis | \n\t
Grade 4 | \n\t\tForefoot gangrene | \n\t
Grade 5 | \n\t\tWhole foot gangrene | \n\t
Wagner-Meggitt grades of diabetic foot ulcer classification.
University of Texas classification, which has been developed by Armstrong and his colleagues, is a more comprehensive scale and includes risk stratification and expresses tissue breakdown, infection and gangrene separately (table 3). [42] The University of Texas scale showed a better correlation with prognosis and risk of amputation: [14]
Grade 0 | \n\t\tPre-ulcerative site, or healed ulcer. | \n\t
Grade 1 | \n\t\tUlcer through the epidermis +/- dermis, but not to tendon, capsule or bone 1A- without infection or ischaemia 1B- with infection but no ischaemia 1C- with ischaemia 1D- with ischaemia and infection | \n\t
Grade 2 | \n\t\tUlcer to capsule or tendon 2A- without infection or ischaemia 2B- with infection but no ischaemia 2C- with ischaemia 2D- with ischaemia and infection | \n\t
Grade 3 | \n\t\tUlcer to bone or joint 3A- without infection or ischaemia 3B- with infection but no ischaemia 3C- with ischaemia 3D- with ischaemia and infection | \n\t
University of Texas grades of diabetic foot ulcer classification
Although Texas classification describes the grade of wound in more details, it does not include measures of neuropathy or ulcer area.
S(AD) SAD system builds upon the Wagner classification to include several additional categories: size (area, depth), sepsis, arteriopathy and denervation. [43] Developed by an English group, the S(AD) SAD classification is a validated system with grades 0 to 3, [44] as shown in table 4:
Area | \n\t\tDepth | \n\t||||
0 | \n\t\tSkin intact | \n\t\tSkin intact | \n\t\tNone | \n\t\tPedal pulses present | \n\t\tPin pricks intact | \n\t
1 | \n\t\t< 1 cm2 | \n\t\tSuperficial (skin and subcutaneous tissue) | \n\t\tSurface | \n\t\tPedal pulses reduced or one missing | \n\t\tPin pricks reduced | \n\t
2 | \n\t\t1-3 cm2 | \n\t\tTendon, periosteum, joint capsule | \n\t\tCellulitis | \n\t\tAbsence of both pedal pulses | \n\t\tPin pricks absent | \n\t
3 | \n\t\t> 3 cm2 | \nBone or joint space | \nOsteomyelitis | \nGangrene | \nCharcot | \n
S(AD) SAD classification for diabetic foot ulcer
RYB Color Classification was developed for the nursing literature [45] and has obtained considerable popularity. The system relies purely on a color scheme with no additional considerations. R/Red wounds are those that exhibit pale pink to beefy red granulation tissue and are deemed to be in the inflammatory or proliferative phase. Y/Yellow wounds are marked by pale ivory, yellowish green or brown color, slough of necrotic but moist tissue, and wound exudates. B/Black wounds are marked by black, brown or tan color, and desiccated eschar. The RYB classification is an easy and widely accepted system in the nursing literature and shows the continuum from acute to chronic wounds. Conversely, it is non-specific with no consideration of depth or size, and no consideration of the contributing factor of neuropathy.
PEDIS classification was proposed by the International Working Group on the Diabetic Foot [46,47] and grades the wounds on the basis of five features: perfusions (arterial supply), extent (area), depth, infection and sensation. There are levels of 1 to 4 for each of these factors. The in-depth nature of this system is appropriate for the research community that desires this amount of detail. Every lesion is described (for example P2E1D2I1S2), according to table 5:
1 | \n\t\tno symptoms/ signs of PAD | \n\t\t\n\t\t | Superficial full-thickness ulcer | \n\t\tno symptoms/signs | \n\t\tNo loss of protective sensation | \n\t
2 | \n\t\tsymptoms or signs of PAD, but not CLI | \n\t\t\n\t\t | Ulcer penetrating below dermis to skin structures | \n\t\tInflammation of skin only | \n\t\tLoss of protective sensation | \n\t
3 | \n\t\tCLI | \n\t\t\n\t\t | All subsequent layers of foot, including bone/joint | \n\t\tExtensive erythema deeper than skin | \n\t\t\n\t |
4 | \n\t\t\n\t\t | \n\t\t | \n\t\t | Systemic inflammatory response syndrome (SIRS) | \n\t\t\n\t |
Grades of PEDIS classification for diabetic foot ulcer
Determination of the level of infection in PEDIS classification system is based on the Severity Classification guideline published by the Infectious Disease Society of America (IDSA), as shown in table 6:
Wound lacking purulence or any manifestations of inflammation. | \n\t\tUninfected | \n\t\t1 | \n\t
Presence of ≥ 2 manifestations of inflammation (purulence, or erythema, pain, tenderness, warmth, or induration), but any cellulitis/erythema extends ≤ 2 cm around the ulcer, and infection is limited to the skin or superficial subcutaneous tissues; no other local complications or systemic illness. | \n\t\tMild | \n\t\t2 | \n\t
Infection (as above) in a patient who is systemically well and metabolically stable, but which has ≥ 1 of the following characteristics: cellulitis extending > 2 cm, lymphangitic streaking, spread beneath the superficial fascia, deep-tissue abscess, gangrene, and involvement of muscle, tendon, joint, or bone. | \nModerate | \n3 | \n
Infection in a patient with systemic toxicity or metabolic instability (e.g., fever, chills, tachycardia, hypotension, confusion, vomiting, leukocytosis, acidosis, severe hyperglycemia, or azotemia). | \n\tSevere | \n\t4 | \n
Severity classification guideline according to IDSA
DEPA Scoring System, is the newest DFU classification system, in which D stands for depth of the ulcer, E for extent of bacterial colonization, P for phase of ulcer, and A for associated etiology (table 7). [48] Ascending scores, from 1 to 3, are assigned for increasing levels of intensity in each category (see the table below). For instance, an ulcer involving soft tissue receives a 2. Contamination of this ulcer receives a 1. The ulcer is in the inflammatory phase, generating a 2 score, and has an underlying bony deformity, generating another 2 score. Accordingly, this ulcer has a total score of 7. Ulcers with a total score of 6 or less are considered “low grade” ulcers. Recommended treatment measures include oral antibiotics (if infected), blood sugar control (type not specified) and debridement. Those with a total score of 7 to 9 are deemed “moderate grade” wounds that one would treat with parenteral antibiotics, insulin, debridement, healing promoting agents and pressure relieving methods. The “high grade” lesions, those with a total score between 10 and 12, require a conservative trial including parenteral antibiotics, insulin, debridement, healing promoting agents and vascular reconstruction. The authors of the DEPA classification system offered acute ischemia patients a below-knee amputation; however, other practitioners may offer revascularization or other interventions. The scores of 11 to 12 are prognostic for amputation and if these are heel ulcers, they were even more likely to lead to amputation. Scores of 10 or greater predict difficulty with healing, while scores of 6 or less indicate probable healing.
Depth of the ulcer | \n\t\tSkin | \n\t\tSoft tissue | \n\t\tBone | \n\t
Extent of bacterial colonization | \n\t\tContamination | \n\t\tInfection | \n\t\tNecrotizing infection | \n\t
Phase of ulcer | \n\t\tGranulating | \n\t\tInflammatory | \n\t\tNonhealing | \n\t
Associated etiology | \n\t\tNeuropathy | \n\t\tBone deformity | \n\t\tIschemia | \n\t
Scores and definitions of DEPA scoring system
Vascular impairment is one of the most important causes of DFU, and in addition to hyperglycemia, is the main impediment in healing the ulcers. Smoking cessation, diet improvement and controlling total and LDL cholesterol, antiplatelet drug treatment, and maintaining an optimum blood pressure will help reducing the impact of vascular impairment on ulcer healing. Vascular impairment in foot ulcers has been discussed in more details in 7.
When a tissue is injured, blood from the broken capillaries streams into the wound. This blood carries platelets and fibrinogen. Fibrinogen is activated in response to the exposed epithelium to form a fibrin mesh that traps platelets. Platelets also adhere to the ruptured blood vessels, preventing further blood loss. Moreover, platelets come into contact with damaged ECM components; they release clotting factors, leading to the formation of a blood clot within the wound site. The activated platelets in the wound release chemical stimuli such as platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), and vascular endothelial growth factor (VEGF). [49,50] Fibroblasts stimulated by these chemoattractants produce collagen, which is a major component of the ECM, a scaffold onto which the endothelial cells can migrate to create and extend the vascular network. Fibroblasts also secrete PDGF and TGF-β, as well as VEGF. This cocktail of growth factors stimulates the endothelial cells of vessels in the nearby healthy tissue to release proteases such as MMPs. [51] MMPs digest the basement membrane, allowing endothelial cells to escape the confines of their parent vessels. [52] VEGF, EGF, bFGF, and TGF-β stimulate the systematic rearrangement of endothelial cells from blood vessels. The cells proliferate, elongate, and align to form a capillary sprout, extending away from the original vessel. [49] This is the beginning of the angiogenesis process. Then, polarized endothelial cells are positioned with a luminal and an abluminal surface forming tubular structures, which act as a multipurpose barrier between the flowing blood and the extravascular tissue. Periendothelial cells, such as pericytes, fibroblasts, and smooth muscle cells, reinforce these tubular endothelial networks. This process is oxygen dependent. Oxygen is required for collagen deposition. Hypoxia causes the hypoxia-inducible factor (HIF) to up-regulate the production of VEGF.
Sprout extension is facilitated by endothelial cell proliferation and further migration toward the chemical attractant.
Vasculogenesis, the formation of blood vessels from the differentiation of progenitor cells, also plays a part in the formation of new blood vessels during this stage of wound healing. [53] Progenitor cells differentiate into early endothelial progenitor cells in the bone marrow and further differentiate into late endothelial progenitor cells in the vasculature system before arriving at the site of vessel formation. [52]
The joining of two capillary sprouts within a healing wound forms a loop through which blood can flow and new sprouts develop from this vessel thus propagating angiogenesis. [54] This capillary extension allows oxygen and other critical nutrients to be transported further into the injured region. This, in turn, allows the macrophage and fibroblast fronts to migrate further into the wound, and thus the healing unit progresses into the injured tissue. [54] When the unit has completely swept through the wound site, blood vessels are networked over the entire space and oxygen levels are returned to normal. Oxygen binds to HIF and leads to a decreased synthesis of VEGF. This ends the angiogenesis process. [49]
Usually diabetes causes excessive and deficient angiogenesis (table 8). Therapeutic factors that can regulate angiogenesis in the diabetic foot conditions are considered as successful treatments for DFU.
Reduced angiogenesis and collateral formation | \n\t\tReduced VEGF, FGF, EPC circulation, cytokines, ECM/BM degradation; increased AGEs and MMP | \n\t\tRetinal capillary occlusion | \n\t\tElevated intraocular pressure | \n\t
Vascular occlusion, inflammation | \n\t\tIncreased free fatty acids, polyol pathway, cytokines, ICAM, VCAM | \n\t\tIncreased vascular permeability | \n\t\tIncreased VEGF | \n\t
Reduced wound healing; transplant failure | \n\t\tReduced VEGF and growth factors; sorbitol-inositol imbalance; increased ACE, Ang-II and tissue factor mRNA | \n\t\tCapillary sprouting | \n\t\tIncreased VEGF, FGF, PDGF; cytokines (TGF-β); integrins | \n\t
Embryonic vasculopathy (anomalous vasculogenesis and angiogenesis) | \n\t\tReduced VEGF, IL-1, TGF-β | \n\t\tVascular remodeling | \n\t\tIncreased laminin, fibronectin, collagen IV, ECM components, lipidosis | \n\t
Comparison of aberrant angiogenesis under diabetes.
A task force of the Foot Care Interest Group of the American Diabetes Association (ADA) released a report in 2008 that specifies recommended components of foot examinations for patients with diabetes (table 9). [55]
0 | \n\t\tNo LOPS, no PAD, no deformity | \n\t\tConsider patient education on foot care, including information on appropriate footwear. | \n\t\tAnnually (by generalist and/or specialist) | \n\t
1 | \n\t\tLOPS±deformity | \n\t\tConsider prescriptive or accommodative footwear. Consider prophylactic surgery if deformity is not able to be safely accommodated in shoes. Continue patient education. | \n\t\tEvery 3-6 months (by generalist or specialist) | \n\t
2 | \n\t\tPAD±LOPS | \n\t\tConsider the use of accommodative footwear. Consider a vascular consultation for combined follow-up. | \n\t\tEvery 2-3 months (by specialist) | \n\t
3 | \n\t\tHistory of ulcer or amputation | \n\t\tConsider patient education on foot care. Consider vascular consultation for combined follow-up if PAD present. | \n\t\tEvery 1-2 months (by specialist) | \n\t
Risk classification system of the Task Force of the Foot Care Interest Group of the ADA
LOPS, loss of protective sensation; PAD, peripheral arterial disease. Adapted from [55]
Foot deformity is an important diagnostic sign for future foot ulcer. In addition to Charcot arthropathy, hyperextension of the metatarsal-phalangeal joint with interphalangeal or distal phalangeal joint flexion leads to hammer toe and claw toe deformities, respectively. The deformities may lead to ulceration by continuous improper contact with the footwear.
In examining for vascular abnormalities of the foot, the dorsalis pedis and posterior tibial pulses should be palpated and characterized as present or absent. Claudication, loss of hair, and the presence of pale, thin, shiny, or cool skin are physical findings suggestive of potential ischemia. [56] If vascular disease is a concern, measuring the ankle brachial index (ABI) can be used in the outpatient setting for determining the extent of vascular disease and need for referral to a vascular specialist. The ABI is obtained by measuring the systolic blood pressures in the ankles (dorsalis pedis and posterior tibial arteries) and arms (brachial artery) using a handheld Doppler and then calculating a ratio. However, in patients with calcified, poorly compressible vessels or aortoiliac stenosis, the results of the ABI can be complicated. [57]
The loss of pressure sensation in the foot has to be identified using a 10-guage monofilament as a significant predictive factor for the likelihood of ulceration. [57]
High vibration perception thresholds (VPTs) using a biothesiometer or a tuning fork, high plantar pressure and 10-gauge monofilaments are used as reliable methods to identify those at risk of future ulceration. [36]
Despite all efforts to treat ischemic and neuropathic ulcers, sometimes the lower-extremity is non-viable and amputation is inevitable. Non-traumatic amputations are high in poorer countries and in uneducated people in wealthy countries. Amputees suffer from direct surgical morbidity and mortality, inadequate and delayed rehabilitation. Also, amputees attract great amount of care from a multidisciplinary team and put additional pressure on countries’ health systems and disability insurances.
The indications for amputation in patients with diabetes are often multiple, mostly a non-healing ulcer, or frequent gangrene and infection occurring simultaneously. [58] Whether primary minor amputation is beneficial in comparison with primary major amputation (below knee) is still controversial. Digital toe amputation eventually leads to limb loss, while a major amputation lowers the risk of re-amputation. [59] Re-amputation widely rates from 21% to 60%, and is greatest in the first 6 to 12 months after the first amputation. [60,61] Once hallux has gone under amputation, changes in mechanical force and pressure on the foot may increase the likelihood of developing further lesions, most probably within 6 months. [62] Studies by Byrne et al. 1992 and Yeager et al. 1998 showed that revascularization may not prevent re-amputation as patients undergoing revascularization procedures are likely to have severe ischaemic disease. [63,64]
Any diabetic patient with a skin break below the knee that has not healed with appropriate care in 2 weeks should be referred urgently to a suitable specialist for an assessment. Assessment of the cause of an ulcer helps clinicians in determining the most appropriate treatment. The assessment includes testing for sensation, palpating for foot pulses, measuring the ankle-brachial pressure index (ABPI) and toe pressures, and often undertaking color-flow duplex ultrasonography. Patients with lower-limb tissue loss from ischemia should be assessed by a vascular surgeon. Magnetic resonance angiography (MRA) or conventional intra-arterial digital subtraction angiography could be needed to help plan the reconstruction. [65-68]
DFU can be successfully treated by a multidisciplinary team consists of diabetologist, shoemaker, orthopedist, psychologist, vascular and general surgeons, podologists, radiologists, educators, nurses and rehabilitation team. [35]
Surgeons (general, vascular, orthopaedic, plastic, podiatric) generally become involved in treating severe tissue infection, especially when gangrene or underlying osteomyelitis remain despite antibiotic treatment. [69] The main purpose of surgery is to remove infected and necrotic soft and bony tissue back to a healthy base that will support granulation tissue and allow healing by secondary intention.
Many diabetic patients with underlying ischemia will need revascularization to provide an adequate arterial blood supply in order to achieve a better healing and resolve underlying infection. Up to a 90% 10-year limb-salvage rate has been demonstrated with surgical bypass procedures of the lower extremity. [70] A standard treatment for ischemic ulceration is still femorodistal bypass with an autogenous tissue (usually saphenous vein), although this treatment is not readily available for all patients. However, it seems reasonable to attempt healing of ischemic and neuroischemic ulcers with drugs before considering revascularization.
Conventional treatments for diabetic peripheral neuropathy include tricyclic compounds, serotonin-norepinephrine reuptake inhibitors (e.g. duloxtine), anticonvulsants (e.g. pregabalin), opiates, membrane stabilizers, the antioxidant alpha lipoic acid and others. [33]
The selection of wound dressings is also an important component of diabetic wound care management. Advanced wound dressing products can help alter the wound environment to optimize healing conditions. Characteristics of a successful wound dressing will be discussed later.
If not managed properly, diabetic foot ulcers are at high risk for infection. Open wounds can be contaminated or infected with microorganisms and even virulent pathogens. The generally accepted clinical definition of infection is the presence of purulent secretions or at least two signs or symptoms of inflammation (erythema, warmth, tenderness, pain, and induration). While ischemia or neuropathy signs such as friable tissue, wound undermining, and foul odor imply infection. [71] Most diabetic foot infections do not produce systemic signs, such as fever or leukocytosis, but when they are present, they typically suggest that any accompanying infection is severe.
To assess the infection, clinicians should obtain material for a wound culture. Tissue specimens are strongly preferred to wound swabs, because they provide more sensitive and specific results. Tissue can be obtained by scraping of the base of the ulcer with a scalpel or dermal curette (curettage) or by wound biopsy. Aseptically obtained aspirates of pus (purulent secretions) or tissue fluid can also provide good specimens for culture. The specimen should be processed for both aerobic and anaerobic cultures and a gram-stained smear, if possible. Blood obtained for a complete blood count (and leucocyte differential), basic serum chemistry panels, and inflammatory markers (erythrocyte sedimentation rate [ESR] or C-reactive protein) can help define the severity of the infection. [72]
Usually, plain radiographs of the foot will help to identify foreign bodies, gas in the tissues, or evidence of osteomyelitis. More sophisticated imaging tests (the best of which being MRI) might be needed to better define the presence or absence of bone or deep soft-tissue infection.
Infection of bone underlying a foot ulcer is an especially difficult diagnostic and therapeutic problem. Osteomyelitis is probably present if the bone is visible or palpable by probing. Bone infection must usually be present for at least 2 weeks before it can be regarded as the cause of abnormalities seen on plain radiographs. Most nuclear medicine tests (e.g., technetium bone scans or labeled leucocyte scans) are more sensitive than plain radiography, but are relatively non-specific and less accurate than MRI. The gold standard test for osteomyelitis is a bone biopsy sample processed for culture and histology. [73]
All available data are required to decide whether infections are safe to treat on an outpatient basis, or whether hospital care is needed for medical, diagnostic, surgical, or psychosocial reasons. [30]
Antibiotics are selected largely based on the probable causative organisms, taking into account any known local antibiotic resistance patterns. Patients with severe infections need parenteral treatment, at least initially; oral therapy is often adequate for those with mild or moderate infections. [74]
Topical antimicrobials are often effective for mildly infected ulcers, however, some topical antiseptics can impair wound healing, but dressings containing silver or iodine seem to be safe, and possibly useful (see later). [75]
The aim of antimicrobial therapy is to cure the infection, not to heal the wound; extended treatment increases the risk of drug-related toxic effects and development of antibiotic resistance. Antibiotic treatment without off-loading a plantar wound (i.e., the relieving of a mechanical load) is unlikely to result in ulcer healing (see later).
Bone infection is best treated by surgical resection of all infected and necrotic bone, but retrospective studies suggest that long-term treatment (at least for 4–6 weeks) with drugs that penetrate well into bone (e.g., fluoroquinolones) can often produce a remission of infection. [73]
Recently developed treatments for diabetic foot ulcers include the use of bone marrow-derived stem cells, [76] use of human or bioengineered skin equivalents, [77,78] growth-factor therapy (such as using PDGF or G-CSF) [79,80] and negative pressure wound therapy (NPWT) [81]. Hyperbaric oxygen treatment (HBOT) seems to reduce the risk of major amputation, but not the time to ulcer healing or the rate of minor amputation. [82,83] Routine debridement of devitalized tissue at follow-up visits is widely recommended. [84] Maggot (larval) biotherapy seems to be effective for debridement [85] and acceleration of healing, [86,87] and perhaps also in reducing antibiotic use and risk of amputation. [88] A recently developed natural-based medicine, ANGIPARSTM, has shown excellent effects on wound closure and shortening the wound healing period in both diabetic foot ulcers [89-93] and pressure ulcers, [94,95] via strong angiogenesis, anti-oxidant, [96] anti-coagulant and properties.
Negative Pressure Wound Therapy (NPWT) is a sealed wound-care system and is particularly indicated for a large chronic persistent wounds and acute complicated wounds. The system consists of an electronically controlled pump and a foam dressing that drains the wound. [97] An adjustable negative pressure is applied via an airtight adhesive film that covers the wound. NPWT drains wound exudates and is thought to promote blood circulation and healing. [98] NPWT benefits include increased local blood flow, [99] rapid wound granulation, increased number of active fibroblasts and macrophages, [99] epithelial isolation, migration and contraction, [94,95] reduction of dressing changes, [100] reduced infection risk, [101] reduced treatment costs, [59] control of exudates that contain harmful fluid and by-products of tissue damage, [99,102] concurrent rehabilitation, [103] and better patient tolerance. [104] However, it is impossible to conclude from the studies that NPWT performs absolutely or relatively better than the control treatments in terms of wound healing. [105] Only one study showed a statistically significant difference in wound healing in the test group compared to the control. Although a few studies showed some NPWT effect in shortening the wound closure time, its total efficacy cannot be fully concluded because the studies were not properly designed in terms of methods of measurement, blinding and follow-ups. [106] There was high potential for bias and diagnostic heterogeneity in the studies. To approve if NPWT has a positive effect on wound healing, further research clinical trials of good methodological quality are required. Moreover, the FDA recently issued a report on six deaths and 77 other complications that were reported within a two-year period in connection with NPWT. All the deaths were caused by acute hemorrhages, and known contraindications for NPWT (e.g. a large blood vessel exposed) had clearly been overlooked. Many of the deaths occurred in outpatient care or care homes, which highlights the need to monitor therapy. [59,107]
Hyperbaric Oxygen Treatment (HBOT), which is used for Wagner Grade 3 diabetic wounds that have failed to resolve after a 30-day course of standard treatment, is the delivery of pure oxygen to patients at higher than normal atmospheric pressures to compensate shortage of blood oxygen due to vascular impairment. [83] The usual pressure for treating DFU is 1.4 to 3 atmospheres absolute pressure (ATA) - with an optimum of 2 ATA - for a compression time of 60 to 120 minutes - with an optimum of 90 minutes - during a course of multiple treatments. [97,108,109] This high pressure results in an increase in the concentration of oxygen in the blood and an increase in the diffusion capacity to the tissues, which, in turn, stimulates neovascularization and fibroblast replication and increases phagocytosis and leukocyte-mediated killing of bacterial pathogens in the wound. [109] A long benefits list of increasing the tissue oxygen is made through several studies [50]: modulation of the production of nitric oxide, promotion of cellular proliferation, stimulation of capillary budding, alteration of ischemic effect, modification of the effect of growth factors and cytokines, acceleration of collagen deposition, reduction of edema, modulation of the immune system response, accelerated microbial oxidative killing, and enhancement of oxygen radical scavengers, thereby reducing ischemia reperfusion injury.
There is enough good evidence that HBOT decreases risk of amputation in patients with complicated or infected DFU. [110,111] Many studies have shown that HBOT results in partial or complete wound healing. Some studies also showed that HBOT in combination with surgery and antibiotics can be used to treat refractory osteomyelitis. HBOT is reasonably safe when administered by experienced practitioners after careful patient screening and selection. [112]
Wound dressing, widely used to cure the infected wounds, is the most important component of a successful wound care. There are a number of available dressing types to consider. Although there is a shortage of published trials to support the use of one type of dressing compared to another, [113] the characteristics of specific dressing types can prove beneficial depending on the characteristics of the individual wound. An ideal dressing should contribute to a moist wound environment, absorb excessive exudates, and not increase the risk for infections. [114] Dressing changes and wound inspection should occur on a daily basis. [113] Saline-soaked gauze dressings, for example, are inexpensive, well tolerated, and contribute to an atraumatic, moist wound environment. Foam and alginate dressings are highly absorbent and can aid in decreasing the risk for maceration in wounds with heavy exudates.
The process of autolysis is important in wound care. If an occlusive dressing is provided as a barrier to the outside environment, the body’s own phagocytic processes will provide debridement of wounds. These products range from occlusive films such as Tegaderm, which are permeable to air and water vapor, but impermeable to fluid and microorganisms to hydrocolloids such as DuoDerm, which are also occlusive but provide absorption of exudates in addition to maintaining a moist environment for autolysis. For heavily exudative wounds, there are a range of absorptive products, including various hydrophilic foam dressings, hydrogels, hydrofibers, and alginates, which can absorb up to 20 times their weight. [115]
Silver dressings have been used for decades with little significant toxicity to cure infected wounds. Silver has a very broad spectrum of microbial coverage, including yeast, fungi, mold, and even antibiotic-resistant organisms, when used at appropriate concentrations. Silver ion binds to negatively charged particles such as proteins, DNA, RNA and chloride ions. [116,117] Introduced in 1968, silver sulfadiazine is known to release active silver ion gradually for a longer time. [118] Nanocrystalline silver dressing developed since 1990s to fix the shortcomings of this type of dressing. It contains two layers of high-density polyethylene net sandwiching a layer of rayon/polyester gauze. The outer layer is coated with a nanocrystalline (<20 nm), uncharged form of silver, and the inner layer helps maintain a moist environment for wound healing. [116] This sandwich provides a sustained release of silver into the wound due to the low affinity of Ag0 to the negatively-charged particles in the wound. Other advantage of nanocrystalline silver dressing is less frequency of dressing changes compared the standard silver dressings, which must be changed up to 12 times a day. This brings less disruption to the wound healing bed.
Growth factors play the most important role in orchestrating the cells in wound bed along the process of wound healing. When a wound occurs, platelets and fibroblasts recruited to the wound bed, start secreting growth factors, such as PDGF, VEGF, EGF, G-CSF (GM-CSF), and TGF-β. G-CSF or GM-CSF has been found to enhance the activity of neutrophils, macrophages, keratinocytes, and fibroblasts, and increase VEGF production in diabetic patients. [119,120] A meta-analysis study revealed that, although the use of G-CSF did not significantly accelerate the resolution of infection in diabetic wounds, there was a decreased likelihood of amputation and the need for other surgical therapies in treated wounds. [121]
In a study by Steed et al., patients who were treated with recombinant human platelet-derived growth factor (rhPDGF) showed statistically significant higher percentage of wound healing (48% vs. 25% in control group), as well as greater reduction in wound size. Now, known as becaplermin or Regranex, rhPDGF is used in treatment regimens for DFU. [122,123]
Stem cell therapy has emerged as a promising treatment modality aiming to address the underlying pathophysiology of DFU. Stem cells secrete chemokines and growth factors (especially EGF, VEGF and fibronectin), which promote angiogenesis and ECM remodeling to mobilize wound healing. Stem cells that have been studied for wound healing can be classified in two groups of allogenic and autologous, based on where their origins are. Placental or amnion-derived mesenchymal stem cells and embryonic stem cells are categorized as allogenic stem cells. On the other hand, bone marrow-derived endothelial progenitor cells, bone marrow-derived mesenchymal stem cells, hematopoietic stem cells, and mesenchymal stem cells derived from adipose tissue are the autologous stem cells. [124] Placenta-derived MSCs are shown to be more effective in chronic wound healing. [125,126] Also, isolated ESC-derived EPCs were shown to improve re-epithelialization when injected subcutaneously into or applied topically on to the wound. [127] In another study, bone marrow-derived stem cells were applied on to chronic wounds that were not healed for more than a year. The treated wounds showed signs of closures within 2-4 weeks post-treatment, where there was a direct correlation between the number of cells applied and the percent decrease in wound size. [128] Another study also showed 81% limb salvage when bone marrow-derived stem cells were injected to the wounds that were otherwise candidates for amputations. [129] Hematopoietic stems cells (HSCs), harvested from either bone marrow or peripheral blood, are shown to enhance wounds healing in both the inflammatory and proliferative phases of DFU. [130] Despite promising results, the majority of these studies are conducted in animals and the few human studies are not providing enough documents to include the stem cell therapies in fixed treatments protocols of foot ulcers. More studies are required to demonstrate the safety, efficacy and improved healing rates. The main obstacle stem cell therapy strategies are facing is a proper system of delivering cells to the precise location within the wound. [124] One other major reason for limited adoption of stem cells or their products is the cost of obtaining and preparing the cells. [74]
Bioengineered skin and skin grafts have also been investigated for wound healing. Tissue-engineered skin substitutes are usually categorized in allogenic cell-containing and autologous cell-containing matrices (both carry living keratinocytes or fibroblasts), as well as acellular matrices. They all release growth factors to stimulate wound healing. [131,132] Some degrees of healing have been demonstrated through some studies, [133-138] however, because the results were susceptible to bias due to the poor methodology, more studies are required to confirm those results. [139]
ANGIPARSTM, an herbal-origin drug, has shown promising results during phase II and III, and post-marketing phase IV studies. [90-93,140] The main ingredient of this medicine is an herb, called
Adult patients with diabetes type 1 and 2 suffering from single and multiple foot ulcer(s) in Wagner’s grade 1 and 2, and infection-controlled grade 3.
Patients with foot ulcers that are caused due to peripheral neuropathy or other neuropathies, foot deformities, traumas, using unsuitable shoes, history of foot ulcer or amputation, joint movement limitation, uncontrolled hyperglycemia, prolonged diabetes, etc.
A widely-collective document registration on case reports is required to confirm ANGIPARSTM as a potent drug in DFU treatment. [74]
One of the easiest, least expensive and most effective ways for preventing foot complications could be careful inspection of the diabetic foot on a regular basis. [14]
Initial management consists of cleansing of the wound, debriding of any necrotic or gangrenous material, and the probing (preferably with a blunt sterile metal instrument) for foreign bodies or exposed bone.
There is no doubt that one of the most important parts of DFU treatments or prevention plans should be off-loading, meaning pressure relief on ulcer. High plantar pressure is usually caused by bony deformity or displacement of soft tissues, and may lead to ulceration and failure to heal. Ulcers can also be caused by contact between the dorsal surface of deformed toes and footwear that does not provide adequate toe room.
A successful off-loading through a total contact cast can decrease the pressure from 1000 kPa to less than 100 kPa. [142] Total casts should be properly made and changed at least weekly. It has been shown that patients bearing ulcer are not usually complaint with a removable off-loading device. [143] Various ambulatory braces, splints, modified shoes, and sandals can off-load the plantar surface or immobilize the foot and ankle or both. A modified half-shoe can help off-load pressure from half of the foot. Felted-foam, soft polymeric insoles and orthoses with load-isolation regions are also used to smoothen the inner layers of shoes. [144] For interdigital lesions, the close or overlapping toes must be separated. Ulcers on the plantar aspect of the heel take longer to heal than those on the forefoot in total contact casts and could benefit from special shoes without a rear-foot platform.
DFU patients are encouraged to reduce their activity levels temporarily. Patients are typically less active in total contact casts than in healing shoes, presumably because of the bulk and weight of the irremovable device. Increased activity, with the consequent high cumulative load, can delay or prevent ulcer healing. [145]
Lifetime prevalence of DFU development is estimated 25% [29,32]. Recurrence rate is also estimated to range from 28% at 12 months to 100% at 40 months. [146] At least 40% of amputations in diabetic patients can be prevented with a team approach to wound care.
Early detection of potential risk factors for ulceration can decrease the frequency of wound development. Diabetic patients should be educated regarding the importance of maintaining good glycemic control, wearing appropriate footwear, avoiding trauma, and performing frequent self-examination. They are also recommended to have their feet professionally examined at least annually (see table 9, according to the Foot Care Interest Group of the ADA) [55] to determine predisposing conditions to ulceration. In both self- and professionally-examining the foot, visual inspection of the bare foot should be performed in a well-lit room. The examination should include an assessment of the shoes; inappropriate footwear can be a contributing factor to the development of foot ulceration. In the visual inspection of the foot, the evaluator should check between the toes for the presence of ulceration or signs of infection. The presence of callus or nail abnormalities should be noted. Additionally, a temperature difference between feet is suggestive of vascular disease.
The foot should also be examined for deformities. The Charcot arthropathy is a commonly mentioned deformity in some affected diabetic patients.
Regardless ulcer treatment method, patients should slowly change to full activity and weight-bearing, using appropriate custom-made therapeutic footwear, while hyperglycemia, and neuron and vascular conditions are under a careful watch. Moreover, a proper patient and care-giver education, and regular foot care are of extreme importance in preventing DFU recurrence.
Chromosomal sex (established at the time of fertilization), gonadal sex (a direct result of the genetic complement), and brain sex (the result of genetic and hormonal actions) tend to be coincident, giving rise to the deep conviction of being male or female. But discrepancies between gender and the sex assigned at birth are also possible. Thus, gender identity could be defined as one’s personal conception of oneself as male, female, a blend of both, or neither [1, 2] that could be coincident or not, with the sex assigned at birth. According to this con- or discordance, we can differentiate into “cisgender” or “transgender” people, respectively [2]. Gender incongruence (GI) in the ICD-11 [3] is characterized by a pronounced and persistent discrepancy between the individual’s experience of gender and their sex assigned at birth.
The brain, like the gonads, is a sexually dimorphic organ, in such a way that genes located on the sex chromosomes will determine the sex of the brain [4], either indirectly by acting on the gonads, which, in turn, will produce different gonadal secretions according to the sex, or through the direct action of the sex chromosome complement XX or XY in brain cells [5].
Once the differentiation of the sexual organs is complete, and gonadal sex is established (ovaries versus testicles), the sexual differentiation of the brain will take place toward the second half of pregnancy. Then, the testicles begin to secrete testosterone, while the ovaries remain quiescent. Testosterone, which is also essential to complete the differentiation of the male sexual organs, will penetrate the brain and act through the androgen receptors (AR), or after its aromatization [6, 7, 8, 9] activating the estrogen receptors ERα and ERβ, respectively involved in masculinization and defeminization of the nervous system [10]. Exposure to testosterone, through activation of the AR during this critical period, is a prerequisite for masculinization of the brain, ensuring that gonadal sex coincides with cerebral sex. The organization of the brain by the action of hormones during this embryonic period, and the subsequent activating effects on sexual behavior in adult life, form the basis of the brain-behavior organizational and activation hypothesis [11].
Since the sexual differentiation of genitalia and the sexual differentiation of the brain occur at different times in intrauterine development, they may take different directions, and in that case, the degree of masculinization of the genitalia may not reflect the degree of masculinization of the brain, giving rise to individuals with XY karyotype and male genitalia, but with feminized brains, or individuals with XX karyotype and female genitalia, but with masculinized brains [12].
Transient perinatal exposure to testosterone or its metabolite, estradiol, causes many of the best-studied sex differences in rodent brains, and recent evidence suggests that epigenetic mechanisms underlie many of these hormonal effects [13, 14, 15, 16, 17]. For example, sex differences in the preoptic area of the hypothalamus are altered by injecting a methyltransferase inhibitor directly into the brain of newborn rats or mice during the critical period for sexual differentiation [18, 19]. Similarly, a neonatal disruption of histone acetylation inhibits the development of sex differences in copulatory behavior in male rats [20] and modifies the size of the bed nucleus of the stria terminalis (BNST) in mice, a region of the brain linked to male sexual behavior [21]. These findings suggest that sexual differentiation of the brain requires orchestrated changes in DNA methylation and histone acetylation [13].
In another approach, based on genome-wide studies, both histone methylation and DNA methylation patterns differ by sex in the mouse preoptic area [22, 23]. Testosterone treatment of newborn female mice partially masculinizes the DNA methylation pattern present in adulthood [23], and sex differences in methylation of specific genes are also reversed by neonatal steroid treatment in rats [24]. Therefore, steroid hormones alter the expression or activity of enzymes that place epigenetic marks [19, 25, 26], which may be the mechanism by which hormones affect the epigenome [13].
Another study in rodents infers the role of chromosomal and hormonal sex in brain epigenetics. In rats, mothers lick their newborns more frequently if they are male than if they are female [27], and the amount of maternal attention that a rat pup receives affects the degree of methylation of the estrogen receptor alpha ESR1 gene in the brain [28, 29]. Edelmann and Auger [30] randomly assigned some female newborns to receive the extra attention normally given to males by simulating anogenital licking with a brush. This, in fact, masculinized the methylation pattern of their DNA and modified the expression of the ESR1 gene in the cerebral amygdala of the treated females [30]. In this case, the differential mother’s care is based on the odor of the newborn’s urine [31], which in turn is due to differences in circulating testosterone, and thus to genetic and hormonal sex.
On the other hand, some sex differences in the brain are independent of gonadal hormones and are instead due to the complement of sex chromosomes itself [32, 33]. In this way, sex chromosomes alone influence the expression of epigenetic enzymes and cause sex differences in the epigenome of rodents and flies [32, 34]. Thus, based on animal studies, the two main determinants of biological sex (sex chromosomes and gonadal steroids) contribute to sex differences in the brain epigenome [13].
But in humans, information on sex differences in the brain epigenome is very limited. During some stages of human fetal development, male and female brains differ in both DNA methylation and hydroxymethylation [35]. Because these differences are seen before birth, and presumably before social influences, they are differences due to sex and hormones. There are also differences in epigenetic marks in the prefrontal cortex of adult men and women [36, 37, 38]. However, adults have had many experiences of gender, so it is not clear whether these differences are due to sex or gender.
The hypothesis of sexual differentiation of the brain has also been studied by verifying to what extent the brain of people with GI agrees with their natal sex or with their gender [39]. Although the role of brain dimorphism in the development of GI remains unclear, it appears that it is the result of a combination of the effects of hormones in the brain, the expression of certain genes, and epigenetic factors. Due to the complexity of this combination, it is especially difficult to determine the degree of the implication that these elements have separately.
Some in vivo studies suggest that, in general, the brain morphology and cognitive performance of the transgender population show a remarkable congruence with that of their natal sex. However, most literature indicates that the structure and functioning of the brain of the transgender population are more consistent with their gender than with their natal sex and that the trend toward cerebral feminization in transgender women, and toward masculinization in the case of transgender men is an innate quality, independent of hormonal treatment [40].
Hahn et al. [41], in a study on brain connectivity networks in transgender people, found a decreased intra-hemispheric connectivity ratio for transgender women in the subcortical and limbic regions compared to the cisgender population. In the group of transgender men, they found a decrease in intra-hemispheric connectivity between the right subcortical/limbic areas, and in the right frontal and temporal lobes compared to the cisgender population and transgender women. Differences between transgender groups and the direction of brain connectivity suggest that GI is characterized by specific but distinct brain signatures for both transgender groups [41].
Research in the field of gender-affirming hormone treatment (GAHT) has provided much insight into the origin and development of brain sex differences, through the manipulation of gonadal steroids [40]. Sex hormones influence the morphology and functional organization of the brain not only during prenatal and peripubertal development, but studies of gender-affirming therapies have shown that sex hormones can affect the brain even when it is fully developed and that they do so in a non-uniform way. So that some structures tend to be modified in favor of the chosen gender, while others do not, or are located in an intermediate position. It has been found that, in transgender women undergoing GAHT, the volume of the amygdala, corpus callosum, and nucleus putamen do not differ from that of cisgender men, corresponding to their natal sex, while the right insular cortex and right temporal–parietal junction are larger than in the two cisgender groups. However, in transgender men, the third ventricle and the nucleus accumbens are different to in cisgender women, coinciding with the chosen gender and not with their natal sex. Cisgender men, like transgender women undergoing GAHT, have higher overall gray matter volume than cisgender women in the posterior superior frontal cortex, whereas both transgender women and transgender men have lower gray matter volume in the insula than cisgender women [40]. In another study, changes in testosterone levels in transgender men were found to be inversely correlated with gray matter volume in Broca’s and Wernicke’s areas after four weeks of GAHT [42]. Despite the differences in the results, in general, these studies indicate that transgender women present demasculinized patterns in terms of cortical thickness of the white matter microstructure, that transgender men present defeminized patterns, and that both, women and men transgender, have a characteristic and complex sexual differentiation in a mosaic form [39, 43].
Regarding its etiology, GI is considered multifactorial and complex. Thus, there is not a single gene or a single factor that could explain GI. It might be associated with neurodevelopmental processes of the brain, as well as hormonal, genetic, and epigenetic factors, among other possible influences. The main studies on the genetic basis of GI have been focused on the genes involved in the sexual differentiation of the brain: the androgen receptor AR, the estrogen receptor α ESR1, the estrogen receptor β ESR2, the aromatase gene CYP19A1 and the CYP17A1 17-alpha-hydroxylase.
The scientific evidence accumulated in recent years points to a complex etiology with hormonal, genetic, epigenetic disruptors, and immunological mechanisms that cause a specific neuropsychological profile [17]. One of the current hypotheses suggests that GI could be related to a different sexual differentiation of the brain, not concordant with natal sex or sex assigned at birth, as a result of changes in the DNA sequence of the estrogen receptor α- β genes (ESR1 and ESR2) and the AR androgen receptor gene, as well as the CYP19A1 and the CYP17A1 genes [44]. These changes in the DNA sequence would imply a variability in the sensitivity of hormone receptors, causing a genetic vulnerability related to the production of hormone receptors that are more or less sensitive to their ligands (estrogens and androgens).
The ERα-β and AR receptors are proteins that bind their ligands (estrogens and androgens, respectively). These receptors are present in most of our cells (including neurons in the hippocampus and hypothalamus) and their presence allows cells to respond to steroid hormones. Generally, these receptors float in the cell cytoplasm in an inactive form, but when they bind to their ligand, they take on an active form (dimerization) that allows them to enter the cell nucleus and bind to specific DNA regions located near the promoter regions of numerous target genes, modulating the transcription of thousands of genes related to sexual development in a domino effect. Therefore, ER and AR are proteins that can act as hormone receptors and, at the same time, as transcriptional regulatory molecules [45]. All these ideas led to the suggestion of the possible involvement of these receptors in the genetic basis of GI.
The first study on the genetic basis of GI was conducted by Henningsson et al. [46], who analyzed for the first time three repeat polymorphisms located in the ERβ and AR receptor genes and the aromatase enzyme gene (CYP19A1) in a population of 29 transgender women. Specifically, they found longer polymorphisms (with a higher number of repeats) in the trans population. In addition, the logistic regression analysis indicated the existence of interactions between the three analyzed polymorphisms that increase the possibility of gender incongruity. In this way, the results obtained by Henningsson et al. [46] suggest that the risk of presenting GI is also influenced by the other polymorphisms (of the aromatase gene and the ERβ), but the contribution of these other genes is much greater in the presence of short AR alleles. In addition, they found that male carriers of less active AR receptors (long alleles) were more likely to show GI.
Later, Hare et al. [47] replicated the study of Henningsson et al. in a larger population of transgender women, also finding longer AR polymorphisms in the transgender population. However, when Ujike et al. [48] analyzed the same polymorphisms (and others) in a Japanese transgender population, they found no statistically significant data. But we must point out that Ujike et al. [48] incorporated small modifications into the analysis (they used the mean instead of the median to obtain the short and long alleles), which makes it impossible to compare their results with the other investigations.
These and other polymorphisms were also analyzed in a Spanish population. Thus, 974 transgender individuals were analyzed versus a cisgender population of 1,327 individuals [49, 50, 51]. The results confirmed the involvement of both ER α-β receptors in the genetic basis of GI. In addition, crossed associations were also found between the analyzed polymorphisms that were overrepresented in the transgender population [44].
In 2008, Bentz et al. [52] increased the list of the analyzed genes in the GI population with a study of the CYP17A1 gene in a transgender population from Northern Europe (Austria) consisting of 102 transgender women and 49 transgender men, who were compared to 1,671 cisgender individuals (756 men and 915 women) [52]. The results supported the association between the CYP17-rs743572 polymorphism and GI since the mutated allele (A2) was overrepresented in the transgender population compared to the cisgender population. Furthermore, the authors found a sex-dependent allelic distribution in the cis population.
In 2016, our group expanded the study of the CYP17-rs743572 polymorphism in a Spanish population with GI (317 transgender women, 223 transgender men, 264 cisgender women, and 358 cisgender men) [53]. Contrary to Bentz et al., in the Spanish population, the allelic and genotypic frequencies did not show statistically significant differences between the cis and transgender populations. Furthermore, the allelic and genotypic frequencies did not differ significantly between both cisgender groups, contrary to what Bentz et al. [52] had previously suggested. Our results, therefore, contradicted the involvement of the CYP17-rs743572 polymorphism in the genetic basis of GI, based not only on the analyzed population but also on data derived from the 1000 Genomes database and those obtained in a bibliographic review carried out specifically for this study.
The existing discrepancies between our work and the study by Bentz et al. (2008) are due to problems in the selection of the female cisgender sample in the Austrian study since the cis group comprised of women who had made medical consultations for perimenopausal disorders. In this sense, the statistical significance obtained by the Bentz group could be related to diseases dependent on the functioning of estrogens, but not with GI. In conclusion, we can state that, according to our data, the CYP17-rs743572 polymorphism is not associated with GI. Our research group did not confirm the involvement of this CYP17-MspA1 (rs743572) polymorphism or CYP19A1 (rs60271534) in the genetic basis of GI when analyzing a Caucasian sample of Spanish origin. Our results were later confirmed by other groups [54, 55].
Subsequently, the interaction analysis between polymorphisms through a logistic regression study showed the existence of an inverse allelic interaction between ERα and AR in a transgender women population. An association between ERα and ERβ was also found in the group of transgender men. These data confirmed the key role of ERβ in brain gender development in humans [44].
On the other hand, Ramírez et al. [56, 57] analyzed the involvement in GI of the activating molecules of the ERs and AR confirming their involvement in the sexual differentiation of the brain and the fundamental role that estrogens play in it. The authors analyzed 247 polymorphisms distributed in the coactivators NCOA-1, NCOA-2, NCOA-3, NCOA-4, NCOA-5, p300, and CREBBP in a population of 94 Spanish transgender individuals versus 94 Spanish cisgender individuals, with the same geographic origin, race, and biological sex. When they compared the distribution of the allele and genotype frequencies, they found significant differences in 11 polymorphisms that correspond to 4.45% of the total analyzed: three polymorphisms located in NCOA-1, five in NCOA-2, two in p300, and one in CREBBP.
These data are in concordance with a recent work that showed that the nuclear receptor coactivators, NCOA-1, NCOA-2, and p300, are essential for efficient ER transcriptional activity in the brain [58]. Moreover, Auger et al. [59] investigated the consequence of reducing NCOA-1 protein during sexual differentiation of the brain and reported that reducing this protein interferes with the defeminizing actions of estrogens in neonatal rat brains. Auger’s data indicated that NCOA-1 expression is critically involved in the hormone-dependent development of normal male reproductive behavior and brain morphology.
On the other hand, epigenetics offers a very interesting complement to genetic studies because it provides a relationship between genes and the environment. Epigenetic modifications determine which genes are expressed at each moment, in response to specific environmental stimuli. But so far, investigation of the implication of epigenetics in GI has been very limited. Two studies in adult transgender populations have shown that certain environmental factors, such as GAHT, modify the methylation profile of the promoter regions of the ESR1, ESR2, and AR genes [60, 61]. Furthermore, one analysis of global DNA methylation showed that there are differences in the methylome of the transgender population even before GAHT treatment [62]. The main finding of that work was that cis and trans populations have different global CpG methylation profiles, even before GAHT. When comparing trans woman versus cis men, 22 CpGs with significant methylation were located in islands. However, with respect to trans men, significant changes of methylation were found in only 2 CpGs. Furthermore, one of this CpGs, related to the MPPED2 gene, was shared by both transgender populations.
The most significant CpGs in trans women were related to genes WDR45B, SLC6A20, NHLH1, PLEKHA5, UBALD1, SLC37A1, ARL6IP1, GRASP, NCOA6, ABT1, and C17orf79. Among the most statistically significant CpGs, at least four of these genes were involved in brain development and neurogenesis (WDR45B, SLC6A20, NHLH1, and PLEKHA5), and three were related to transcriptional functions (NHLH1, NCOA6, and ABT1). Furthermore, the gene C17orf79 is related to chromatin organization and its activation stimulates the transcription of the AR. Finally, another two genes were related to glutamate synapses (ARL6IP1 and GRASP).
With respect to the MPPED2 gene, it is expressed in most human tissues, and the brain, in men and women, and is expressed predominantly in fetal brains. Furthermore, MPPED2 expression is modulated during development, attributing to this gene an important role in the processes of neuronal differentiation at the embryonic stage [63]. Cg23944405 related to the MPPED2 gene is hypermethylated in both trans populations before GAHT. Thus, the investigation of Ramírez et al. [62] tells us that epigenetics also plays an important role in the etiology of GI.
Mitochondria are intracellular organelles that are fundamentally involved in energy generation processes. Mitochondria have their own genetic material made up of DNA, with certain peculiarities. Among them, it stands out that DNA is double-stranded, circular and occurs in multiple copies (>1000) in the same cell. More than 93% of mitochondrial DNA is coding (compared to only 1.5% of nuclear DNA) and its 37 genes are intron-free [64]. Another of the most relevant aspects of mitochondria is that they are only inherited from the mother since they are found in the cytoplasm of the egg fertilized by the sperm (which only provides the nucleus for the newly formed organism). Therefore, the mitochondrial genetic material of any individual is inherited exclusively through the mother.
Mitochondria perform various interconnected functions, producing ATP and biosynthetic intermediates that contribute to cellular stress responses such as autophagy and apoptosis. They produce ATP through oxidative phosphorylation (OXPHOS) and play a key role in global energy modulation. An increased need for ATP is satisfied by increasing mitochondrial mass and inducing OXPHOS. The regulation of mitochondrial biogenesis is closely coordinated with pathways that induce vascularization and improve oxygen delivery to tissues [65].
Mitochondrial functioning is also sexually dimorphic. Association studies in humans have revealed sex-specific quantitative trait loci (QTLs) that regulate the mitochondrial content of blood tissue [66].
Other work has also suggested that sex hormones play a role in regulating mitochondrial dynamics, metabolism, and cross-talk with other organelles. Specifically, the female sex hormone estrogen has both a direct and indirect role in regulating mitochondrial biogenesis through PGC-1α, a mitochondrial gene coactivator. On the other hand, testosterone is cardioprotective in men and can regulate mitochondrial biogenesis through PGC-1α and PGC-1α.
Both the estrogen receptor ER and the androgen receptor AR are associated with mammalian mitochondria. Estrogens are best known for being antiapoptotic in muscle and neural tissues in the event of stress. Data demonstrate that mammalian sex steroids are potent regulators of stress response at tissue and individual cell levels [67].
To our knowledge, no studies have been published about the role of mitochondria in the genetic basis of GI. Nevertheless, given the association between ER, AR, and mammalian mitochondria, our team deemed it interesting to analyze 242 mitochondrial single nucleotide polymorphisms (SNPs) in a transgender versus a cisgender population, and the results of the whole study are presented here.
The study was conducted in a population of 94 transgender individuals and 94 cisgender individuals, with similar characteristics of race, biological sex, and geographic origin. The inclusion criteria were: presenting gender incongruence according to ICD-11 and having no disorder of sexual development. The exclusion criteria for all participants were DSD (differences in sex development), neurological and hormonal disorder, major medical condition, and history of alcohol and/or drug abuse.
The cisgender population was selected from a country census (Pizarra, Málaga, Spain) matched by geographic origin, race, and sex. Written informed consent was obtained from the transgender group after a full explanation of the procedures. The study was approved by the UNED Ethics Committee.
The analyses were conducted by chromosomic sex, in two independent populations: individuals assigned as females at birth and individuals assigned as males at birth, considering significant a P-value lower than .05. The allele and genotype frequencies were analyzed by the x2 test. The strength of the associations with GI was measured by binary logistic regression, estimating the odds ratio (OR) for each genotype.
Statistically significant differences were found in 26 out of 242 mitochondrial polymorphisms (P ≤ 0.05), but only the Affx-34461653 polymorphism passed Bonferroni correction. This polymorphism is related to the MT-ND4 and MT-ND5 genes that are linked to the effects of oxidative phosphorylation [68]. MT-ND5 interacts with glutamine synthetase (GS) that predominates in the brain, kidney, and liver [69].
In the brain, glutamine synthetase participates in the metabolic regulation of glutamate, in the recycling of neurotransmitters, and the termination of their signals [70, 71]. Glutamine synthetase is an ATP-dependent enzyme found in most species that synthesizes glutamine from glutamate and ammonia. In the brain, glutamine synthetase is primarily located in astrocytes where it works to maintain the glutamate-glutamine cycle as well as nitrogen metabolism. More recent studies indicate that glutamine synthetase may also be present in other CNS cells, including neurons, microglia, and oligodendrocytes [69].
It is estimated that 95% of excitatory neurotransmission in the brain occurs in dendritic spines, and AMPA/kainate glutamate and NMDA receptors are found in a high proportion on the surface of these structures. Furthermore, in the adult mammalian brain, the expression of male sexual behavior correlates with high concentrations of extracellular excitatory glutamate in the preoptic area POA [72]. Blocking the NMDA receptor and, consequently, glutamatergic transmission in this brain region (POA) reduces male sexual behavior in mice, including the number of mounts and intromissions, and does not allow improvement of these measurements with experience [73], while increasing synaptic glutamate has the opposite effect, improving male sexual performance.
Therefore, given the theoretical importance of glutamatergic neurotransmission in adult male sexual behavior, the mitochondrial genes MT-ND4 and MT-ND5 could be involved in the genetic basis of GI. Thus, it has been shown that estradiol induces glutamate release in the hypothalamus to promote defeminization [9]. The ventromedial nucleus (VMN) located in the mediobasal hypothalamus (MBH) is a key brain region for the control of female sexual behavior in mice [74, 75]. Ventromedial nucleus (VMN) neuron dendrites in males branch more frequently and therefore generally have more synapses than females [76, 77, 78].
Estradiol induces both masculinization and defeminization in mice but through different cellular mechanisms. In the MBH, estradiol-induced defeminization begins with rapid (~1 hour) activation of ER-mediated PI3 kinase and enhanced release of presynaptic glutamate. The increase in synaptic glutamate leads to increased activation of postsynaptic NMDA receptors followed by dendritic branching and the construction and stabilization of dendritic spines [79]. These results demonstrate that estradiol-mediated brain sexual differentiation is not an autonomous cellular process in which only ER-containing neurons change morphology in response to steroid exposure. Instead, a neurotransmitter serves as a signaling factor that causes a morphological change in an entire network of cells, suggesting that all neural inputs to sexually differentiated brain regions, such as POA and VMN, are considered and interpreted according to the sex of the individual, regardless of whether the incoming signals are relevant to sex or other functions of the POA. Both the POA and the VMN are implicated in many other functions, including maternal behavior, temperature regulation, and feeding, to name a few [9].
In conclusion, our results have shown that mitochondria could play a role in the genetic basis of GI. Furthermore, our data continue to support the hypothesis that GI is a complex multifactorial trait, involving intricate interactions between sex steroids, sex steroid receptors, coactivators, and epigenetics. In addition, mitochondria now come into play as one more factor that could intervene in this complex process through the action of glutamate.
Furthermore, we can conclude that people who question their gender need protection against discrimination, high-quality services, and clear information. In addition to discovering the biological basis of GI, it is necessary to train health professionals to deal with GI. In conclusion, we can say that more studies are needed to give an adequate explanation of the factors associated with GI.
This work was supported by grants: Xunta de Galicia ED431 B 019/02 (EP), Ministerio de ciencia, innovación y universidades: PGC2018-094919-B-C21 (AG), and PGC2018-094919-B-C22 (RF, EP). None of these funding sources played any role in the writing of the manuscript or the decision to submit it for publication. We are grateful to everyone who contributed to the study, and to the trans and cis individuals who participated in particular.
The authors declare no conflict of interest.
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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:250,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. His research interests include computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, intelligent systems, information technology, and information systems. Prof. Sarfraz has been a keynote/invited speaker on various platforms around the globe. He has advised various students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He is a member of various professional societies and a chair and member of the International Advisory Committees and Organizing Committees of various international conferences. Prof. Sarfraz is also an editor-in-chief and editor of 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:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/267434/images/system/267434.jpg",biography:"Dr. Rohit Raja received Ph.D. in Computer Science and Engineering from Dr. CVRAMAN University in 2016. His main research interest includes Face recognition and Identification, Digital Image Processing, Signal Processing, and Networking. Presently he is working as Associate Professor in IT Department, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur (CG), India. He has authored several Journal and Conference Papers. He has good Academics & Research experience in various areas of CSE and IT. He has filed and successfully published 27 Patents. He has received many time invitations to be a Guest at IEEE Conferences. He has published 100 research papers in various International/National Journals (including IEEE, Springer, etc.) and Proceedings of the reputed International/ National Conferences (including Springer and IEEE). He has been nominated to the board of editors/reviewers of many peer-reviewed and refereed Journals (including IEEE, Springer).",institutionString:"Guru Ghasidas Vishwavidyalaya",institution:{name:"Guru Ghasidas Vishwavidyalaya",country:{name:"India"}}},{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:{name:"University of Silesia",country:{name:"Poland"}}},{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:null,institution:{name:"Beijing University of Technology",country:{name:"China"}}},{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:"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:{name:"Medical University Plovdiv",country:{name:"Bulgaria"}}},{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:"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:"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:"Igor Victorovich Lakhno 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.\nPh.D. – 1999, Kharkiv National Medical Univesity.\nDSC – 2019, PL Shupik National Academy of Postgraduate Education \nProfessor – 2021, Department of Obstetrics and Gynecology of VN Karazin Kharkiv National University\nHead of Department – 2021, Department of Perinatology, Obstetrics and gynecology of Kharkiv Medical Academy of Postgraduate Education\nIgor Lakhno has been graduated from international training courses on reproductive medicine and family planning held at Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor in 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 been a professor in the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics, and gynecology department. He’s affiliated with Kharkiv Medical Academy of Postgraduate Education as a Head of Department from November 2021. Igor Lakhno has participated in several international projects on fetal non-invasive electrocardiography (with Dr. J. A. Behar (Technion), Prof. D. Hoyer (Jena University), and José Alejandro Díaz Méndez (National Institute of Astrophysics, Optics, and Electronics, Mexico). He’s an author of about 200 printed works and there are 31 of them in Scopus or Web of Science databases. Igor Lakhno is a member of the Editorial Board of Reproductive Health of Woman, Emergency Medicine, and Technology Transfer Innovative Solutions in Medicine (Estonia). He is a medical Editor of “Z turbotoyu pro zhinku”. Igor Lakhno is a reviewer of the Journal of Obstetrics and Gynaecology (Taylor and Francis), British Journal of Obstetrics and Gynecology (Wiley), 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 a DSc degree “Pre-eclampsia: prediction, prevention, and treatment”. Three years ago Igor Lakhno has participated in a training course on innovative technologies in medical education at Lublin Medical University (Poland). 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: are obstetrics, women’s health, fetal medicine, and cardiovascular medicine. \nIgor Lakhno is a consultant at Kharkiv municipal perinatal center. He’s graduated from training courses on endoscopy in gynecology. He has 28 years of practical experience in the field.",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:"243698",title:"Dr.",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:null,institution:null},{id:"7227",title:"Dr.",name:"Hiroaki",middleName:null,surname:"Matsui",slug:"hiroaki-matsui",fullName:"Hiroaki Matsui",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Tokyo",country:{name:"Japan"}}},{id:"312999",title:"Dr.",name:"Bernard O.",middleName:null,surname:"Asimeng",slug:"bernard-o.-asimeng",fullName:"Bernard O. Asimeng",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{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"}}}]}},subseries:{item:{id:"15",type:"subseries",title:"Chemical Biology",keywords:"Phenolic Compounds, Essential Oils, Modification of Biomolecules, Glycobiology, Combinatorial Chemistry, Therapeutic peptides, Enzyme Inhibitors",scope:"Chemical biology spans the fields of chemistry and biology involving the application of biological and chemical molecules and techniques. In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. This topic will closely deal with all emerging trends in this discipline.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11411,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. 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